掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/ppul.26611

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: A previous clinical trial for autoimmune pulmonary alveolar proteinosis (APAP) demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation reduced the mean density of the lung field on computed tomography (CT) across 18 axial slice planes at a two-dimensional level. In contrast, in this study, we challenged three-dimensional analysis for changes in CT density distribution using the same datasets. METHODS: As a sub-study of the trial, CT data of 31 and 27 patients who received GM-CSF and placebo, respectively, were analyzed. To overcome the difference between various shooting conditions, a newly developed automatic lung field segmentation algorithm was applied to CT data to extract the whole lung volume, and the accuracy of the segmentation was evaluated by five pulmonary physicians independently. For normalization, the percent pixel (PP) in a certain density range was calculated as a percentage of the total number of pixels from -1,000 to 0 HU. RESULTS: The automatically segmented images revealed that the lung field was accurately extracted except for 7 patients with minor deletion or addition. Using the change in PP from baseline to week 25 (ΔPP) as the vertical axis, we created a histogram with 143 HU bins set for each patient. The most significant difference in ΔPP between GM-CSF and placebo groups was observed in two ranges: from -1,000 to -857 and -143 to 0 HU. CONCLUSION: Whole lung extraction followed by density histogram analysis of ΔPP may be an appropriate evaluation method for assessing CT improvement in APAP.

DOI： 10.1159/000528038

PubMed

researchmap

掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Background

Autologous tissue-engineered periosteal sheets, which have been clinically applied for periodontal regeneration, sinus lift, and alveolar ridge augmentation, are enriched with osteoblast precursor cells and the abundant deposition of collagen type I in the extracellular spaces. Their quality is inspected prior to clinical use; however, most criteria cannot be evaluated without sacrificing samples. To reduce such losses, we developed a non-destructive optical method that can quantitatively evaluate the thickness of the periosteal sheet.

Methods

Dispersed periosteal cells were inoculated into small pieces of collagen sponge (Terudermis®) and plated into 60-mm dishes for further explant culture using a conventional medium and a stem-cell culture medium. The thickness of periosteal sheets was evaluated using inverted microscopic, histological, labeling (CellVue®)-based imaging and spectrophotometric (Spectro-1®) methods.

Results

The three-dimensional growth of periosteal sheets did not necessarily correlate with two-dimensional growth. The periosteal sheet prepared with the stem-cell medium formed cell multilayers, a phenomenon that could be observed qualitatively by inverted microscopy. The spectrophotometric analysis enabled the quantitative evaluation of the thickness of the cell multilayer without sacrificing the samples processed for scheduled cell therapy.

Conclusions

The growth of periosteal sheets is influenced by several major factors, including the basic quality of the individual original periosteal tissue segments, the technical expertise of doctors and operators involved in tissue harvesting and processing, and culture conditions. This newly developed spectrophotometric analysis can quantify the thickness of cell-multilayered periosteal sheets for quality assurance in a non-destructive manner, thereby contributing to better bone augmentation prior to implant therapy.

DOI： 10.1186/s40729-022-00419-1

researchmap

その他リンク： https://link.springer.com/article/10.1186/s40729-022-00419-1/fulltext.html

記述言語：日本語   出版者・発行元：東京慈恵会医科大学成医会  

researchmap

その他リンク： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J00884&link_issn=&doc_id=20220627080047&doc_link_id=http%3A%2F%2Fhdl.handle.net%2F10328%2F00010751&url=http%3A%2F%2Fhdl.handle.net%2F10328%2F00010751&type=%E6%9D%B1%E4%BA%AC%E6%85%88%E6%81%B5%E4%BC%9A%E5%8C%BB%E7%A7%91%E5%A4%A7%E5%AD%A6%EF%BC%9A%E6%9D%B1%E4%BA%AC%E6%85%88%E6%81%B5%E4%BC%9A%E5%8C%BB%E7%A7%91%E5%A4%A7%E5%AD%A6_%E5%AD%A6%E8%A1%93%E3%83%AA%E3%83%9D%E3%82%B8%E3%83%88%E3%83%AA&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F80093_3.gif

掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Polyphosphate (polyP), a biopolymer of inorganic phosphate, is widely distributed in living organisms. In platelets, polyP is released upon activation and plays important roles in coagulation and tissue regeneration. However, the lack of a specific quantification method has delayed the in-depth study of polyP. The fluorescent dye 4′,6-diamidine-2-phenylindole dihydrochloride (DAPI) has recently received attention as a promising probe for the visualization and quantification of cellular polyP levels. In this study, we further optimized quantification conditions and applied this protocol in quantification of platelet polyP levels in a Japanese population. Blood samples were collected from non-smoking, healthy Japanese subjects (23 males, 23 females). Washed platelets were fixed and probed with DAPI for fluorometric determination. PolyP levels per platelet count were significantly higher in women than that in men. A moderate negative correlation between age and polyP levels was found in women. Responsiveness to CaCl2 stimulation was also significantly higher in women than that in men. Overall, our optimized protocol requires neither purification nor degradation steps, reducing both the time and bias for reproducible quantification. Thus, we suggest that despite its low specificity, this DAPI-based protocol would be useful in routine laboratory testing to quantify platelet polyP levels efficiently and economically.

DOI： 10.3390/ijms22147257

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10-12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10-12), followed by an additional independent risk allele at HLA-DPβ1 amino acid position 8 (OR = 0.28; P = 3.4 × 10-7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (β = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.

DOI： 10.1038/s41467-021-21011-y

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

全身麻酔下片側全肺洗浄(whole lung lavage:WLL)法は、自己免疫性肺胞蛋白症(autoimmune pulmonary alveolar proteinosis:aPAP)に対する標準的治療法である。1967年、Ramirez-Rはmassive pulmonary lavage(MPL)法を報告したが、標準的なWLL方法は確立していない。現在、日本呼吸器学会でaPAPのガイドラインを作成中であるが、WLLに関する内容を捕捉する意味で、aPAP20例に対して施行した114回のWLL自験例に文献的考察を加え、厚生労働省と日本医療研究開発機構(Japan Agency for Medical Research and Development:AMED)研究班で検討したWLLに関するワークショップサマリーを報告する。(著者抄録)

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本輸血・細胞治療学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Secondary pulmonary alveolar proteinosis (sPAP) is a complication of myelodysplastic syndrome (MDS). A 60-year-old woman was diagnosed with MDS with excess blasts-1. Fifty-four months after the initial diagnosis, treatment with azacitidine was initiated. Seventy-three months after the diagnosis, a bone marrow examination revealed increased myeloblasts, at which time computed tomography showed diffuse ground-glass opacities and interlobular septal thickening in the bilateral lower lung fields. A lung biopsy revealed the presence of PAP; therefore, the clinical diagnosis of MDS/sPAP was confirmed. Careful attention should be paid to the development of sPAP in MDS patients with pulmonary lesions during azacitidine treatment.

DOI： 10.2169/internalmedicine.3770-19

PubMed

researchmap

記述言語：英語  

PAP is a rare disease characterized by the accumulation of surfactant materials in the alveolar spaces due to the imbalance of surfactant homeostasis (production and clearance). We herein report a case of an 8-year-old girl who developed PAP after BMT from her mother for the treatment of DBA. The anemia was improved by BMT; however, respiratory dysfunction due to graft-versus-host disease gradually progressed. She eventually underwent right single LDLLT from her mother when she was 14 years old. A pathological examination of the excised lung confirmed the finding of diffuse bronchiolitis obliterans and unexpectedly revealed widespread alveolar proteinosis. Interestingly, the GGO of her native left lung on chest X-ray was improved after LDLLT. We present the very unique clinical course of this patient and discuss the mechanisms underlying the development of PAP after BMT and its improvement after LDLLT from the same donor.

DOI： 10.1111/petr.13659

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

It is generally accepted that citrate or the A-form of acid-citrate-dextrose (ACD-A) are suitable for preparing platelet-rich plasma (PRP) for regenerative therapy. However, this is based on evidence from blood transfusions and not from regenerative medicine. Thus, we examined the effects of anticoagulants, such as ACD-A, ethylenediaminetetraacetic acid (EDTA), and heparin, on the regenerative quality of PRP to address this gap. The blood samples were collected in the presence of anticoagulants and were processed to prepare pure-PRP. Platelet size, activation status, and intra-platelet free Ca2+ concentration were determined while using a hematology analyzer and flow cytometer. Platelet-derived growth factor-BB (PDGF-BB) was quantified while using an ELISA. In pure-PRP samples, EDTA caused platelet swelling and activation, but yielded the highest number of platelets. Heparin aggregated platelets and disturbed the overall counting of blood cells. However, no significant differences in PDGF-BB levels were observed among the anticoagulants tested. Moreover, when considering the easy preparation of platelet suspensions, without the need for high-level pipetting skills, these findings suggest the comparable potency of EDTA-derived pure-PRP in tissue regeneration and support the use of EDTA in the preparation of pure-PRP. Further in vivo studies are required in animal models to exclude the possible negative effects of including EDTA in pure-PRP preparations.

DOI： 10.3390/biomedicines8030042

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Very recently, a modest but significant efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation therapy for the treatment of mild to moderate autoimmune pulmonary alveolar proteinosis (aPAP) has been reported. As the ability to measure the level of GM-CSF autoantibody (GMAb) in the serum is required to decide the indication for this therapy, we developed a high-performance GMAb testing kit for clinical use. As the kit succeeded in reducing nonspecific IgG binding to the ELISA plate, the predictive performance shown in the training study to discriminate aPAP patients from healthy subjects was perfect, providing a cut-off value of 1.65 U·mL-1 in 78 patients with aPAP and 90 healthy subjects in an operator-blinded manner using logistic regression analysis. As in the validation study, serum samples from another 213 patients with aPAP were also blinded and evaluated in an operator-blinded manner against external 207 samples from patients with other types of PAP and patients exhibiting various ground-glass opacities on chest high-resolution computed tomography that require discrimination from PAP. The logistic regression analysis of these validation data sets revealed values of 97.6% and 100% for specificity and sensitivity, respectively. Thus, this new GMAb testing kit is reliable for the diagnosis of aPAP and differential diagnosis of other lung diseases.

DOI： 10.1183/23120541.00259-2019

PubMed

researchmap

DOI： 10.1056/NEJMc1914606

PubMed

researchmap

DOI： 10.1002/rcr2.494

PubMed

researchmap

DOI： 10.3390/dj7040109

PubMed

researchmap

DOI： 10.1111/jicd.12458

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Pulmonary alveolar proteinosis is a disease characterized by abnormal accumulation of surfactant in the alveoli. Most cases are autoimmune and are associated with an autoantibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) that prevents clearing of pulmonary surfactant by alveolar macrophages. An open-label, phase 2 study showed some therapeutic efficacy of inhaled recombinant human GM-CSF in patients with severe pulmonary alveolar proteinosis; however, the efficacy in patients with mild-to-moderate disease remains unclear. METHODS: We conducted a double-blind, placebo-controlled trial of daily inhaled recombinant human GM-CSF (sargramostim), at a dose of 125 μg twice daily for 7 days, every other week for 24 weeks, or placebo in 64 patients with autoimmune pulmonary alveolar proteinosis who had a partial pressure of arterial oxygen (Pao2) while breathing ambient air of less than 70 mm Hg (or <75 mm Hg in symptomatic patients). Patients with severe pulmonary alveolar proteinosis (Pao2 <50 mm Hg) were excluded to avoid possible exacerbation of the disease in patients who were assigned to receive placebo. The primary end point was the change in the alveolar-arterial oxygen gradient between baseline and week 25. RESULTS: The change in the mean (±SD) alveolar-arterial oxygen gradient was significantly better in the GM-CSF group (33 patients) than in the placebo group (30 patients) (mean change from baseline, -4.50±9.03 mm Hg vs. 0.17±10.50 mm Hg; P = 0.02). The change between baseline and week 25 in the density of the lung field on computed tomography was also better in the GM-CSF group (between-group difference, -36.08 Hounsfield units; 95% confidence interval, -61.58 to -6.99, calculated with the use of the Mann-Whitney U test and the Hodges-Lehmann estimate of confidence intervals for pseudo-medians). Serious adverse events developed in 6 patients in the GM-CSF group and in 3 patients in the placebo group. CONCLUSIONS: In this randomized, controlled trial, inhaled recombinant human GM-CSF was associated with a modest salutary effect on the laboratory outcome of arterial oxygen tension, and no clinical benefits were noted. (Funded by the Japan Agency for Medical Research and Development and the Ministry of Health, Labor, and Welfare of Japan; PAGE ClinicalTrials.gov number, NCT02835742; Japan Medical Association Center for Clinical Trials number, JMA-IIA00205.).

DOI： 10.1056/NEJMoa1816216

PubMed

researchmap

DOI： 10.1016/j.alit.2019.05.015

PubMed

researchmap

DOI： 10.3390/jfb10030043

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/trf.15312

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.imlet.2019.05.013

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI Multidisciplinary Digital Publishing Institute  

Although platelet-rich plasma (PRP) is now widely used in regenerative medicine and dentistry, contradictory clinical outcomes have often been obtained. To minimize such differences and to obtain high quality evidence from clinical studies, the PRP preparation protocol needs to be standardized. In addition, emphasis must be placed on quality control. Following our previous spectrophotometric method of platelet counting, in this study, another simple and convenient spectrophotometric method to determine platelet aggregation activity has been developed. Citrated blood samples were collected from healthy donors and used. After centrifugation twice, platelets were suspended in phosphate buffered saline (PBS) and adenosine diphosphate (ADP)-induced aggregation was determined using a spectrophotometer at 615 nm. For validation, platelets pretreated with aspirin, an antiplatelet agent, or hydrogen peroxide (H2O2), an oxidative stress-inducing agent, were also analyzed. Optimal platelet concentration, assay buffer solution, and representative time point for determination of aggregation were found to be 50-100 × 104/μL, PBS, and 3 min after stimulation, respectively. Suppressed or injured platelets showed a significantly lower aggregation response to ADP. Therefore, it suggests that this spectrophotometric method may be useful in quick chair-side evaluation of individual PRP quality.

DOI： 10.3390/dj7020061

Scopus

researchmap

DOI： 10.3390/biomedicines7020045

PubMed

researchmap

DOI： 10.1183/13993003.02066-2018

PubMed

researchmap

DOI： 10.1038/s41572-019-0066-3

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The incidence and prevalence of autoimmune pulmonary alveolar proteinosis in Japan were previously estimated to be 0.49 and 6.2 per million, respectively. Thereafter, an increase in serological diagnosis forced a re-estimation of the incidence based on more contemporaneous data using more robust methods. Sera of 702 patients were positive for granulocyte-macrophage colony-stimulating factor autoantibody during the 2006-2016 period (group A). Of these patients, 43 were actively surveyed in Niigata prefecture (group B) for estimation of the incidence. To estimate the survival period, 103 patients (group C) were investigated retrospectively for the 1999-2017 period using restricted mean survival time. In group A, the number of patients diagnosed in each prefecture was closely correlated with the corresponding population, indicating no regional integration of onset. In group B, a total of 43 patients were diagnosed, the annual number followed a Poisson distribution and the incidence was thus estimated to be 1.65 per million. In group C, the retrospective cohort study revealed the mean survival period to be 16.1 years. Taken together, the prevalence was estimated to be 26.6 per million, indicating that the previous data for incidence and prevalence was an underestimation.

DOI： 10.1183/23120541.00190-2018

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier Ltd  

Platelet activation and aggregation have been conventionally evaluated using an aggregometer. However, this method is suitable for short-term but not long-term quantitative evaluation of platelet aggregation, morphological changes, and/or adhesion to specific materials. The recently developed digital holographic microscopy (DHM) has enabled the quantitative evaluation of cell size and morphology without labeling or destruction. Thus, we aim to validate its applicability in quantitatively evaluating changes in cell morphology, especially in the aggregation and spreading of activated platelets, thus modifying typical image analysis procedures to suit aggregated platelets. Freshly prepared platelet-rich plasma was washed with phosphate-buffered saline and treated with 0.1% CaCl2. Platelets were then fixed and subjected to DHM, scanning electron microscopy (SEM), atomic force microscopy, optical microscopy, and flow cytometry (FCM). Tightly aggregated platelets were identified as single cells. Data obtained from time-course experiments were plotted two-dimensionally according to the average optical thickness versus attachment area and divided into four regions. The majority of the control platelets, which supposedly contained small and round platelets, were distributed in the lower left region. As activation time increased, however, this population dispersed toward the upper right region. The distribution shift demonstrated by DHM was essentially consistent with data obtained from SEM and FCM. Therefore, DHM was validated as a promising device for testing platelet function given that it allows for the quantitative evaluation of activation-dependent morphological changes in platelets. DHM technology will be applicable to the quality assurance of platelet concentrates, as well as diagnosis and drug discovery related to platelet functions.

DOI： 10.1016/j.micron.2018.06.011

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s40729-018-0140-8

researchmap

DOI： 10.1002/jbm.b.34234

PubMed

researchmap

記述言語：英語   出版者・発行元：EUROPEAN RESPIRATORY SOC JOURNALS LTD  

DOI： 10.1183/13993003.congress-2018.OA3783

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jim.2018.05.012

PubMed

researchmap

DOI： 10.1186/s40729-018-0134-6

PubMed

researchmap

DOI： 10.3109/14397595.2016.1153443

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of a surfactant-like substance in alveolar spaces and hypoxemic respiratory failure. Genetic PAP (GPAP) is caused by mutations in genes encoding surfactant proteins or genes encoding a surfactant phospholipid transporter in alveolar type II epithelial cells. GPAP is also caused by mutations in genes whose products are implicated in surfactant catabolism in alveolar macrophages (AMs). We performed whole-exome sequence analysis in a family affected by infantile-onset PAP with hypogammaglobulinemia without causative mutations in genes associated with PAP: SFTPB, SFTPC, ABCA3, CSF2RA, CSF2RB, and GATA2. We identified a heterozygous missense variation in OAS1, encoding 2,'5'-oligoadenylate synthetase 1 (OAS1) in three affected siblings, but not in unaffected family members. Deep sequence analysis with next-generation sequencing indicated 3.81% mosaicism of this variant in DNA from their mother's peripheral blood leukocytes, suggesting that PAP observed in this family could be inherited as an autosomal-dominant trait from the mother. We identified two additional de novo heterozygous missense variations of OAS1 in two unrelated simplex individuals also manifesting infantile-onset PAP with hypogammaglobulinemia. PAP in the two simplex individuals resolved after hematopoietic stem cell transplantation, indicating that OAS1 dysfunction is associated with impaired surfactant catabolism due to the defects in AMs.

DOI： 10.1016/j.ajhg.2018.01.019

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(株)先端医学社  

ヒト顆粒球マクロファージコロニー刺激因子(GM-CSF)に95%の相同性のあるGM-CSFをもつカニクイザルに経気道的にヒトGM-CSFの間歇的長期投与を行い、GM-CSF抗体価やGM-CSF生物活性の抑制効果がみられるかどうかについて検討した。大腸菌由来GM-CSF製剤とCHO細胞由来GM-CSF製剤の2種類を用いて、気管内スプレーでの12週の間歇的長期投与を3コース行った。その結果、どちらの製剤においても、3コース目には週1回の投与でも抗体価が維持された。また、BALFで泡沫マクロファージに加えて少量の無構造沈着物がみられる例があることが明らかとなった。高い中和活性の上昇がみられた例がCHO細胞由来GM-CSF製剤投与群で1例、大腸菌由来GM-CSF製剤投与群で1例あった。

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media S.A.  

Platelet-rich fibrin (PRF) clots have been used in regenerative dentistry most often, with the assumption that growth factor levels are concentrated in proportion to the platelet concentration. Platelet counts in PRF are generally determined indirectly by platelet counting in other liquid fractions. This study shows a method for direct estimation of platelet counts in PRF. To validate this method by determination of the recovery rate, whole-blood samples were obtained with an anticoagulant from healthy donors, and platelet-rich plasma (PRP) fractions were clotted with CaCl2 by centrifugation and digested with tissue-plasminogen activator. Platelet counts were estimated before clotting and after digestion using an automatic hemocytometer. The method was then tested on PRF clots. The quality of platelets was examined by scanning electron microscopy and flow cytometry. In PRP-derived fibrin matrices, the recovery rate of platelets and white blood cells was 91.6 and 74.6%, respectively, after 24 h of digestion. In PRF clots associated with small and large red thrombi, platelet counts were 92.6 and 67.2% of the respective total platelet counts. These findings suggest that our direct method is sufficient for estimating the number of platelets trapped in an insoluble fibrin matrix and for determining that platelets are distributed in PRF clots and red thrombi roughly in proportion to their individual volumes. Therefore, we propose this direct digestion method for more accurate estimation of platelet counts in most types of platelet-enriched fibrin matrix.

DOI： 10.3389/fbioe.2018.00004

Scopus

PubMed

researchmap

記述言語：英語  

BackgroundGenetic variants responsible for childhood interstitial lung disease (chILD) have not been studied extensively in Japanese patients.MethodsThe study population consisted of 62 Japanese chILD patients. Twenty-one and four patients had pulmonary hypertension resistant to treatment (PH) and hypothyroidism, respectively. Analyses of genetic variants were performed in all 62 patients for SFTPC and ABCA3, in all 21 PH patients for FOXF1, and in a limited number of patients for NKX2.1.ResultsCausative genetic variants for chILD were identified in 11 (18%) patients: SFTPC variants in six, NKX2.1 variants in three, and FOXF1 variants in two patients. No patients had ABCA3 variants. All three and two patients with NKX2.1 variants had hypothyroidism and developmental delay, respectively. We found six novel variants in this study.ConclusionMutations in SFTPC, NKX2.1, and FOXF1 were identified among Japanese infants and children with chILD, whereas ABCA3 mutations were rare.

DOI： 10.1038/pr.2017.217

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1183/23120541.00071-2017

PubMed

researchmap

DOI： 10.1186/s40729-017-0068-4

PubMed

researchmap

DOI： 10.1186/s40729-017-0081-7

PubMed

researchmap

記述言語：日本語   出版者・発行元：生命科学系学会合同年次大会運営事務局  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

PurposeLymphangioleiomyomatosis is a rare lung disease caused by proliferation of abnormal smooth muscle-like cells and typically occurs in premenopausal women. Sirolimus is now the first-line drug for the treatment of lymphangioleiomyomatosis. Sirolimus-induced stomatitis is the most frequent adverse event experienced during treatment. To identify risk factors, we investigated the association of stomatitis incidence with patient background data and treatment parameters, using data from the multicenter long-term sirolimus trial.
MethodsSubjects received sirolimus for 2years at doses adjusted to maintain a trough blood level of 5 to 15ng/mL. The incidence of stomatitis was correlated with baseline demographics, clinical characteristics, and changes in the longitudinal data. Risk factors at baseline were assessed by using univariate and multivariate analyses.
ResultsThe most frequent adverse event was stomatitis, with the cumulative rate reaching 88.9% by 9months, higher than that reported in postrenal transplant patients. The repetition, the duration, and the severity of stomatitis events were variable among patients. We found that patients with low hemoglobin (Hb) (&lt;14.5g/dL) showed significantly higher incidence than those with high Hb (14.5g/dL, P&lt;.01). The cumulative rate for stomatitis incidence was significantly associated with a decrease in the mean corpuscular volume, while the Hb level was constant; thus, red blood cell count in patients increased during the study.
ConclusionsBaseline Hb levels and a decrease in mean corpuscular volume during treatment were correlated with the incidence of stomatitis.

DOI： 10.1002/pds.4259

Web of Science

PubMed

researchmap

DOI： 10.1183/1393003.congress-2017.PA882

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

The platelet-rich fibrin-like matrix (PRFM) is usually prepared onsite and immediately used for regenerative therapy. Nonetheless, to meet the clinical necessity of preserving the PRFM without quality deterioration, we developed a method for preparation of PRFMs from short-term-stored whole blood (WB) samples. In this study, to evaluate the practical expiration date of storage, we extended the storage time of WB samples from 2 to 7 days and assessed the quality of the resulting PRFMs. WB samples collected with acid-citrate-dextrose were stored with gentle agitation at ambient temperature. To prepare PRFMs, the stored WB samples were mixed with CaCl2 in glass tubes and centrifuged. Fibrin fiber networks, CD41 and CD62P expression, and Platelet Derived Growth Factor-BB (PDGF-BB) levels were examined by scanning electron microscopy (SEM), flow cytometry, and an Enzyme-Linked ImmunoSorbent Assay (ELISA), respectively. Long-term storage had no significant effect on either blood cell counts or platelet functions tested. The resulting PRFMs were visually identical to freshly prepared ones. PDGF-BB levels did not markedly decrease in a time-dependent manner. However, fibrin fibers gradually became thinner after storage. Although the coagulation activity may diminish, we propose that PRFMs can be prepared-without evident loss of quality-from WB samples stored for up to 7 days by our previously developed method.

DOI： 10.3390/biomedicines5030057

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Thoracic Society  

Rationale: A useful semiquantitative method of using computed tomographic (CT) images to evaluate therapeutic response in pulmonary alveolar proteinosis (PAP) has not been established, although the extent score or grading score of ground-glass opacities has been used. Objectives: The purpose of this study was to establish a semiquantitative method for evaluating therapeutic response in PAP. Methods: CT scans were obtained within 1 month before and after therapy from 32 patients with PAP who participated in a multicenter phase II trial of granulocyte-macrophage colony-stimulating factor inhalation therapy. The scans were evaluated by two chest radiologists independently. Increased parenchymal opacity was evaluated on the basis of its intensity and extent (CT grade), and the severity scores were compared with CT scores based on the extent alone (CT extent), as well as on the basis of physiological and serological results. Results: CT grade score and CT extent score had significant correlationwith diffusing capacity of the lung for carbon monoxide percent predicted (%DLCO), PaO2, VC percent predicted (%VC), Krebs von den Lungen (KL)-6, and surfactant protein D. The change in CT grade score between pre- and post-treatment examinations (ΔCT grade) correlated better with difference of PaO2 between pre- and post-treatment examinations (ΔPaO2) than DCT extent (difference of CT extent score between pre- and post-treatment examinations). In univariate analysis, ΔCT grade, ΔCT extent, ΔKL-6, Δ%DLCO, Δ%VC, and change in surfactant protein D correlated significantly with ΔPaO2. Inmultivariate analysis, ΔCT grade and ΔKL-6 correlated more closely with ΔPaO2.

DOI： 10.1513/AnnalsATS.201607-574OC

Scopus

PubMed

researchmap

記述言語：英語   出版者・発行元：EUROPEAN RESPIRATORY SOC JOURNALS LTD  

DOI： 10.1183/1393003.congress-2017.PA3859

Web of Science

researchmap

DOI： 10.1513/AnnalsATS.201607-574OC

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

Rationale: A useful semiquantitative method of using computed tomographic (CT) images to evaluate therapeutic response in pulmonary alveolar proteinosis (PAP) has not been established, although the extent score or grading score of ground-glass opacities has been used.
Objectives: The purpose of this study was to establish a semiquantitative method for evaluating therapeutic response in PAP.
Methods: CT scans were obtained within 1 month before and after therapy from 32 patients with PAP who participated in a multicenter phase II trial of granulocyte-macrophage colony-stimulating factor inhalation therapy. The scans were evaluated by two chest radiologists independently. Increased parenchymal opacity was evaluated on the basis of its intensity and extent (CT grade), and the severity scores were compared with CT scores based on the extent alone (CT extent), as well as on the basis of physiological and serological results.
Results: CT grade score and CT extent score had significant correlationwith diffusing capacity of the lung for carbon monoxide percent predicted (% DLCO), Pa-O2, VC percent predicted (% VC), Krebs von den Lungen (KL)-6, and surfactant protein D. The change in CT grade score between pre-and post-treatment examinations (Delta CT grade) correlated better with difference of Pa-O2 between pre-and post-treatment examinations (Delta Pa-O2) than Delta CT extent (difference of CT extent score between pre-and post-treatment examinations). In univariate analysis, Delta CT grade, Delta CT extent, Delta KL-6, Delta%DLCO, Delta%VC, and change in surfactant protein D correlated significantly with Delta Pa-O2. Inmultivariate analysis, Delta CT grade and DKL-6 correlated more closely with Delta Pa-O2.
Conclusions: Although a number of CT variables were collected, the currently proposed grading system that correlates well with Pa-O2 should be viewed as a retrospective scoring system that needs future validation with another PAP cohort.

DOI： 10.1513/AnnalsATS.201607-574OC

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Thoracic Society  

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by the excessive accumulation of surfactant proteins within the alveolar spaces and by higher titers of autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) in the serum and bronchoalveolar lavage fluid. The antibodies inhibit the maturation and phagocytosis of alveolar macrophages. Although the standard therapy for aPAP has been whole-lung lavage (WLL), this procedure is invasive and needs to be repeated for several years. GM-CSF inhalation therapy is a new procedure for treating aPAP and can induce remission with less invasiveness, although it is generally less effective in severe cases. We evaluated five cases with remarkable improvement by using sequential GM-CSF inhalation therapy after WLL
however, the treatment failed when this therapy preceded WLL. Therefore, sequential GM-CSF inhalation after WLL may reinforce the efficiency of WLL in patients with severe aPAP.

DOI： 10.1513/AnnalsATS.201611-892BC

Scopus

PubMed

researchmap

DOI： 10.1513/AnnalsATS.201611-892BC

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by the excessive accumulation of surfactant proteins within the alveolar spaces and by higher titers of autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) in the serum and bronchoalveolar lavage fluid. The antibodies inhibit the maturation and phagocytosis of alveolar macrophages. Although the standard therapy for aPAP has been whole-lung lavage (WLL), this procedure is invasive and needs to be repeated for several years. GM-CSF inhalation therapy is a new procedure for treating aPAP and can induce remission with less invasiveness, although it is generally less effective in severe cases. We evaluated five cases with remarkable improvement by using sequential GM-CSF inhalation therapy after WLL; however, the treatment failed when this therapy preceded WLL. Therefore, sequential GM-CSF inhalation after WLL may reinforce the efficiency of WLL in patients with severe aPAP.

DOI： 10.1513/AnnalsATS.201611-892BC

Web of Science

researchmap

記述言語：日本語   出版者・発行元：日本臨床免疫学会  

researchmap

記述言語：日本語   出版者・発行元：(株)先端医学社  

自己免疫性肺胞蛋白症患者の血液から比重遠心法を用いて末梢血単核細胞(PBMC)を分離した。分離したB細胞とビオチン化GM-CSFを反応させ、結合した細胞をGM-CSF反応性B細胞(自己抗体BCR陽性細胞)と考え、抗ビオチン抗体ビーズを用いて磁気分離した。33検体(患者24、健常者3)の解析をおこない、全体のリード数が16万リード、合計クラスターは2万4千クラスターであった。抗体が実際に産生されていると考えられるproductive sequenceの割合は全体の76%を占めた。アイソタイプの違いについて検討し、ほぼ全ての検体においてκ鎖の場合、Vκ1およびVκ3、Lambda鎖の場合、Vλ1、Vλ2、Vλ3のシークエンスが占める割合が高かった。患者検体CDR1の配列において平均連結法を用いてAlignmentおよび樹形図解析をおこなった。GM-CSFに反応するBCR陽性B細胞とGM-CSFに反応しないBCRをもつB細胞のシークエンスの間では、お互いの配列にまったく類似性がなく、自己抗体の軽鎖配列がそれ以外の軽鎖配列と分子レベルで異なることを確認した。

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by surfactant accumulation, and is caused by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling. Abnormalities in CSF2 receptor alpha (CSF2RA) were reported to cause pediatric hereditary PAP. We report here the first case of CSF2RA-mutated, elderly-onset hereditary (h) PAP.
Case presentation: The patient developed dyspnea on exertion, and was diagnosed with PAP at the age of 77 years, based on findings from chest computed tomography scan and bronchoalveolar lavage. She tested negative for GM-CSF autoantibodies, with no underlying disease. Her serum GM-CSF level was elevated (91.3 pg/mL), indicating GM-CSF signaling impairment and genetic defects in the GM-CSF receptor. GM-CSF-stimulated phosphorylation in signal transducer and activator of transcription 5 (STAT5) was not observed, and GM-CSF-Ra expression was defective in her blood cells. Genetic screening revealed a homozygous, single-base C &gt; T mutation at nt 508-a nonsense mutation that yields a stop codon (Q170X)-in exon 7 of CSF2RA. High-resolution analysis of single nucleotide polymorphism array confirmed a 22.8-Mb loss of heterozygosity region in Xp22.33p22.11, encompassing the CSF2RA gene. She was successfully treated with whole lung lavage (WLL), which reduced the serum levels of interleukin (IL)-2, IL-5, and IL-17, although IL-3 and M-CSF levels remained high.
Conclusions: This is the first known report of elderly-onset hPAP associated with a CSF2RA mutation, which caused defective GM-CSF-Ra expression and impaired signaling. The analyses of serum cytokine levels during WLL suggested that GM-CSF signaling might be compensated by other signaling pathways, leading to elderly-onset PAP.

DOI： 10.1186/s12890-017-0382-x

Web of Science

PubMed

researchmap

DOI： 10.3390/dj5010007

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley-Blackwell  

A human-cultured alveolar bone-derived periosteal (hCP) sheet is an osteogenic grafting material used clinically in periodontal regenerative therapy, while platelet-rich fibrin (PRF), a platelet concentrate with fibrin clot, is considered to augment the wound healing process. Therefore, whether the combined use of hCP-PRF complex could facilitate bone regeneration synergistically was evaluated in animal models. Human periosteal segments (1 × 1 mm) were cultured initially on plastic dishes and formed an hCP sheet. The hCP sheet was implanted with freshly prepared human PRF into subcutaneous tissue (hCP: n = 4, hCP + PRF: n = 4) and 4 mm diameter calvarial bone defect models (hCP: n = 4, hCP + PRF: n = 4, control [defect-only]: n = 4) that prepared in nude mice. At 4 weeks postimplantation, new bone formation was evaluated by using μCT. Cell growth and neovascularization were evaluated by histochemical and immunohistological methods. In the subcutaneous tissue, mineral deposit formation, collagen deposition, and number of vessels were higher in the hCP + PRF group than in the hCP alone group. In the calvarial defect models, new bone formation was significantly higher in the hCP + PRF group than in the hCP alone group and defect-only control group. The numbers of vessels and PCNA-positive cells in calvarial defects were also increased in the hCP + PRF group more than in the hCP alone group. Platelet-rich fibrin preparations support the proliferation and the growth of periosteal cells to form well-combined active biological materials. Platelet-rich fibrin also stimulates the local angiogenesis in the implantation site. Therefore, the combined use of hCP and PRF could be clinically applicable in bone regeneration therapy.

DOI： 10.1002/cre2.71

Scopus

PubMed

researchmap

DOI： 10.1186/s40729-016-0052-4

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Thoracic Society  

Rationale: Sirolimus has been shown in a randomized, controlled clinical trial to stabilize lung function in patients with lymphangioleiomyomatosis (LAM) treated for a 12-month time period
however the pretreatment decline in lung function after the drug was discontinued indicated that continued exposure is required to suppress disease progression. Objectives: To elucidate the durability and tolerability of long-term sirolimus treatment in Asian patients with LAM. Methods: We conducted a single-arm, open-label, investigatorinitiated safety and efficacy study of sirolimus in 63 women with LAM at 9 sites in Japan. Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5-15 ng/ml. Measurements and Main Results: Fifty-two subjects (82.5%) completed the trial with mean drug compliance of more than 80% overall during the study. The number of adverse events was greatest during the initial 6 months of therapy, but they continued to occur with declining frequency throughout the 2-year study period. Of the 1,549 adverse events, 27 were classified as serious, including reversible sirolimus pneumonitis in 3 patients. New hypercholesterolemia occurred in 30 patients (48%)
microcytosis in 10 patients
loss of body weight in 33 patients
and increase in blood pressure that required treatment in 5 patients. FEV1, FVC, and quality-of-life parameters were stable in the overall study cohort during the study period, but baseline to 2-year improvements in lung function occurred in the subset of patients with a prior history of chylothorax. Conclusions: Although long-term sirolimus treatment of Asian patients with LAM was associated with a large number of adverse events, including three episodes of pneumonitis, most patients completed the 2-year course of medication with good drug compliance and stable quality of life and lung function.

DOI： 10.1513/AnnalsATS.201605-335OC

Scopus

PubMed

researchmap

DOI： 10.1513/AnnalsATS.201605-335OC

PubMed

researchmap

掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

Rationale: Sirolimus has been shown in a randomized, controlled clinical trial to stabilize lung function in patients with lymphangioleiomyomatosis (LAM) treated for a 12-month time period; however the pretreatment decline in lung function after the drug was discontinued indicated that continued exposure is required to suppress disease progression. Objectives: To elucidate the durability and tolerability of long-term sirolimus treatment in Asian patients with LAM. Methods: We conducted a single-arm, open-label, investigator-initiated safety and efficacy study of sirolimus in 63 women with LAM at 9 sites in Japan. Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5-15 ng/ml. Measurements and Main Results: Fifty-two subjects (82.5%) completed the trial with mean drug compliance of more than 80% overall during the study. The number of adverse events was greatest during the initial 6 months of therapy, but they continued to occur with declining frequency throughout the 2-year study period. Of the 1,549 adverse events, 27 were classified as serious, including reversible sirolimus pneumonitis in 3 patients. New hypercholesterolemia occurred in

DOI： 10.1513/AnnalsATS.201605-335OC

researchmap

記述言語：英語   出版者・発行元：EUROPEAN RESPIRATORY SOC JOURNALS LTD  

DOI： 10.1183/13993003.congress-2016.PA3873

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ROENTGEN RAY SOC  

OBJECTIVE. The CT findings of pulmonary fibrosis in patients with pulmonary alveolar proteinosis (PAP) are not yet well defined. The objective of this study was to evaluate the CT findings of PAP with a focus on pulmonary fibrosis secondary to PAP.
MATERIALS AND METHODS. High-resolution CT (HRCT) scans of 44 patients with PAP were evaluated retrospectively with a focus on pulmonary fibrosis: 33 patients had autoimmune PAP, and 11 patients had secondary PAP. The intervals between the initial and last CT examinations ranged from 1 to 284 months (median, 60 months). The HRCT images were assessed by two chest radiologists independently; when the two radiologists disagreed, a final decision was made by consensus.
RESULTS. A crazy-paving pattern was a more common HRCT finding in patients with autoimmune PAP than in those with secondary PAP. Traction bronchiectasis was found in four patients (9%) on the initial scans and in 10 patients (23%) on the last scans. There was no honeycombing on the initial scans. Honeycombing developed in two patients (5%): It was detected on 2-year follow-up in one patient and on 6-year follow-up in the other patient. Among the patients with autoimmune PAP, those with fibrosis detected on HRCT during follow-up had a worse prognosis than those without fibrosis detected on HRCT (p = 0.041).
CONCLUSION. Fibrosis develops in approximately 20% of patients with PAP. The CT findings of parenchymal fibrosis suggest a poor outcome.

DOI： 10.2214/AJR.15.14982

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Background and Purpose: Sinus lift (SL) using cultured autogenous periosteal cells (CAPCs) combined with autogenous bone and platelet-rich plasma (PRP) was performed to evaluate the effect of cell administration on bone regeneration, by using high-resolution three-dimensional computed tomography (CT).
Materials and Methods: SL with autogenous bone and PRP plus CAPC [CAPC(+)SL] was performed in 23 patients. A piece of periosteum taken from the mandible was cultured in M199 medium with 10% fetal bovine serum (FBS) for 6 weeks. As control, 16 patients received SL with autogenous bone and PRP [CAPC(-)SL]. Three-dimensional CT imaging was performed before and 4 months and 1 year after SL, and stratification was performed based on CT numbers (HUs) corresponding to soft tissue and cancellous or cortical bone.
Results: The augmented bone in CAPC(+)SL revealed an increase in HUs corresponding to cancellous bone as well as a decrease in HUs corresponding to grafted cortical bone. In addition, HUs corresponding to cancellous bone in the graft bed were increased in CAPC(+)SL but were decreased in CAPC(-)SL. Insertion torque during implant placement was significantly higher in CAPC(+)SL.
Conclusion: By promoting bone anabolic activity both in augmented bone and graft bed, CAPCs are expected to aid primary fixation and osseointegration of implants in clinical applications.

DOI： 10.1111/cid.12356

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Whole lung lavage (WLL) is the current standard of care treatment for patients affected by pulmonary alveolar proteinosis (PAP). However, WLL is not standardized and international consensus documents are lacking. Our aim was to obtain a factual portrayal of WLL as currently practiced with respect to the procedure, indications for its use, evaluation of therapeutic benefit and complication rate.
Methods: A clinical practice survey was conducted globally by means of a questionnaire and included 27 centers performing WLL in pediatric and/or adult PAP patients.
Results: We collected completed questionnaires from 20 centres in 14 countries, practicing WLL in adults and 10 centers in 6 countries, practicing WLL in pediatric patients.
WLL is almost universally performed under general anesthesia, with a double-lumen endobronchial tube in two consecutive sessions, with an interval of 1-2 weeks between sessions in approximately 50 % of centres. The use of saline warmed to 37 degrees C, drainage of lung lavage fluid by gravity and indications for WLL therapy in PAP were homogenous across centres.
There was great variation in the choice of the first lung to be lavaged: 50 % of centres based the choice on imaging, whereas 50 % always started with the left lung. The choice of position was also widely discordant; the supine position was chosen by 50 % of centres. Other aspects varied significantly among centres including contraindications, methods and timing of follow up, use of chest percussion, timing of extubation following WLL and lung isolation and lavage methods for small children. The amount of fluid used to perform the WLL is a critical aspect. Whilst a general consensus exists on the single aliquot of fluid for lavage (around 800 ml of warm saline, in adults) great variability exists in the total volume instilled per lung, ranging from 5 to 40 liters, with an average of 15.4 liters/lung.
Conclusions: This international survey found that WLL is safe and effective as therapy for PAP. However these results also indicate that standardization of the procedure is required; the present survey represents the a first step toward building such a document.

DOI： 10.1186/s13023-016-0497-9

Web of Science

PubMed

researchmap

記述言語：英語   出版者・発行元：AMER COLL CHEST PHYSICIANS  

DOI： 10.1016/j.chest.2016.04.030

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MARY ANN LIEBERT, INC  

In preparing cell-based products for regenerative therapy, cell quality should be strictly controlled. Methodologies for evaluating cell viability, identity, and purity are established and used routinely, whereas current methodologies for evaluating cell safety, particularly genetic integrity or tumorigenicity, are time-consuming and relatively insensitive. As part of developing a more practical screening system, the authors previously demonstrated that gamma-H2AX and p53 were useful markers for evaluating the history of DNA damage. To validate these markers further and develop a more quantitative methodology, single cell-based expression of these markers and two additional candidates have now been examined using flow cytometry (FCM). FCM analysis and immunofluorescent staining demonstrated that gamma-ray-irradiation suppressed proliferation, enlarged cells, and cell nuclei, and immediately upregulated gamma-H2AX and p21(waf1) in large numbers of cells for up to 12 days. Gamma-H2AX foci were formed in the nuclei of many affected cells. An initial sharp increase in p53 expression declined slowly over 12 days, while Rb expression increased linearly. The present findings suggest that this high-throughput, cell-based, combinational evaluation of protein markers and cell size enables a small number of cells with a history of DNA damage to be detected quickly and routinely from within a very large cell population. Using this screening methodology will improve the ability to verify the quality of cell-based products used in regenerative therapy.

DOI： 10.1089/bio.2015.0072

Web of Science

PubMed

researchmap

記述言語：英語   出版者・発行元：Public Library of Science  

Background: Lung transplantation has been established as the definitive treatment option for patients with advanced lymphangioleiomyomatosis (LAM). However, the prognosis after registration and the circumstances of lung transplantation with sirolimus therapy have never been reported. Methods: In this national survey, we analyzed data from 98 LAM patients registered for lung transplantation in the Japan Organ Transplantation Network. Results: Transplantation was performed in 57 patients as of March 2014. Survival rate was 86.7% at 1 year, 82.5% at 3 years, 73.7% at 5 years, and 73.7% at 10 years. Of the 98 patients, 21 had an inactive status and received sirolimus more frequently than those with an active history (67% vs. 5%, p<0.001). Nine of twelve patients who remained inactive as of March 2014 initiated sirolimus before or while on a waiting list, and remained on sirolimus thereafter. Although the statistical analysis showed no statistically significant difference, the survival rate after registration tended to be better for lung transplant recipients than for those who awaited transplantation (p = 0.053). Conclusions: Lung transplantation is a satisfactory therapeutic option for advanced LAM, but the circumstances for pre-transplantation LAM patients are likely to alter with the use of sirolimus.

DOI： 10.1371/journal.pone.0146749

CiNii Article

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Taylor and Francis Ltd  

Introduction: Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by surfactant accumulation within pulmonary alveoli, resulting in progressive respiratory insufficiency. Approximately 90% of PAP patients have autoimmune PAP (aPAP), which is associated with high levels of autoantibodies against granulocyte/macrophage-colony stimulating factor (GM-CSF). These autoantibodies neutralize the GM-CSF activity and are thought to cause the disorder by impairing alveolar macrophage-mediated surfactant clearance. aPAP has been commonly treated by whole-lung lavage, a procedure requiring general anesthesia. Based on the molecular pathogenesis of aPAP, GM-CSF inhalation has been investigated as a novel therapy since 2000.Areas covered: This manuscript outlined the clinical and pathological features of PAP and reports on GM-CSF inhalation treatment.Expert opinion: GM-CSF inhalation is a promising treatment for aPAP, and is feasible in outpatient settings. To obtain the approval of regulatory authorities, chronic toxicity studies and randomized control trials will be required. Standard assay kit for detecting anti-GM-CSF antibody should be developed. GM inhalation could be tested in other pulmonary diseases such as acute respiratory distress syndrome. The combination treatment of whole-lung lavage and subsequent GM-CSF inhalation therapy will be a potential measure to enable nebulized GM-CSF to reach the peripheral alveoli.

DOI： 10.1517/21678707.2016.1123150

Web of Science

Scopus

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley-Blackwell  

Platelet-rich plasma (PRP) is widely used in regenerative medicine because of its high concentrations of various growth factors and platelets. However, the distribution of blood cell components has not been investigated in either PRP or other PRP derivatives. In this study, we focused on plasma rich in growth factors (PRGF), a PRP derivative, and analyzed the distributions of platelets and white blood cells (WBCs). Peripheral blood samples were collected from healthy volunteers (N = 14) and centrifuged to prepare PRGF and PRP. Blood cells were counted using an automated hematology analyzer. The effects of PRP and PRGF preparations on cell proliferation were determined using human periosteal cells. In the PRGF preparations, both red blood cells and WBCs were almost completely eliminated, and platelets were concentrated by 2.84-fold, whereas in the PRP preparations, both platelets and WBCs were similarly concentrated by 8.79- and 5.51-fold, respectively. Platelet counts in the PRGF preparations were positively correlated with platelet counts in the whole blood samples, while the platelet concentration rate was negatively correlated with red blood cell counts in the whole blood samples. In contrast, platelet counts and concentration rates in the PRP preparations were significantly influenced by WBC counts in whole blood samples. The PRP preparations, but not the PRGF preparations, significantly suppressed cell growth at higher doses in vitro. Therefore, these results suggest that PRGF preparations can clearly be distinguished from PRP preparations by both inclusion of WBCs and dose-dependent stimulation of periosteal cell proliferation in vitro.

DOI： 10.1002/cre2.26

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/09553002.2016.1230242

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W.B. Saunders Ltd  

Hereditary pulmonary alveolar proteinosis (PAP) caused by mutations in CSF2RA or CSF2RB, which encode GM-CSF receptor α and β respectively, is a rare disease. Although some experimental therapeutic strategies have been proposed, no clinical evidence has yet been reported. We herein describe the clinical course and recurrence of hereditary PAP after lung transplantation. A 36-year-old woman developed PAP of unknown etiology. She underwent bilateral lung transplantation from living donors at the age of 42 years because of severe respiratory failure complicated by pulmonary fibrosis. However, PAP recurred after 9 months, and we found that donor-origin alveolar macrophages had been almost completely replaced with recipient-origin macrophages. We performed a genetic analysis and identified a point deletion in the CSF2RB gene that caused a GM-CSF receptor-mediated signaling defect. PAP progressed with fibrosis in both transplanted lungs, and the patient died of respiratory failure 5 years after the lung transplantation. Distinct from recent reports on pulmonary macrophage transplantation in mice, this case suggests that human alveolar macrophages might not maintain their population only by self-renewal but may depend on a supply of precursor cells from the circulation. Bone marrow transplantation should be considered for treatment of severe PAP with GM-CSF receptor gene deficiency.

DOI： 10.1016/j.rmcr.2016.06.011

Scopus

PubMed

researchmap

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Igaku-Shoin Ltd  

Scopus

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.resinv.2015.04.005

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.resinv.2015.06.002

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Although no report has demonstrated the efficacy of corticosteroid therapy for autoimmune pulmonary alveolar proteinosis (aPAP), we sometimes encounter patients who have received this therapy for various reasons. However, as corticosteroids can suppress alveolar macrophage function, corticosteroid therapy might worsen disease severity and increase the risk of infections.
Methods: For this retrospective cohort study, we sent a screening form to 165 institutions asking for information on aPAP patients treated with corticosteroids. Of the resulting 45 patients screened, 31 were enrolled in this study. We collected demographic data and information about corticosteroid treatment period, dose, disease severity score (DSS) over the treatment period, and complications.
Results: DSS deteriorated during corticosteroid therapy in 23 cases (74.1 %) and the estimated overall cumulative worsening rate was 80.8 % for the total observation period. The worsening rate was significantly higher in patients treated with high-dose prednisolone (&gt; 18.9 mg/day, n = 16) than treated with low-dose prednisolone (&lt;= 18.9 mg/day, n = 15) divided by median daily dose (p &lt; 0.02). Of patients with worsening, one died of disseminated aspergillosis and another of respiratory failure. Infections newly emerged in 6 cases during corticosteroid therapy (p &lt; 0.05). Median serum granulocyte/macrophage colony-stimulating factor (GM-CSF) autoantibody levels were similar to previously reported data in a large cohort study.
Conclusion: The results demonstrate that corticosteroid therapy may worsen DSS of aPAP, increasing the risk for infections.

DOI： 10.1186/s12890-015-0085-0

Web of Science

PubMed

researchmap

DOI： 10.1513/AnnalsATS.201503-175LE

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC IMMUNOLOGISTS  

Antitumor immunity is augmented by cytotoxic lymphodepletion therapies. Adoptively transferred naive and effector T cells proliferate extensively and show enhanced antitumor effects in lymphopenic recipients. Although the impact of lymphodepletion on transferred donor T cells has been well evaluated, its influence on recipient T cells is largely unknown. The current study demonstrates that both regulatory T cells (Tregs) and effector CD8(+) T cells from lymphopenic recipients play critical roles in the development of antitumor immunity after lymphodepletion. Cyclophosphamide (CPA) treatment depleted lymphocytes more efficiently than other cytotoxic agents; however, the percentage of CD4(+)CD25(+) Foxp3(+) Tregs was significantly increased in CPA-treated lymphopenic mice. Depletion of these chemoresistant Tregs following CPA treatment and transfer of naive CD4(+) T cells augmented the antitumor immunity and significantly suppressed tumor progression. Further analyses revealed that recipient CD8(+) T cells were responsible for this augmentation. Using Rag2(-/-) mice or depletion of recipient CD8(+) T cells after CPA treatment abrogated the augmentation of antitumor effects in CPA-treated reconstituted mice. The transfer of donor CD4(+) T cells enhanced the proliferation of CD8(+) T cells and the priming of tumor-specific CD8(+) T cells originating from the lymphopenic recipients. These results highlight the importance of the recipient cells surviving cytotoxic regimens in cancer immunotherapies.

DOI： 10.4049/jimmunol.1401468

Web of Science

PubMed

researchmap

記述言語：日本語   出版者・発行元：一般社団法人 日本内科学会  

肺胞蛋白症は末梢気道内にサーファクタント由来の不溶性物質が異常に貯留する疾患であり，進行すると呼吸不全を呈する．病因により，自己免疫性，続発性，遺伝性に分類される．自己免疫性肺胞蛋白症は患者に豊富に存在する抗顆粒球マクロファージコロニー刺激因子（granulocyte macrophage colony stimulating factor：GM-CSF）に対する自己抗体（以下，GM-CSF自己抗体）が病因である．標準療法は全身麻酔下での肺胞洗浄であるが，近年，GM-CSF吸入療法の有効性が示唆されている．続発性肺胞蛋白症のおよそ8割は，血液疾患に続発する．中でも骨髄異形成症候群によるものが多い．治療は原疾患の治療に準ずる．遺伝性肺胞蛋白症では，近年GM-CSF受容体の変異が報告された．細胞治療，遺伝子治療の開発が進められている．

DOI： 10.2169/naika.104.314

PubMed

CiNii Article

CiNii Books

researchmap

その他リンク： https://jlc.jst.go.jp/DN/JLC/20005479199?from=CiNii

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Whole-lung lavage (WLL) remains the standard therapy for pulmonary alveolar proteinosis (PAP), a process in which accumulated surfactants are washed out of the lung with 0.5-2.0 l of saline aliquots for 10 -30 wash cycles. The method has been established empirically. In contrast, the kinetics of protein transfer into the lavage fluid has not been fully evaluated either theoretically or practically. Seventeen lungs from patients with autoimmune PAP underwent WLL. We made accurate timetables for each stage of WLL, namely, instilling, retaining, draining, and preparing. Subsequently, we measured the volumes of both instilled saline and drained lavage fluid, as well as the concentrations of proteins in the drained lavage fluid. We also proposed a mathematical model of protein transfer into the lavage fluid in which time is a single variable as the protein moves in response to the simple diffusion. The measured concentrations of IgG, transferrin, albumin, and beta(2)-microglobulin closely matched the corresponding theoretical values calculated through differential equations. Coefficients for transfer of beta(2)-microglobulin from the blood to the lavage fluid were two orders of magnitude higher than those of IgG, transferrin, and albumin. Simulations using the mathematical model showed that the cumulative amount of eliminated protein was not affected by the duration of each cycle but dependent mostly on the total time of lavage and partially on the volume instilled. Although physicians have paid little attention to the transfer of substances from the lung to lavage fluid, WLL seems to be a procedure that follows a diffusion-based mathematical model.

DOI： 10.1152/ajplung.00239.2014

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jcyt.2014.08.005

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

A 59-year-old man, ex-smoker, was diagnosed with pulmonary aspergillosis according to chest radiography findings of a fungus ball and Aspergillus fumigatus detection in the bronchial lavage fluid. Two years after anti-fungal therapy, he was diagnosed with autoimmune pulmonary alveolar proteinosis (APAP) according to a crazy paving pattern in computed tomography scans of the chest, milky bronchoalveolar lavage effluent, and positive anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody in the serum. The patient ultimately died of respiratory failure caused by APAP four months after GM-CSF therapy commenced. Aspergillus infection may thus be associated with the onset and progression of APAP and tolerance to GM-CSF therapy.

DOI： 10.2169/internalmedicine.54.5034

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

The Majewski syndrome or short rib-polydactyly syndrome (SRPS) type II is a lethal skeletal dysplasia characterized by severe IUGR (intrauterine growth restriction) and dysmorphic face, polydactyly, relatively proportionate head size at birth with later progression to microcephaly. A case of second trimester ultrasound diagnosis of SRPS type II is reported with review of the medical record of previous observed cases. Postmortem examination and radiogram confirmed the clinical diagnosis. Histological examination of the femoral epypheseal chondral plate showed an expanded and irregular hypertrophic zone. Moreover, characteristic cortico-medullary cysts of both kidneys and portal fibrosis were also demonstrated; findings consistent with the broad phenotypic spectrum of this rare skeletal disease.

DOI： 10.1111/cga.12066

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC VET SCI  

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine, sharing a common beta subunit (CDw131) with interleukins 3 and 5. GM-CSF is important for its direct and indirect involvement in host defense. In veterinary medicine, human (h) GM-CSF has been used as a substitute for canine GM-CSF to stimulate canine granulocytes and macrophages. In this study, we compared the effects of three distinct hGM-CSFs produced by bacteria, yeasts and Chinese hamster ovary (CHO) cells with those of Escherichia (E) coli-produced canine GM-CSF on the cluster of differentiation 11b (CD11b) expression in canine granulocytes. The median effective dose (ED50) of hGM-CSFs from bacteria, yeasts and CHO cells was 3.09, 4.09 and 4.27 ng/ml, respectively, with no significant difference among three. In contrast, a significant difference was observed between ED50 of canine GM-CSF (0.56 ng/ml) and three hGM-CSFs according to the paired t-test (P&lt;0.05). We conclude that hGM-CSF can activate canine granulocytes, but the average activity of the three rhGM-CSFs was approximately 15% of that of canine GM-CSF.

DOI： 10.1292/jvms.14-0056

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

To date, the biological activity of granulocyte macrophage-colony stimulating factor (GM-CSF) has been investigated by using mostly Escherichia coli- or yeast cell-derived recombinant human GM-CSF (erhGM-CSF and yrhGM-CSF, respectively). However, Chinese hamster ovary cell-derived recombinant human GM-CSF (crhGM-CSF), as well as natural human GM-CSF, is a distinct molecule that includes modifications by complicated oligosaccharide moieties. In the present study, we reevaluated the bioactivity of crhGM-CSF by comparing it with those of erhGM-CSF and yrhGM-CSF. The effect of short-term stimulation (0.5 h) on the activation of neutrophils/monocytes or peripheral blood mononuclear cells (PBMCs) by crhGM-CSF was lower than those with erhGM-CSF or yrhGM-CSF at low concentrations (under 60 pM). Intermediate-term stimulation (24 h) among the different rhGM-CSFs with respect to its effect on the activation of TF-1 cells, a GM-CSF-dependent cell line, or PBMCs was not significantly different. In contrast, the proliferation/survival of TF-1 cells or PBMCs after long-term stimulation (72-168 h) was higher at low concentrations of crhGM-CSF (15-30 pM) than that of cells treated with other GM-CSFs. The proportion of apoptotic TF-1 cells after incubation with crhGM-CSF for 72 h was lower than that of cells incubated with other rhGM-CSFs. These effects were attenuated by desialylation of crhGM-CSF. Clearance of crhGM-CSF but not desialylated-crhGM-CSF by both TF-1 cells and PBMCs was delayed compared with that of erhGM-CSF or yrhGM-CSF. These results suggest that sialylation of oligosaccharide moieties delayed the clearance of GM-CSF, thus eliciting increased long-term bioactivity in vitro. (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.cyto.2014.03.009

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCI LTD  

Background aims. Cultured human periosteal sheets more effectively function as an osteogenic grafting material at implantation sites than do dispersed periosteal cells. Because adherent cell growth and differentiation are regulated by cell-cell and cell extracellular matrix contacts, we hypothesized that this advantage is a result of the unique cell adhesion pattern formed by their multiple cell layers and abundant extracellular matrix. To test this hypothesis, we prepared three distinct forms of periosteal cell cultures: three-dimensional cell-multilayered periosteal sheets, two-dimensional dispersed cell cultures, and three-dimensional hybrid mock-ups of cells dispersed onto collagen sponges. Methods. Periosteal cells were obtained from human alveolar bone. Cell adhesion and extracellular matrix molecules were quantitatively determined at the messenger RNA and protein levels by means of real-time quantitative polymerase chain reaction and flow cytometry, respectively. Results. Real-time quantitative polymerase chain reaction analysis demonstrated that regardless of culture media al integrin, vascular cell adhesion molecule-1, fibronectin and collagen type 1 were substantially upregulated, whereas CD44 was strongly downregulated in periosteal sheets compared with dispersed cell monolayers. With increased thickness, stem cell medium upregulated several integrins (beta 1, alpha 1 and alpha 4), CD146, vascular cell adhesion molecule-1, fibronectin and collagen type 1 in the periosteal sheets. Flow cytomeftic analysis revealed that the active configuration of beta 1 integrin was substantially downregulated in the stem cell medium expanded cell cultures. The cell adhesion pattern found in the mockup cultures was almost identical to that of genuine periosteal sheets. Conclusions. Integrin alpha 1 beta 1 and CD44 function as the main cell adhesion molecule in highly cell-multilayered periosteal sheets and dispersed cells, respectively. This difference may account for the more potent osteogenic activity shown by the thicker periosteal sheets.

DOI： 10.1016/j.jcyt.2013.11.003

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER COLL CHEST PHYSICIANS  

Background: Treatment of autoimmune pulmonary alveolar proteinosis (aPAP) by subcutaneous injection or inhaled therapy of granulocyte-macrophage colony-stimulating factor (GM-CSF) has been demonstrated to be safe and efficacious in several reports. However, some reports of subcutaneous injection described transient benefit in most instances. The durability of response to inhaled GM-CSF therapy is not well characterized.
Methods: To elucidate the risk factors for recurrence of aPAP after GM-CSF inhalation, 35 patients were followed up, monitoring for the use of any additional PAP therapies and disease severity score every 6 months. Physiologic, serologic, and radiologic features of the patients were analyzed for the findings of 30-month observation after the end of inhalation therapy.
Results: During the observation, 23 patients remained free from additional treatments, and twelve patients required additional treatments. There were no significant differences in age, sex, symptoms, oxygenation indexes, or anti-GM-CSF antibody levels at the beginning of treatment between the two groups. Baseline vital capacity (% predicted, % VC) were higher among those who required additional treatment (P &lt;.01). Those patients not requiring additional treatment maintained the improved disease severity score initially achieved. A significant difference in the time to additional treatment between the high % VC group (% VC &gt;= 80.5) and the low % VC group was seen by a Kaplan-Meier analysis and a log-rank test (P &lt;.0005).
Conclusions: These results demonstrate that inhaled GM-CSF therapy sustained remission of aPAP in more than one-half of cases, and baseline % VC might be a prognostic factor for disease recurrence.

DOI： 10.1378/chest.13-0603

Web of Science

PubMed

researchmap

記述言語：英語  

BACKGROUND: Secondary pulmonary alveolar proteinosis (sPAP) is a very rare lung disorder comprising approximately 10% of cases of acquired PAP. Hematological disorders are the most common underlying conditions of sPAP, of which 74% of cases demonstrate myelodysplastic syndrome (MDS). However, the impact of sPAP on the prognosis of underlying MDS remains unknown. The purpose of this study was to evaluate whether development of sPAP worsens the prognosis of MDS. METHODS: Thirty-one cases of sPAP and underlying MDS were retrospectively classified into mild and severe cases consisting of very low-/low-risk groups and intermediate-/high-/very high-risk groups at the time of diagnosis of MDS, according to the prognostic scoring system based on the World Health Organization classification. Next, we compared the characteristics, disease duration, cumulative survival, and prognostic factors of the groups. RESULTS: In contrast to previous reports on the prognosis of MDS, we found that the cumulative survival probability for mild MDS patients was similar to that in severe MDS patients. This is likely due to the poor prognosis of patients with mild MDS, whose 2-year survival rate was 46.2%. Notably, 75% and 62.5% of patients who died developed fatal infectious diseases and exacerbation of PAP, respectively, suggesting that the progression of PAP per se and/or PAP-associated infection contributed to poor prognosis. The use of corticosteroid therapy and a diffusing capacity of the lung for carbon monoxide of less than 44% were predictive of poor prognosis. CONCLUSION: Development of sPAP during the course of MDS may be an important adverse risk factor in prognosis of patients with mild MDS.

DOI： 10.1186/1471-2466-14-37

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Background and objectiveSerum markers, including Krebs von den Lungen (KL-6), surfactant protein (SP)-D, SP-A and carcinoembryonic antigen (CEA), are reported to reflect autoimmune pulmonary alveolar proteinosis (APAP) disease severity. We evaluated serum CYFRA21-1 levels as a marker of APAP.
MethodsIn addition to KL-6, SP-D and CEA, we prospectively measured serum CYFRA 21-1 levels in 48 patients with APAP, consecutively diagnosed between 2002 and 2010. Diagnostic usefulness of CYFRA 21-1 was determined from 68 patients with interstitial lung diseases by receiver operator characteristic curve analysis. We evaluated the association between these serum markers and other disease severity markers, including pulmonary function parameters, alveolar-arterial oxygen gradient, British Medical Research Council score reflecting shortness of breath, and disease severity score. CYFRA 21-1 localization in the lung was examined by immunohistochemistry.
ResultsReceiver operator characteristic curve demonstrated that CYFRA 21-1 effectively identified APAP. Serum CYFRA 21-1 levels at diagnosis were significantly associated with the measured disease severity parameters. Following whole lung lavage (n=10) and granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation (n=20), serum CYFRA 21-1 levels were significantly decreased. Responders (n=11) to GM-CSF inhalation revealed significantly higher serum CYFRA 21-1 levels than non-responders (n=9). Serum CYFRA 21-1 appeared to be a significant predictor of effectiveness of GM-CSF based on regression analysis. Immunohistochemistry showed that CYFRA 21-1 was localized on hyperplastic alveolar type II cells and lipoproteinaceous substances in alveoli.
ConclusionsSerum CYFRA 21-1 is a sensitive and useful serum marker for diagnosis and evaluation of disease severity of APAP, and may predict the response to GM-CSF inhalation.
Serum CYFRA 21-1 is useful for the diagnosis of autoimmune pulmonary alveolar proteinosis (APAP) by receiver operating characteristic curve analysis and significantly correlated with other disease severity markers of APAP. Serum CYFRA 21-1 might be a predictor of responsiveness to GM-CSF inhalation therapy in APAP.

DOI： 10.1111/resp.12210

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Autoantibodies against granulocyte/macrophage colony-stimulating factor (GMAbs) cause autoimmune pulmonary alveolar proteinosis (PAP) and measurement of the GMAb level in serum is now commonly used to identify this disease, albeit, in a clinical research setting. The present study was undertaken to optimize and standardize serum GMAb concentration testing using a GMAb enzyme-linked immunosorbent assay (GMAb ELISA) to prepare for its introduction into routine clinical use. The GMAb ELISA was evaluated using serum specimens from autoimmune PAP patients, healthy people, and GMAb-spiked serum from healthy people. After optimizing assay components and procedures, its accuracy, precision, reliability, sensitivity, specificity, and ruggedness were evaluated. The coefficient of variation in repeated measurements was acceptable (&lt;15%) for well-to-well, plate-to-plate, day-to-day, and inter-operator variation, and was not affected by repeated freeze-thaw cycles of serum specimens or the reference standards, or by storage of serum samples at 80 degrees C. The lower limit of quantification (LLOQ) of the PAP patient-derived polyclonal GMAb reference standard (PCRS) was 0.78 ng/ml. Receiver operating characteristic curve analysis identified a serum GMAb level of 5 mu g/m1 (based on PCRS) as the optimal cut off value for distinguishing autoimmune PAP serum from normal serum. A pharmaceutical-grade, monoclonal GMAb reference standard (MCRS) was developed as the basis of a new unit of measure for GMAb concentration: one International Unit (IU) of GMAb is equivalent to 1 mu g/ml of MCRS. The median [interquartile range] serum GMAb level was markedly higher in autoimmune PAP patients than in healthy people (21.54 [12.83-3638] versus 0.08 [0.05-0.14] IU; n = 56, 38; respectively; P &lt; 0.0001). Results demonstrate that serum GMAb measurement using the GMAb ELISA was accurate, precise, reliable, had an acceptable LLOQ and could be accurately expressed in standardized units. These findings support the use of this GMAb ELISA for the routine clinical diagnosis of autoimmune PAP and introduce a new unit of measure to enable standardized reporting of serum GMAb data from different laboratories. (C) 2013 Published by Elsevier B.V.

DOI： 10.1016/j.jim.2013.11.011

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.resinv.2013.05.005

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mycoplasma pneumoniae (Mp) is a leading cause of community acquired pneumonia. Knowledge regarding Mp pneumonia obtained from animal models or human subjects has been discussed in many different reports. Accumulated expertise concerning this critical issue has been hard to apply clinically, and potential problems may remain undiscovered. Therefore, our multidisciplinary team extensively reviewed the literature regarding Mp pneumonia, and compared findings from animal models with those from human subjects. In human beings, the characteristic pathological features of Mp pneumonia have been reported as alveolar infiltration with neutrophils and lymphocytes and lymphocyte/plasma cell infiltrates in the peri-bronchovascular area. Herein, we demonstrated the novel aspects of Mp pneumonia that the severity of the Mp pneumonia seemed to depend on the host innate immunity to the Mp, which might be accelerated by antecedent Mp exposure (re-exposure or latent respiratory infection) through up-regulation of Toll-like receptor 2 expression on bronchial epithelial cells and alveolar macrophages. The macrolides therapy might be beneficial for the patients with macrolide-resistant Mp pneumonia via not bacteriological but immunomodulative effects. This exhaustive review focuses on pathogenesis and extends to some therapeutic implications such as clarithromycin, and discusses the various diverse aspects of Mp pneumonia. It is our hope that this might lead to new insights into this common respiratory disease.

DOI： 10.3389/fmicb.2014.00410

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.clim.2013.10.002

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCI LTD  

Background VEGF-D is a lymphangiogenic growth factor that has a key role in tumour metastasis. Serum VEGF-D concentrations are increased in most patients with lymphangioleiomyomatosis, a rare neoplasm associated with mTOR-activating tuberous sclerosis gene mutations, lymphadenopathy, metastatic spread, and pulmonary cyst formation. We used data from the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial to assess the usefulness of serum VEGF-D concentration as a marker of severity and therapeutic response to sirolimus in patients with lymphangioleiomyomatosis.
Methods In the MILES trial, patients with lymphangioleiomyomatosis who had forced expiratory volume in 1 second (FEV1) of 70% or less of predicted were randomly assigned (1:1) to 12 months masked treatment with sirolimus or placebo. Serum VEGF-D concentrations were measured at baseline, 6 months, and 12 months. We used a linear regression model to assess associations of baseline VEGF-D concentrations with markers of disease severity, and a linear mixed effects model to assess the associations of VEGF-D concentrations with between-group differences in clinical, physiological, and patient-reported outcomes.
Findings We included 42 patients from the placebo group and 45 from the sirolimus group in our analysis. Baseline VEGF-D concentrations in individual patients varied from 0.34 ng/mL to 16.7 ng/mL. Baseline VEGF-D concentrations were higher in patients who needed supplemental oxygen than in those who did not need supplemental oxygen (1.7 ng/mL [IQR 0.99-3.36] vs 0.84 ng/mL [0.52-1.39]; p&lt;0.0001) and in those who had a bronchodilator response than in those who did not (2.01 ng/mL [0.99-2.86] vs 1.00 ng/mL [0.61-2.15]; 0.0273). Median serum VEGF-D concentrations were similar at baseline in the sirolimus and placebo groups, and fell from baseline at 6 and 12 months in the sirolimus group but remained roughly stable in the placebo group. Each one-unit increase in baseline log(VEGF-D) was associated with a between-group difference in baseline-to-12-month FEV1 change of 134 mL (p=0.0007). In the sirolimus group, improvement in baseline-to-12-month FEV1 occurred in 15 of 23 (65%) VEGF-D responders (ie, those in whom baseline-to-12-month VEGF-D concentrations decreased by more than they did in any patients in the placebo group) and four of 15 (27%) VEGF-D non-responders (p=0.0448).
Interpretation Serum VEGF-D is a biologically plausible and useful biomarker in lymphangioleiomyomatosis that correlates with disease severity and treatment response. Measurement of serum VEGF-D concentrations could inform the risk-benefit analysis of sirolimus therapy in patients with lymphangioleiomyomatosis and reduce the numbers of patients needed for clinical trials.

DOI： 10.1016/S2213-2600(13)70090-0

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：QUINTESSENCE PUBLISHING CO INC  

One-year data after autologous grafting of infrabony periodontal defects with human cultured periosteum sheets in combination with platelet-rich plasma and hydroxyapatite granules have shown favorable clinical and radiographic results. A 5-year follow-up evaluation of 22 selected patients indicated that treated infrabony defects remained stable. Radiographically, there was an increase in osseous radiopacity and bone trabeculation suggesting further bone maturation. This novel tissue-engineered periodontal treatment approach has resulted in significant clinical improvement, and defects remained stable after 5 years.

DOI： 10.11607/prd.1545

Web of Science

PubMed

researchmap

記述言語：英語  

Mycoplasma pneumoniae (Mp) may cause immune cell reactions as pivotal aspects of this clinically common respiratory pathogen. Our aim is to determine if Mp extract induces a cellular immune response associated with interleukin (IL)-17, leading to lung inflammation and lung injury. BALB/c mice were immunized with Mp extract intraperitoneally followed by its intratracheal administration, to mimic repeated Mp infection found in humans (repeated inoculation, RI group). Those with a single inoculation were compared as single inoculation group (SI group). Analysis of bronchoalveolar lavage fluid (BALF) demonstrated that keratinocyte-derived cytokine, tumor necrosis factor-α, and IL-6 were produced and peaked on days 0.5 or 1, followed by IL-17 on day 2. Levels of these mediators in BALF were higher in RI group than SI group (P < 0.05). Further, significantly more neutrophils were recruited to the lungs of the RI group (P < 0.05). These observations suggest that IL-17 is involved in the prolonged induction of neutrophils in mice treated with Mp extract.

DOI： 10.1007/s10753-012-9545-3

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cytotoxic lymphodepletion therapies augment antitumor immune responses. The generation and therapeutic efficacy of antitumor effector T cells (T Es) are enhanced during recovery from lymphopenia. Although the effects of lymphodepletion on naive T cells (TNs) and TEs have been studied extensively, the influence of lymphodepletion on suppressor cells remains poorly understood. In this study, we demonstrate a significant increase of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in sublethally irradiated lymphopenic mice. These radio-resistant Tregs inhibited the induction of TEs in tumor-draining lymph-nodes (TDLNs) during recovery from lymphopenia. The transfer of TNs into lymphopenic tumor-bearing mice resulted in some antitumor effects
however, Treg depletion after whole-body irradiation and reconstitution strongly inhibited tumor progression. Further analyses revealed that tumor-specific T cells were primed from the transferred TNs, whereas the Tregs originated from irradiated recipient cells. As in irradiated lymphopenic mice, a high percentage of Tregs was observed in cyclophosphamide-treated lymphopenic mice. The inhibition of Tregs in cyclophosphamide-treated mice significantly reduced tumor growth. These results indicate that the Tregs that survive cytotoxic therapies suppress antitumor immunity during recovery from lymphopenia and suggest that approaches to deplete radio and chemoresistant Tregs can enhance cancer immunotherapies. © 2012 by The American Society of Hematology.

DOI： 10.1182/blood-2012-02-411124

Scopus

PubMed

researchmap

記述言語：英語   出版者・発行元：EUROPEAN RESPIRATORY SOC JOURNALS LTD  

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC IMMUNOLOGISTS  

The Runx1 transcription factor is abundantly expressed in naive T cells but rapidly downregulated in activated T cells, suggesting that it plays an important role in a naive stage. In the current study, Runx1(-/-) Bcl2(tg) mice harboring Runx1-deleted CD4(+) T cells developed a fatal autoimmune lung disease. CD4(+) T cells from these mice were spontaneously activated, preferentially homed to the lung, and expressed various cytokines, including IL-17 and IL-21. Among these, the deregulation of IL-21 transcription was likely to be associated with Runx binding sites located in an IL-21 intron. IL-17 produced in Runx1-deleted cells mobilized innate immune responses, such as those promoted by neutrophils and monocytes, whereas IL-21 triggered humoral responses, such as plasma cells. Thus, at an initial stage, peribronchovascular regions in the lung were infiltrated by CD4(+) lymphocytes, whereas at a terminal stage, interstitial regions were massively occupied by immune cells, and alveolar spaces were filled with granular exudates that resembled pulmonary alveolar proteinosis in humans. Mice suffered from respiratory failure, as well as systemic inflammatory responses. Our data indicate that Runx1 plays an essential role in repressing the transcription of cytokine genes in naive CD4(+) T cells and, thereby, maintains cell quiescence. The Journal of Immunology, 2012, 188: 5408-5420.

DOI： 10.4049/jimmunol.1102991

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Nei T, Urano S, Motoi N, Takizawa J, Kaneko C, Kanazawa H, Tazawa R, Nakagaki K, Akagawa KS, Akasaka K, Ichiwata T, Azuma A, Nakata K. IgM-type GM-CSF autoantibody is etiologically a bystander but associated with IgG-type autoantibody production in autoimmune pulmonary alveolar proteinosis. Am J Physiol Lung Cell Mol Physiol 302: L959-L964, 2012. First published February 24, 2012; doi: 10.1152/ajplung.00378.2011.-The granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody (GMAb) is the causative agent underlying autoimmune pulmonary alveolar proteinosis (aPAP). It consists primarily of the IgG isotype. At present, information on other isotypes of the autoantibody is limited. We detected serum the IgM isotype of GMAb (IgM-GMAb) in more than 80% of patients with aPAP and 22% of healthy subjects, suggesting that a continuous antigen pressure may be present in most patients. Levels of the IgM isotype were weakly correlated with IgG-GMAb levels but not IgA-GMAb, suggesting that its production may be associated with that of IgG-GMAb. The mean binding avidity to GM-CSF of the IgM isotype was 100-fold lower than the IgG-GMAb isotype, whereas the IC50 value for neutralizing capacity was 20,000-fold higher than that of IgG-GMAb, indicating that IgM-GMAb is only a very weak neutralizer of GM-CSF. In bronchoalveolar lavage fluid from nine patients, IgG-GMAb was consistently detected, but IgM-GMAb was under the detection limit in most patients, confirming that IgM-GMAb is functionally a bystander in the pathogenesis of aPAP. It rather may be involved in the mechanism for development of IgG-GMAb in vivo.

DOI： 10.1152/ajplung.00378.2011

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

In ongoing clinical research into the use of cultured autogenous periosteal cells (CAPCs) in alveolar bone regeneration, CAPCs were grafted into 33 sites (15 for alveolar ridge augmentation and 18 for maxillary sinus lift) in 25 cases. CAPCs were cultured for 6 weeks, mixed with particulate autogenous bone and platelet-rich plasma, and then grafted into the sites. Clinical outcomes were determined from high-resolution three-dimensional computed tomography (3D-CT) images and histological findings. No serious adverse events were attributable to the use of grafted CAPCs. Bone regeneration was satisfactory even in cases of advanced atrophy of the alveolar process. Bone biopsy after bone grafting with CAPCs revealed prominent recruitment of osteoblasts and osteoclasts accompanied by angiogenesis around the regenerated bone. 3D-CT imaging suggested that remodeling of the grafted autogenous cortical bone particles was faster in bone grafting with CAPCs than in conventional bone grafting. The use of CAPCs offers cell-based bone regeneration therapy, affording complex bone regeneration across a wide area, and thus expanding the indications for dental implants. Also, it enables the content of particulate autogenous bone in the graft material to be reduced to as low as 40%, making the procedure less invasive, or enabling larger amounts of graft materials to be prepared. It may also be possible to dispense with the use of autogenous bone altogether in the future. The results suggest that CAPC grafting induces bone remodeling, thereby enhancing osseointegration and consequently reducing postoperative waiting time after dental implant placement. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bone.2012.02.631

Web of Science

PubMed

researchmap

記述言語：英語   出版者・発行元：European Respiratory Society  

DOI： 10.1183/09031936.00076711

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W B SAUNDERS CO LTD  

Background: Autoimmune pulmonary alveolar proteinosis (aPAP) is caused by granulocyte/macrophage-colony stimulating factor (GM-CSF) autoantibodies in the lung. Previously, we reported that GM-CSF inhalation therapy improved alveolar-arterial oxygen difference and serum biomarkers of disease severity in these patients. It is plausible that inhaled GM-CSF improves the dysfunction of alveolar macrophages and promotes the clearance of the surfactant. However, effect of the therapy on components in bronchoalveolar lavage fluid (BALF) remains unclear.
Objectives: To figure out changes in surfactant clearance during GM-CSF inhalation therapy. Methods: We performed retrospective analyses of BALF obtained under a standardized protocol from the same bronchus in each of 19 aPAP patients before and after GM-CSF inhalation therapy (ISRCTN18931678, JMA-IIA00013; total dose 10.5-21 mg, duration 12-24 weeks). For evaluation, the participants were divided into two groups, high responders with improvement in alveolar-arterial oxygen difference &gt;= 13 mmHg (n = 10) and low responders with that &lt; 13 mmHg (n = 9).
Results: Counts of both total cells and alveolar macrophages in BALF did not increase during the therapy. However, total protein and surfactant protein-A (SP-A) were significantly decreased in high responders, but not in low responders, suggesting that clearance of surfactant materials is correlated with the efficacy of the therapy. Among 94 biomarkers screened in bronchoalveolar lavage fluid, we found that the concentration of interleukin-17 and cancer antigen-125 were significantly increased after GM-CSF inhalation treatment.
Conclusions: GM-CSF inhalation decreased the concentration of total protein and SP-A in BALF, and increase interleukin-17 and cancer antigen-125 in improved lung of autoimmune pulmonary alveolar proteinosis. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.rmed.2011.10.019

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）  

DOI： 10.1111/j.1440-1843.2012.02132.x

CiNii Article

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1089/bio.2011.0051

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

A 55-year-old non-smoking woman was admitted to our hospital for re-evaluation of unimproved peripheral ground-glass opacities despite prednisolone and cyclosporine treatment. She was diagnosed with autoimmune pulmonary alveolar proteinosis (PAP) based on transbronchial lung biopsy and granulocyte/macrophage colony-stimulating factor (GM-CSF) antibody testing. GM-CSF inhalation therapy markedly improved the opacities. Bilateral, centrally located lung opacities are typical in PAP, however 10 PAP cases with peripheral infiltration were reported in Japan recently, of which GM-CSF antibody was positive in six. To avoid inappropriate immunosuppressant treatment, PAP should be considered in the differential diagnosis of such peripheral opacities. GM-CSF antibody might be useful for diagnosis.

DOI： 10.2169/internalmedicine.51.6093

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Accumulating evidence suggests that cancer cells possess a small subpopulation that survives during potentially lethal stresses, including chemotherapy, radiation treatment, and molecular-targeting therapy. CD133 is a putative marker that distinguishes a minor subpopulation from normal differentiated tumor cells in many cancers. Although it is necessary to eradicate all cancer cells to obtain a cure, effective treatment to eliminate the CD133(+) treatment-tolerant cells has not been elucidated. In this study, we demonstrated that a CD133(+) subpopulation in murine melanoma is immunogenic and that effector T cells specific for the CD133(+) melanoma cells mediated potent antitumor reactivity, curing the mice of the parental melanoma. CD133(+) melanoma antigens preferentially induced type 17 T helper (Th17) cells and Th1 cells but not Th2 cells. CD133(+) melanoma cell-specific CD4(+) T-cell treatment eradicated not only CD133(+) tumor cells but also CD133(-) tumor cells while inducing long-lasting accumulation of lymphocytes and dendritic cells with upregulated MHC class II in tumor tissues. Further, the treatment prevented regulatory T-cell induction. These results indicate that T-cell immunotherapy is a promising treatment option to eradicate CD133(+) drug-tolerant cells to obtain a cure for cancer.

DOI： 10.1007/s00262-011-1063-x

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/1465-9921-12-143

PubMed

researchmap

記述言語：英語   出版者・発行元：AMER THORACIC SOC  

DOI： 10.1164/ajrccm.184.6.741a

Web of Science

PubMed

researchmap

記述言語：日本語   出版者・発行元：公益社団法人 日本薬理学会  

肺胞蛋白症は肺胞内にサーファクタント物質が蓄積して呼吸不全を呈する疾患である．その患者の9割は，顆粒球／マクロファージコロニー刺激因子（GM-CSF）に対する自己抗体による肺胞マクロファージの機能障害のため，肺サーファクタント物質の除去能が低下して生ずることが，最近の研究で明らかになった．この分子病態に基づく新規治療としてGM-CSFでの治療研究が進められてきた．GM-CSF吸入治療は標準治療の全肺洗浄に比べて簡便で，外来治療が可能である．本邦での多施設第II相試験で重篤な有害事象なく，60%をこえる奏効率を示し，その効果は治療期間と用量によることが示唆された．GM-CSF製剤は本邦では未承認であり，適切な対照群をおいた第III相試験は，本症が稀少疾患であるため，1国のみでは困難なことが予想される．本治療の開発・普及には，患者組織，研究者，製薬会社，国，そして国際共同研究施設が参加する新しい枠組みが必要と考えられる．

DOI： 10.1254/fpj.138.64

PubMed

CiNii Article

CiNii Books

researchmap

その他リンク： https://jlc.jst.go.jp/DN/JALC/00375032217?from=CiNii

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/1465-9921-12-93

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recently, combination treatment with a macrolide and a steroid for Mycoplasma pneumoniae (Mp) pneumonia has been reported to be effective. Thus, the effect of this combination on a mouse model of lung inflammation associated with Mp extract (the LIMEX mouse) was studied. Interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) were induced in Mp extract-treated RAW264.7 cells, and this induction was inhibited by dexamethasone, parthenolide, SB203580 or LY294002. This suggested that Mp extract activates nuclear factor κB-, p38- and PI-3K-linked pro-inflammatory signals. The LIMEX mice were then either treated with or without clarithromycin and/or dexamethasone. Clarithromycin administration enhanced the production of IL-6, TNF-α, macrophage inflammatory protein-1α, monocyte chemotactic protein-1 and RANTES, while their production was perfectly suppressed by the combination of clarithromycin and dexamethasone. IL-17, IL-23, keratinocyte-derived chemokine (KC) and interferon-γ levels were not affected by clarithromycin treatment, but they were significantly suppressed by the combination of dexamethasone and clarithromycin. Collectively, some components of Mp extract provoked an inflammatory reaction in the RAW 264.7 cell line and LIMEX mice. Whereas the lung reaction in LIMEX mice was further exacerbated by clarithromycin treatment, it was resolved by the combinational treatment with clarithromycin and dexamethasone.

DOI： 10.1111/j.1574-695X.2011.00799.x

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JOURNAL OF VISUALIZED EXPERIMENTS  

BACKGROUNDS: Previously, we demonstrated that neutralizing capacity but not the concentration of GM-CSF autoantibody was correlated with the disease severity in patients with autoimmune pulmonary alveolar proteinosis (PAP) (1-3). As abrogation of GM-CSF bioactivity in the lung is the likely cause for autoimmune PAP(4,5), it is promising to measure the neutralizing capacity of GM-CSF autoantibodies for evaluating the disease severity in each patient with PAP.
Until now, neutralizing capacity of GM-CSF autoantibodies has been assessed by evaluating the growth inhibition of human bone marrow cells or TF-1 cells stimulated with GM-CSF6-8. In the bioassay system, however, it is often problematic to obtain reliable data as well as to compare the data from different laboratories, due to the technical difficulties in maintaining the cells in a constant condition.
OBJECTIVE: To mimic GM-CSF binding to GM-CSF receptor on the cell surface using cell-free receptor-binding-assay.
METHODS: Transgenic silkworm technology was applied for obtaining a large amount for recombinant soluble GM-CSF receptor alpha (sGMR alpha) with high purity(9-13). The recombinant sGMRa was contained in the hydrophilic sericin layers of silk threads without being fused to the silk proteins, and thus, we can easily extract from the cocoons in good purity with neutral aqueous solutions(14,15). Fortunately, the oligosaccharide structures, which are critical for binding with GM-CSF, are more similar to the structures of human sGMRa than those produced by other insects or yeasts.
RESULTS: The cell-free assay system using sGMRa yielded the data with high plasticity and reliability. GM-CSF binding to sGMRa was dose-dependently inhibited by polyclonal GM-CSF autoantibody in a similar manner to the bioassay using TF-1 cells, indicating that our new cell-free assay system using sGMRa is more useful for the measurement of neutralizing activity of GM-CSF autoantibodies than the bioassay system using TF-1 cell or human bone marrow cells.
CONCLUSIONS: We established a cell-free assay quantifying the neutralizing capacity of GM-CSF autoantibody.

DOI： 10.3791/2742

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MASSACHUSETTS MEDICAL SOC  

BACKGROUND
Lymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease in women; it is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth and lymphangiogenesis. Sirolimus (also called rapamycin) inhibits mTOR and has shown promise in phase 1-2 trials involving patients with LAM.
METHODS
We conducted a two-stage trial of sirolimus involving 89 patients with LAM who had moderate lung impairment - a 12-month randomized, double-blind comparison of sirolimus with placebo, followed by a 12-month observation period. The primary end point was the difference between the groups in the rate of change (slope) in forced expiratory volume in 1 second (FEV1).
RESULTS
During the treatment period, the FEV1 slope was -12 +/- 2 ml per month in the placebo group (43 patients) and 1 +/- 2 ml per month in the sirolimus group (46 patients) (P&lt;0.001). The absolute between-group difference in the mean change in FEV1 during the treatment period was 153 ml, or approximately 11% of the mean FEV1 at enrollment. As compared with the placebo group, the sirolimus group had improvement from baseline to 12 months in measures of forced vital capacity, functional residual capacity, serum vascular endothelial growth factor D (VEGF-D), and quality of life and functional performance. There was no significant between-group difference in this interval in the change in 6-minute walk distance or diffusing capacity of the lung for carbon monoxide. After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group. Adverse events were more common with sirolimus, but the frequency of serious adverse events did not differ significantly between the groups.
CONCLUSIONS
In patients with LAM, sirolimus stabilized lung function, reduced serum VEGF-D levels, and was associated with a reduction in symptoms and improvement in quality of life. Therapy with sirolimus may be useful in selected patients with LAM.

DOI： 10.1056/NEJMoa1100391

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：B M J PUBLISHING GROUP  

Background Disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signalling causes pulmonary alveolar proteinosis (PAP). Rarely, genetic defects in neonatal or infant-onset PAP have been identified in CSF2RA. However, no report has clearly identified any function-associated genetic defect in CSF2RB.
Methods and results The patient was diagnosed with PAP at the age of 36 and developed respiratory failure. She was negative for GM-CSF autoantibody and had no underlying disease. Signalling and genetic defects in GM-CSF receptor were screened. GM-CSF-stimulated STAT5 phosphorylation was not observed and GM-CSF-R beta c expression was defective in the patient&apos;s blood cells. Genetic screening revealed a homozygous, single-base deletion at nt 631 in exon 6 of CSF2RB on chromosome 22, which caused reductions in GM-CSF dependent signalling and function. Both parents, who were second cousins, showed no pulmonary symptoms, and had normal GM-CSF-signalling, but had a CSF2RB allele with the identical deletion, indicating that the mutant allele may give rise to PAP in an autosomal recessive manner.
Conclusions This is the first report identifying a genetic defect in CSF2RB that causes deficiency of GM-CSF-Rbc expression and impaired signalling downstream. These results suggested that GM-CSF signalling was compensated by other signalling pathways, leading to adult-onset PAP.

DOI： 10.1136/jmg.2010.082586

Web of Science

PubMed

researchmap

記述言語：英語  

DOI： 10.1183/09031936.00092910

PubMed

researchmap

記述言語：英語  

Human Mycoplasma pneumoniae (MP) pneumonia is characterized by alveolar infiltration with neutrophils and lymphocytes and lymphocyte/plasma cell infiltrates in the peri-bronchovascular area (PBVA). No mouse model has been able to mimic the pathological features seen in human MP pneumonia, such as plasma cell-rich lymphocytic infiltration in PBVA. To figure out the mechanism for inflammation by MP infection using a novel mouse model that mimics human MP pneumonia, mice were pre-immunized intraperitoneally with Th2 stimulating adjuvant, alum, alone or MP extracts with an alum, followed by intratracheal challenge with MP extracts. The toll-like receptor-2, which is the major receptor for mycoplasma cell wall lipoproteins, was strongly up-regulated in alveolar macrophages in a latter group after the pre-immunization but prior to the intratracheal challenge. Those findings demonstrated that acceleration of innate immunity by antecedent antigenic stimulation can be an important positive-feedback mechanism in lung inflammation during MP pneumonia.

DOI： 10.1016/j.rinim.2011.11.001

PubMed

researchmap

記述言語：英語   出版者・発行元：ELSEVIER SCI LTD  

Numerous reports have documented the presence of autoantibodies working against naturally occurring cytokines in humans in health and disease. In most instances, their physiological and pathophysiological significance remains unknown. However, recent advances in the methodologies for detecting cytokine autoantibodies and their application in research focused on specific disorders have shown that some cytokine autoantibodies play an important role in the pathogenesis of disease. Additionally, levels of cytokine autoantibodies may also correlate with disease severity and progression in certain infectious and autoimmune diseases but not in others. This suggests that cytokine-specific pathogenic differences exist. While multiple lines of evidence support the notion that high avidity cytokine autoantibodies are present and likely to be ubiquitous in healthy individuals, their potential physiological role, if any, is less clear. It is believed that they may function by scavenging pro-inflammatory cytokines and thereby inhibiting deleterious &apos;endocrine&apos; effects, or by serving as carrier proteins, providing a &apos;reservoir&apos; of inactive cytokines and thus modulating cytokine bioactivity. A central hypothesis is that sustained or repeated high-level exposure to cytokines triggers defects in T-cell tolerance, resulting in the expansion of existing cytokine autoantibody-producing B cells. (C) 2010 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.cytogfr.2010.03.003

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

The aim of the project is to develop a novel method estimating granulocyte-macrophage colony-stimulating factor (GM-CSF) neutralizing capacity with high-throughput and good reproducibility. For that purpose, we designed a cell-free receptor binding assay consisting of a solid-phase recombinant soluble GM-CSF receptor alpha (GMR alpha) and a biotinylated GM-CSF (bGM-CSF). Using this system, competitive inhibition of bGM-CSF binding to soluble GM-CSF receptor alpha (sGMR alpha) by GM-CSF autoantibody or IgG fractions from the sera of patients with pulmonary alveolar proteinosis was examined, resulting in excellent reproducibility. Binding inhibition was correlated with growth inhibition of TF-1 cells, a GM-CSF dependent cell line. These results suggest that our cell-free system can be applied to estimate the neutralizing capacity of GM-CSF autoantibodies ex vivo. (C) 2010 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jim.2010.07.001

Web of Science

PubMed

researchmap

記述言語：日本語   出版者・発行元：The Japanese Society of Internal Medicine  

肺胞蛋白症患者の9割は，顆粒球/マクロファージコロニー刺激因子（GM-CSF）に対する自己抗体による肺胞マクロファージの機能障害のため，肺サーファクタント物質の除去能が低下して生ずるとされる自己免疫性肺胞蛋白症である．分子病態に基づく新規治療としてGM-CSF治療の研究が進められてきた．標準治療の全肺洗浄に比して簡便で，外来治療が可能なGM-CSF吸入治療は，本邦での多施設第II相試験で重篤な有害事象なく，60％をこえる奏効率を示し，その効果は治療期間と用量によることが示唆された．本症は稀少疾患であるため，国際共同研究でさらに検討することを計画中である．<br>

DOI： 10.2169/naika.99.1623

CiNii Article

CiNii Books

researchmap

その他リンク： https://jlc.jst.go.jp/DN/JALC/00354066011?from=CiNii

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

Rationale: Granulocyte/macrophage colony-stimulating factor (GMCSF) autoantibodies (GMAb) are strongly associated with idiopathic pulmonary alveolar proteinosis (PAP) and are believed to be important in its pathogenesis. However, levels of GMAb do not correlate with disease severity and GMAb are also present at low levels in healthy individuals.
Objectives: Our primary objective was to determine whether human GMAb would reproduce PAP in healthy primates. A secondary objective was to determine the concentration of GMAb resulting in loss of GM-CSF signaling in vivo (i.e., critical threshold).
Methods: Nonhuman primates (Macaca fascicularis) were injected with highly purified, PAP patient-derived GMAb in dose-ranging (2.2-50 mg) single and multiple administration studies, and after blocking antihuman immunoglobulin immune responses, in chronic administration studies maintaining serum levels greater than 40 mu g/ml for up to 11 months.
Measurements and Main Results: GMAb blocked GM-CSF signaling causing (1) a milky-appearing bronchoalveolar lavage fluid containing increased surfactant lipids and proteins; (2) enlarged, foamy, surfactant-filled alveolar macrophages with reduced PU.1 and PPAR gamma mRNA, and reduced tumor necrosis factor-a secretion; (3) pulmonary leukocytosis; (4) increased serum surfactant protein-D; and (5) impaired neutrophil functions. GM-CSF signaling varied inversely with GMAb concentration below a critical threshold of 5 mu g/ml, which was similar in lungs and blood and to the value observed in patients with PAP.
Conclusions: GMAb reproduced the molecular, cellular, and histopathologic features of PAP in healthy primates, demonstrating that GMAb directly cause PAP. These results have implications for therapy of PAP and help define the therapeutic window for potential use of GMAb to treat other disorders.

DOI： 10.1164/rccm.201001-0008OC

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

Rationale: Inhaled granulocyte/macrophage-colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied.
Objectives: To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP.
Methods: We conducted a national, multicenter, self-controlled, phase II trial at nine pulmonary centers throughout japan. Patients who had lung biopsy or cytology findings diagnostic of PAP, an elevated serum GM-CSF antibody level, and a Pa(O2) of less than 75 mm Hg entered a 12-week observation period. Those who improved (i.e., alveolar-arterial oxygen difference [A-aDO(2)] decreased by 10 mm Hg) during observation were excluded. The rest entered sequential periods of high-dose therapy (250 mu g Days 1-8, none Days 9-14; x six cycles; 12 wk); low-dose therapy (125 mu g Days 1-4, none Days 5-14; x six cycles; 12 wk), and follow-up (52 wk).
Measurements and Main Results: Fifty patients with PAP were enrolled in the study. During observation, nine improved and two withdrew; all of these were excluded. Of 35 patients completing the high- and low-dose therapy, 24 improved, resulting in an overall response rate of 62% (24/39; intention-to-treat analysis) and reduction in A-aDO(2) of 12.3 mm Hg (95% confidence interval, 8.4-16.2; n = 35, P &lt; 0.001). No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged. A treatment-emergent correlation occurred between A-aDO(2) and diffusing capacity of the lung, and high-resolution CT revealed improvement of ground-glass opacity. Twenty-nine of 35 patients remained stable without further therapy for 1 year.
Conclusions: Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP.

DOI： 10.1164/rccm.200906-0978OC

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：EUROPEAN RESPIRATORY SOC JOURNALS LTD  

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease without proven effective therapy.
A multicentre, double-blind, placebo-controlled, randomised phase III clinical trial was conducted in Japanese patients with well-defined IPF to determine the efficacy and safety of pirfenidone, a novel antifibrotic oral agent, over 52 weeks. Of 275 patients randomised (high-dose, 1,800 mg.day(-1); low-dose, 1,200 mg.day(-1); or placebo groups in the ratio 2: 1: 2), 267 patients were evaluated for the efficacy of pirfenidone. Prior to unblinding, the primary end-point was revised; the change in vital capacity (VC) was assessed at week 52. Secondary end-points included the progression-free survival (PFS) time.
Significant differences were observed in VC decline (primary end-point) between the placebo group (-0.16 L) and the high-dose group (-0.09 L) (p=0.0416); differences between the two groups (p=0.0280) were also observed in the PFS (the secondary end-point). Although photosensitivity, a well-established side-effect of pirfenidone, was the major adverse event in this study, it was mild in severity in most of the patients.
Pirfenidone was relatively well tolerated in patients with IPF. Treatment with pirfenidone may decrease the rate of decline in VC and may increase the PFS time over 52 weeks. Additional studies are needed to confirm these findings.

DOI： 10.1183/09031936.00005209

Web of Science

PubMed

researchmap

記述言語：英語   出版者・発行元：AMER THORACIC SOC  

DOI： 10.1164/rccm.200912-1800ED

Web of Science

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：英語   出版者・発行元：AMER SOC HEMATOLOGY  

DOI： 10.1182/blood-2009-11-246041

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER COLL CHEST PHYSICIANS  

Background: Acquired pulmonary alveolar proteinosis (PAP) has been reclassified into autoimmune or secondary PAP according to the occurrence of serum granulocyte macrophage colony-stimulating factor autoantibody. Most patients undergo high-resolution CT (HRCT) scanning in order for physicians to make a differential diagnosis of diffuse lung diseases, but no information is available to distinguish the HRCT scan features of secondary PAP from those of autoimmune PAP. The objective of this study was to characterize the HRCT scan features of autoimmune and secondary PAP.
Methods: HRCT scans of 42 patients (21 patients each in the autoimmune PAP and secondary PAP groups) were centrally collected and evaluated in a blinded manner.
Results: Ground-glass opacities (GGO) were a major finding in both the autoimmune PAP and secondary PAP groups. In the secondary PAP group, GGOs typically showed a diffuse pattern (62%), whereas GGOs showed a patchy geographic pattern in the autoimmune PAP group (71%; p &lt; 0.005). The so-called "crazy-paving" appearance and subpleural sparing were frequently seen in the autoimmune PAP group (both 71%), whereas they were less frequently seen in the secondary PAP group (14% and 33%, respectively). The involved area of GGO was even in craniocaudal distribution for the secondary PAP group, whereas it was predominant in the lower lung field compared with the upper lung field in the autoimmune PAP group (p &lt; 0.05).
Conclusions: Typical HRCT scan findings for autoimmune PAP patients were GGO with a patchy geographic pattern, subpleural sparing, crazy-paving appearance, and predominance in the lower lung field. These findings were rather infrequent for secondary PAP patients. (CHEST 2009; 136:1348-135-5)

DOI： 10.1378/chest.09-0097

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

The information conveyed from dendritic cells (DCs) to naive CD4(+) T cells has crucial influence on their differentiation toward effector T cells. In an effort to identify DC-derived molecules directly contributing to T cell differentiation, we searched for molecules distinctively expressed between two DC subtypes, which were differentiated from peripheral monocytes by cultivation with GM-CSF (for DC1) or IL-3 (for DC2) in the presence of IL-4 and had the ability to induce nave T cells to differentiate into Th1 or Th2 cells, respectively. As the first step to address this issue, we subtracted DC1 transcripts from those of DC2 and compiled the gene profile dominantly expressed in DC2, whose products are known to reside in other than the nucleus. Intriguingly, many of them were molecules involved in Th2-skewed disease pathologies, such as FN1, ITGAE, GPNMB, PLAUR, FPRL2, LILRB4, SERPINE1, ALOX15, TBXAS1, NCF2, CCL3, IL1RN, SPARC, and STAB1, suggesting that DCs function not only as antigen presenting cells but also as producers of Th2 pathology specific milieus leading to disease deteriorations. We also found that expressions of CYP27A1, PPAP2B, RSAD2, and ABCC3 were up-regulated in DC2, implying their significant function in Th2-deviated states. The identification of differentially expressed genes between DC subtypes provides new insights into their functions and our comparative gene expression profile will be highly useful for the identification of DC-derived key molecules for T cell differentiation. (C) 2009 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.imlet.2009.07.008

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：UNIV CHICAGO PRESS  

Host genetic susceptibility to adult pulmonary Mycobacterium avium complex disease remains unknown. To identify genetic loci for the disease, we prepared 3 sets of pooled DNA samples from 300 patients and 300 sex-matched control subjects and genotyped 19,651 microsatellite markers in a case-control manner. D6S0009i-located in the MICA (major histocompatibility complex class I chain-related A) gene, which encodes a ligand of the NKG2D receptor-had the lowest P value in pooled and individual DNA typing. The A6 allele of the microsatellite was significantly associated with female patients (P &lt; .001), whereas the classical HLA-B and HLA-DRB1 alleles did not show significant association. Functional analysis of allelic expression imbalance revealed that A6-derived messenger RNA was more highly expressed than non-A6-derived messenger RNA in human bronchial epithelial cells. MICA was expressed in bronchiolar epithelium, alveolar macrophages, and granulomatous lesions. These findings suggest that MICA might be one of the immune molecules affecting the pathogenesis of the disease.

DOI： 10.1086/598982

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JOHN WILEY & SONS LTD  

Our recent clinical studies have demonstrated that autologous implantation of human cultured periosteal (hCP) sheets in combination with porous hydroxylapatite (HAp) particles at the site of periodontal bone defects strikingly facilitates tissue regeneration. To better understand how the hCP sheet functions at the implantation site, we have now examined its biochemical and morphological characteristics in vitro and its ectopic osteoinductivity in nude mice. Cultured human periosteal tissue segments produced periosteal cells that migrated out from the central region within 4-8 days and grew more rapidly with longer culture times. Alkaline phosphatase activity increased in parallel with actual osteoblastic induction. Cytokine array assays demonstrated that osteoblastic induction downregulated IL-6 and thrombopoietin, but upregulated IL-8, IL-13, IGF-I and IGFBP-2 in hCP sheets. When differentiated hCP sheets were implanted alone, areas of osteoid and mineralized tissue were formed within 2 weeks, but non-induced, immature hCP sheets did not produce much mineralization. These findings suggest that mature hCP sheets potentially function not only as seeds of ectopic bone formation without the need of synthetic tissue scaffolds, but also as living drug-delivery systems, to influence cells near implantation sites by producing several important cytokines. These two major characteristics indicate that a mature hCP sheet is a promising osteoinductive biomaterial, even without conventional scaffolds for periodontal regenerative therapy. Copyright (c) 2009 John Wiley & Sons, Ltd.

DOI： 10.1002/term.156

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

Secondary pulmonary alveolar proteinosis (PAP) has been described in several clinical settings that can be grouped into three main categories: infections of the lung; haematological malignancies and other conditions that alter the patient&apos;s immune status; and exposure to inhaled chemicals and minerals. Recent studies reported that anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody was present in the serum of patients with idiopathic PAP but not in patients with secondary PAP or in normal subjects. The present report describes the interesting case of a patient with Behcet&apos;s disease and PAP. The absence of anti-GM-CSF antibodies in this patient suggested a diagnosis of secondary PAP.

DOI： 10.1111/j.1440-1843.2008.01450.x

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC HEMATOLOGY  

High levels of granulocyte/macrophage colony-stimulating factor (GM-CSF) autoantibodies are thought to cause pulmonary alveolar proteinosis (PAP), a rare syndrome characterized by myeloid dysfunction resulting in pulmonary surfactant accumulation and respiratory failure. Paradoxically, GM-CSF autoantibodies have been reported to occur rarely in healthy people and routinely in pharmaceutical intravenous immunoglobulin (IVIG) purified from serum pooled from healthy subjects. These findings suggest that either GM-CSF autoantibodies are normally present in healthy people at low levels that are difficult to detect or that serum pooled for IVIG purification may include asymptomatic persons with high levels of GM-CSF autoantibodies. Using several experimental approaches, GMCSF autoantibodies were detected in all healthy subjects evaluated (n = 72) at low levels sufficient to rheostatically regulate multiple myeloid functions. Serum GMCSF was more abundant than previously reported, but more than 99% was bound and neutralized by GM-CSF autoantibody. The critical threshold of GM-CSF autoantibodies associated with the development of PAP was determined. Results demonstrate that free serum GM-CSF is tightly maintained at low levels, identify a novel potential mechanism of innate immune regulation, help define the therapeutic window for potential clinical use of GMCSF autoantibodies to treat inflammatory and autoimmune diseases, and have implications for the pathogenesis of PAP. (Blood. 2009; 113:2547-2556)

DOI： 10.1182/blood-2008-05-155689

Web of Science

PubMed

researchmap

記述言語：日本語   出版者・発行元：特定非営利活動法人 日本歯周病学会  

DOI： 10.14833/amjsp.2009f.0.88.0

CiNii Article

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

Purpose: Small cell lung cancer (SCLC) possesses high tendency to disseminate. However, SCLC patients with paraneoplastic syndrome mediated by immunity against onconeural antigens remain in limited-stage disease (LD) without distant metastases. Cumulative evidence regulates that a balance between immune and regulatory T (Treg) cells determines the magnitude of immune responses to not only self-antigens but also tumor-associated antigens. The purpose of this study was to elucidate the immunologic balance induced in SCLC patients.
Experimental Design: We analyzed T cells in the peripheral blood of 35 consecutive SCLC patients, 8 long-term survivors, and 19 healthy volunteers.
Results: Purified CD4(+) Tcells with down-regulated expression of CD62L (CD62L(low)) produced IFN-gamma, interleukin (IL)-4, and IL-17, thus considered to be immune effector Tcells (Teff). Significantly moreTeff cell numbers were detected in LD-SCLC patients than that of extended-stage SCLC (ED-SCLC). By contrast, induction of CD62L(high) CD25(+) CD4(+) Treg cells was significantly higher in ED-SCLC patients. Long-term survivors of SCLC maintained a high Teff to Treg cell ratio, whereas patients with recurrent disease exhibited a low Teff to Treg cell ratio. Teff cells in LD-SCLC patients included more IL-17-producing CD4(+) Tcells (Th17). Moreover, dendritic cells derived from CD14(+) cells of LD-SCLC patients secreted more IL-23.
Conclusion: These results show that CD4(+) T-cell balance may be a biomarker that distinguishes ED-SCLC from LD-SCLC and predicts recurrence. This study also suggests the importance of inducing Teff cells, particularly Th17 cells, while eliminating Treg cells to control systemic dissemination of SCLC.

DOI： 10.1158/1078-0432.CCR-08-1156

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

Systemic and inhalation therapy of granulocyte-macrophage colony-stimulating factor (GM-CSF) is usually effective in controlling autoimmune pulmonary alveolar proteinosis (PAP), but some cases are refractory to GM-CSF therapy and subjected to whole lung lavage (WLL). A 9-year-old girl developed severe respiratory failure due to autoimmune PAP was treated with inhalational 250 mu g of GM-CSF daily, however, it was ineffective. Unilateral WLLwas performed three times and subsequent GM-CSF inhalation therapy yielded marked physiological and radiological improvement and was continued for 1 year.

DOI： 10.1002/ppul.20856

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

Rationale Acquired pulmonary alveolar proteinosis (PAP) is a syndrome characterized by pulmonary surfactant accumulation occurring in association with granulocyte/macrophage colony-stimulating factor autoantibodies (autoimmune PAP) or as a consequence of another disease (secondary PAP). Because PAP is rare, prior reports were based on limited patient numbers or a synthesis of historical data.
Objectives: To describe the epidemiologic, clinical, physiologic, and laboratory features of autoimmune PAP in a large, contemporaneous cohort of patients with PAP.
Methods: Over 6 years, 248 patients with PAP were enrolled in a Japanese national registry, including 223 with autoimmune PAP.
Measurements and Main Results: Autoimmune PAP represented 89.9% of cases and had a minimum incidence and prevalence of 0.49 and 6.2 per million, respectively. The male to female ratio was 2.1: 1, and the median age at diagnosis was 51 years. A history of smoking occurred in 56%, and dust exposure occurred in 23%; instances of familial onset did not occur. Dyspnea was the most common presenting symptom, occurring in 54.3%. Importantly, 31.8% of patients were asymptomatic and were identified by health screening. Intercurrent illnesses, including infections, were infrequent. A disease severity score reflecting the presence of symptoms and degree of hypoxemia correlated well with carbon monoxide diffusing capacity and serum biomarkers, less well with pulmonary function, and not with granulocyte/macrophage colony-stimulating factor autoantibody levels or duration of disease.
Conclusions: Autoimmune PAP had an incidence and prevalence higher than previously reported and was not strongly linked to smoking, occupational exposure, or other illnesses. The disease severity score and biomarkers provide novel and potentially useful outcome measures in PAP.

DOI： 10.1164/rccm.200708-1271OC

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

PU.1, which is a transcription factor, promotes the terminal differentiation of alveolar macrophages (AMs). Its expression is regulated by granulocyte/macrophage colony-stimulating factor (GM-CSF). In this study of AMs in newborn rats, we performed immunohistochemical staining, acid phosphatase staining, reverse transcriptase polymerase chain reaction (RT-PCR), quantitative real-time PCR, cytokine assay, and electron microscopy. AMs at 3 and 7 days after birth had a large foamy appearance with an intracytoplasmic accumulation of surfactants. Weak expression of PU.1 was observed in the nuclei. AMs at 15 days after birth were smaller, and PU.1 expression had increased. Ultrastructurally, AMs at 1 day after birth had a smooth surface and abundant lamellar structures in the cytoplasm, whereas AMs at 56 days after birth were characterized by (1) abundant microvillar projections on the cell surface, and (2) well-developed lysosomes and a few lamellar structures in the cytoplasm. Acid phosphatase activity and the expression of mannose receptor, scavenger receptor, and GM-CSF receptor alpha were enhanced in AMs with time after birth. These results suggest that AMs are initially immature, and that their terminal differentiation starts after birth concomitantly with an increased expression of PU.1.

DOI： 10.1007/s00441-007-0405-7

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：EUROPEAN RESPIRATORY SOC JOURNALS LTD  

The present study aimed to elucidate risk factors for nonimmunocompromised pulmonary Mycobacterium avium complex (MAC) infection.
Epidemiological data and variations of candidate genes for mycobacterial diseases were analysed in 111 patients with pulmonary MAC infection. Four polymorphisms of the human natural resistance-associated macrophage protein (NRAMP)1 gene, the 5'(GT)n, 469+14 G/C, D543N and the 3'untranslated region (3'TGTG) insertion/deletion, were genotyped using PCR-based methods. Fok I and Taq I polymorphisms of the vitamin D receptor gene and -221 X/Y and codon 54 A/B polymorphisms of the mannose binding lectin gene were also evaluated.
Females were more susceptible to MAC infection mainly affecting the right middle lobe or lingular segment of the lung. Patients' residence at the onset of the disease was distributed evenly irrespective of a waterfront or city water supply system. As compared with homozygotes for major alleles of the D543N and TGTG insertion/deletion polymorphism of the NRAMP1 gene, heterozygotes containing minor alleles were less often observed in MAC cases than in controls. This genetic effect was more significant in patients without comorbidity but not in patients with comorbidity. Other polymorphisms did not show any association with the MAC infection.
The human natural resistance-associated macrophage protein 1 gene might be involved in susceptibility to pulmonary Mycobacterium avium complex infection.

DOI： 10.1183/09031936.00042506

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：UNIV CHICAGO PRESS  

Background. Pulmonary tuberculosis (TB) can present with polymorphonuclear neutrophil (PMN)-predominant alveolitis. TB accelerates acquired immunodeficiency syndrome by increasing human immunodeficiency virus type 1 (HIV-1) replication and mutation in alveolar macrophages. A 16-kDa CCAAAT/enhancer-binding protein beta (C/EBPb) isoform is a strong transcriptional repressor of the HIV long terminal repeat (LTR) in resting alveolar macrophages, leading to latent viral infection; its expression is lost during TB, derepressing the HIV LTR.
Methods. Lung segments were sampled from HIV/Mycobacterium tuberculosis-coinfected patients by means of bronchoalveolar lavage. In vitro coculture experiments defined the mechanism of induction of HIV-1 infection in macrophages by PMNs.
Results. Lung segments from patients with PMN-predominant TB had a markedly elevated viral load. Direct contact between activated PMNs and macrophages stimulated HIV-1 replication and LTR transcription and down-regulated inhibitory C/EBP beta. Isolated PMN membranes substituted for PMN contact, derepressing the HIV-1 LTR. The lipid raft fraction of PMN membranes expressed CD40 ligand (CD40L), CD28, and leukocyte function associated antigen 1 (LFA-1 [i.e., CD11a and CD18]), and PMN activation increased lipid raft expression of CD40L and CD28. Blocking antibodies to CD40L, CD28, and LFA-1 inhibited PMN membrane-mediated HIV-1 LTR derepression. Alternately, cross-linking of macrophage receptors for CD40L, CD28, and LFA-1 (CD40, CD80/86, and intercellular adhesion molecule 1) abolished inhibitory C/EBPb expression.
Conclusion. PMN-macrophage contact derepresses the HIV-1 LTR and enhances HIV-1 replication in alveolar macrophages during pulmonary TB. Derepression is mediated through costimulatory molecule signaling.

DOI： 10.1086/513438

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Anti-cytokine autoantibodies in healthy individuals have been widely reported but the occurrence is variable and inconstant. We hypothesized that cytokine-hinding in vivo may explain their variable and infrequent detection. Therefore, we focused on the detection of the cytokine-autoanti body complexes and found that anti-cytokine autoantibody to IL-2, IL-8, tumor necrosis factor-alpha, vascular endothelial growth factor and granulocyte-colony stimulating factor were present in all 15 individuals evaluated, while those to IL-3, osteopontin and macrophage-colony stimulating factor were not detected in anyone. Autoantibodies against IL4, IL-6, M-10, and interferon-gamma were variously detected. Thus, we discovered that anti-cytokine autoantibodies to multiple cytokines are ubiquitous in healthy individuals. (C) 2007 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.

DOI： 10.1016/j.febslet.2007.04.029

Web of Science

PubMed

researchmap

記述言語：日本語   出版者・発行元：日本内科学会  

特発性肺胞蛋白症 (I-PAP) は, 抗GM-CSF自己抗体による自己免疫疾患である. 自己抗体が肺胞内のGM-CSF活性をブロックし, 最終的に肺胞内のサーファクタントが蓄積する. 最近, 自己抗体の解析がすすみ, より詳細な機能が明らかになった. 治療ではGM-CSF吸入療法の有効性が示された. 自己抗体の解析とGM-CSF療法前後の評価は, I-PAPの病態を理解する上できわめて重要である.

DOI： 10.2169/naika.95.1042

CiNii Article

CiNii Books

researchmap

その他リンク： http://hdl.handle.net/10191/17980

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TOHOKU UNIV MEDICAL PRESS  

Here we describe a case of idiopathic pulmonary alveolar proteinosis (I-PAP), in which anti-granulocyte/macrophage colony-stimulating factor (GM-CSF) antibody and high level of KL-6 were found in the serum. Anti-GM-CSF antibody is responsible for I-PAP, and KL-6 is a serum marker for the activity of diffuse interstitial lung disease. A 38-year-old woman, who had no symptoms, was found to have an abnormal shadow on chest radiograph 5 years previously at a health check up. Chest radiograph showed a patchy shadow in the left lower lung field. Thoracoscopic biopsy was performed because the shadow had gradually expanded during the 5 years. Histological examination revealed proteinous material filling the alveoli and positive staining by the PAS method, suggesting PAP. Anti-GM-CSF antibody and a high level of KL-6 were detected in the serum at the time of diagnosis. Three years later, the shadow disappeared spontaneously. During this period, the level of KL-6 dramatically decreased, although that of GM-CSF antibody remained unchanged. The present case suggests that the serum level of the anti-GM-CSF antibody represents a useful marker for the diagnosis but not for follow-up of the clinical course. On the contrary, KL-6 is an excellent marker for the assessment of the clinical course of I-PAP.

DOI： 10.1620/tjem.208.349

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING  

Idiopathic pulmonary alveolar proteinosis (IPAP) is a rare disease characterized by excessive amounts of lipoproteinaceous material in the alveolus. This report presents an interim analysis of nationwide epidemiological data from Japanese patients with pulmonary alveolar proteinosis, and the roles of serum markers for IPAP (i) The nationwide demographic data from 166 Japanese patients with IPAP are shown. The female to male ratio was 1:2, and the average age was 51 14 years old (age range: 15-79 years) at registration or diagnosis. A total of 30% of patients with IPAP have a poor clinical course. In total, 30% of patients were treated with whole lung lavage therapy (WWL). UnderWLL, the patients significantly improved in the short term, but 40% of the patients who underwent WLL worsened again. A new strategy such as granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy for intractable PAP is required. (ii) The correlation of serum KL-6, carcinoembryonic antigen, surfactant proteins D and A, and LDH with disease severity suggests their potential as disease markers. In contrast, serum anti-GM-CSF antibody did not correlate with disease severity, but is a specific marker for the diagnosis of WAR The combined measurements of the serum markers may well prove very useful for both the diagnosis and the management of IPAP patients.

DOI： 10.1111/j.1440-1843.2006.00810.x

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING  

The authors report a female patient with congenital pulmonary alveolar proteinosis (PAP). She had two brothers who died from the same disease. BAL did not improve her progressive respiratory failure. After intravenous immunoglobulin G (IVIG) administration for complicated hypogammaglobulinemia, she recovered from respiratory failure. The efficacy of IVIG was confirmed by recovery from deterioration in respiratory status and improvement in chest CT findings on two separate occasions. Subsequently, the patient remains free from respiratory symptoms for more than 3 years on an ongoing regimen of monthly IVIG. She had no surfactant protein (SP) B deficiency. Alveolar macrophages (AM) obtained from her BAL fluid were small and showed decreased phagocytotic activity. Immunostaining revealed weak expression of PU.1 in her AM, a key protein in AM maturation. All nucleotide sequences of granulocyte-macrophage colony stimulating factor (GMCSF), GM-CSF-receptor and PU.1 were normal. Endotoxin-induced GM-CSF release from peripheral mononuclear cells (PMNC), and proliferation of PMNC in response to GM-CSF were normal. In addition, an antibody against GM-CSF, as seen in adult patients with idiopathic PAP, was not detected in the serum or BAL fluid. Although the patient's PMNC secreted only small amounts of IgG and IgM, an EB virus-derived cell line of her B cells secreted IgM as much as normal control cells. In a flow cytometric study, IgM was expressed on the cell surface. In conclusion, an abnormality in a single gene may have decreased secretion of immunoglobulin from the B cells and the AM phagocytotic activity in the patient.

DOI： 10.1111/j.1440-1843.2006.00814.x

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING  

Objectives: During the course of investigating the etiology of idiopathic pulmonary alveolar proteinosis (IPAP), the authors found that the autoantibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) was consistently present in both sera and the lung tissue. The autoantibody completely blocked bioactivity by direct binding with high specificity and avidity. Because of the existence of patients with congenital PAP who lack GM-CSF receptors and the development of PAP in GM-CSF and GM-CSF receptor knock-out mice, the autoantibody is likely to be the causative agent for IPAP. However, this finding posed the question as to why the autoantibody against GM-CSF caused lesions only in the lung.
Methodology: To answer this question, the authors investigated, using immunohistochemistry, confocal laser microscopy, and immunoblotting, the expression of PU.1 in tissue macrophages. PU. I is a critical transcription factor for terminal differentiation of alveolar macrophage (ANI), as reported previously in the lung, liver, spleen, kidney, intestine and brain.
Results: PU.1 was consistently expressed in the nuclei of normal AM, but faintly or not at all in IPAP-AM. Moreover, it was not expressed in the nuclei of any other normal tissue macrophages tested. Blood monocytes expressed PU.1 in the cytosol but not in the nuclei. These results suggested that the differentiation pathway is different between AM and other tissue macrophages. PU. I was not expressed in the nuclei of newborn rat lung AM but was gradually expressed during the first 10 days.
Conclusions: The authors demonstrated that GM-CSF is crucial for terminal differentiation of AM, but not for that of other tissue macrophages.

DOI： 10.1111/j.1440-1843.2006.00812.x

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING  

Idiopathic pulmonary alveolar proteinosis (IPAP) is considered to be caused by an autoantibody to the granulocyte-macrophage colony-stimulating factor (GM-CSF), which neutralizes GM-CSF and therefore impairs the differentiation of alveolar macrophages. The authors have previously characterized the BAL fluid and alveolar macrophages obtained from three IPAP patients who were successfully treated with aerosolized GM-CSF and demonstrated restoration of the cell number, expression of surface marker, and phagocytic ability of the alveolar macrophages as well as a decrease in the autoantibody levels in the BAL fluid. The condition recurred in one of the patients after 20 months. This patient underwent a second and third course of GM-CSF inhalation therapy with the same dose and schedule as the first one. Since the second therapeutic intervention did not succeed in producing any improvement in the symptoms and disease markers, the authors used a new nebulizer and a liquid preparation of the drug instead of the lyophilized preparation for the third therapeutic session and this restored the respiratory function considerably. A 6-month maintenance therapeutic regimen with a lower GM-CSF inhalation frequency brought about a further improvement in the disease markers. The results suggest that the efficacy of GM-CSF inhalation therapy might be related to the drug preparation mode, choice of nebulizer, and duration of treatment.

DOI： 10.1111/j.1440-1843.2006.00811.x

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）  

DOI： 10.1111/j.1440-1843.2006.00815.x

Scopus

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

In order to investigate polymorphic backgrounds of the cystic fibrosis transmembrane conductance regulator gene (CFTR) in the Vietnamese, we analyzed 495 blood samples of randomly selected healthy individuals in Hanoi for the delta F508 mutation and TG-repeats, poly-T, and M470V polymorphisms. We compared their distributions with those of Caucasians and other Asian populations. No delta F508 mutation was found, being consistent with the extremely low incidence of cystic fibrosis (CF) in Vietnam. Allele frequency of the T5 allele promoting exon 9 skipping was 0.037. Greater number of TG-repeats, which is known to facilitate this aberrant splicing, was a predominant trend in the Vietnamese and other Asians. A "T5-TG12-V470" haplotype was most common (29/37) among T5-bearing haplotypes. Three major haplotypes, T7-TG12-M470, T7-TG11-V470, and T7-TG12-V470, estimated by PHASE program, related to 92% of the population. This is the first study of the CFTR gene among the Vietnamese. (c) 2005 Wiley-Liss, Inc.

DOI： 10.1002/ajmg.a.30826

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

The anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody is inferred to cause idiopathic pulmonary alveolar proteinosis (iPAP): the antibody neutralizes GM-CSF and thereby impairs differentiation of alveolar macrophages. Administration of GM-CSF improves respiratory function of patients with iPAP, as confirmed in this study using aerosolized GM-CSF. To elucidate its mechanism, we characterized bronchoalveolar lavage fluid and alveolar macrophages obtained from three patients with iPAP who were treated successfully with aerosolized GM-CSF. Cell number, expressions of surface mannose receptor and the transcription factor PU.1, and phagocytic ability of alveolar macrophages were all restored to control levels. With treatment, the neutralizing capacity of GM-CSF activity was reduced markedly, concomitant with the decreasing autoantibody levels. Interestingly, the amount of GMCSF autoantibody complex also decreased. In one case in which the complex was analyzed, the majority of GM-CSF binding the complex was endogenous protein, suggesting that the complex is removed immediately from the lung after treatment. Our study shows that GM-CSF administration engenders a decrease in the neutralizing capacity against the protein in the lungs. Thereby, it facilitates restoration of the normal function of alveolar macrophages.

DOI： 10.1164/rccm.200406-716OC

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

Diffuse panbronchiolitis (DPB) is a chronic inflammatory airway disease predominantly affecting Asian populations. DPB is considered to be a complex genetic disease. Considering the mucous hypersecretion of the disease, we hypothesized that the transcriptional activity of mucin genes may be altered in DPB. We analyzed nucleotide sequences of regulatory region of six mucin genes-MUC1, MUC2, MUC4, MUC5AC, MUC5B, and MUC7-and detected their promoter polymorphisms. Among them, the insertion/deletion polymorphism identified in the MUC5B gene was significantly associated with the disease (p = 0.0001). Transcriptional activity observed in the three major promoter haplotypes corresponded to the strength of the disease association in which these haplotypes are involved. Immunohistochemistry of the lung tissues of DPB revealed that MUC5B was abundantly expressed not only in bronchial glands but also in increased numbers of goblet cells on the bronchial surface, where MUC5AC is predominant and MUC5B expression is generally scarce in the normal lung. Marked mucous hypersecretion observed in DPB may be partly explained by increased and aberrant expression of MUC58. The possible involvement of MUC5B gene in DPB was demonstrated. A further role of the MUC5B polymorphism in its pathogenesis should be studied in the future.

DOI： 10.1164/rccm.200409-1168OC

Web of Science

PubMed

researchmap

記述言語：日本語   出版者・発行元：日本内科学会  

肺胞蛋白症(Pulmonary alveolar proteinosis, PAP)は肺胞および呼吸細気管支内にサーファクタント(Surfactant, SF)が貯留する希な肺疾患である.臨床的には先天性,二次性,特発性に分類される.二次性は血液疾患や感染症に続発し,特発性は抗GM-CSF自己抗体により発症する. GM-CSF欠損マウスの研究により, GM-CSFシグナル異常,肺胞マクロファージの成熟障害,サーファクタントの代謝障害が主要な病態であることがわかった.また,特発性で出現する自己抗体は, GM-CSFを強力に中和しPAPを発症する.これらの研究より,肺におけるGM-CSFの重要な役割が明らかになった.治療として全肺洗浄が有効であるが,近年はGM-CSF療法が良好な成績をあげている.本稿では,肺内におけるGM-CSFの役割とPAPの病態,最近の治療法について概説する.

DOI： 10.2169/naika.94.763

CiNii Article

CiNii Books

researchmap

その他リンク： http://hdl.handle.net/10191/17975

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：FONDAZIONE PNEUMOLOGIA U I P ONLUS  

Background: In studies of the unknown etiology of sarcoidosis, Propionibacterium acnes (a possible agent) was found in the lungs and lymph nodes of many sarcoldosis patients and some control subjects. P acnes might be commensal not only to the skin, conjunctivae, and intestine, but also to the lungs and lymph nodes of individuals without sarcoidosis. Methods: We cultured peripheral lung tissue and various lymph nodes obtained from patients with diseases other than sarcoidosis. DNA of 45 isolates of P acnes from these patients, 67 isolates from normal skin, conjunctiva, and intestine, and 39 isolates from sarcoid lymph nodes were compared by random amplified polymorphic DNA analysis. Results: P acnes was isolated from half of 43 lungs and 8 of 11 mediastinal lymph nodes, mostly in pure culture. P acnes was isolated from half of 20 gastric and 3 of 12 intestinal lymph nodes; intestinal bacteria were also numerous. In general, fewer than 500 colony-forming units of P acnes per gram tissue were isolated, but 4 lung tissue specimens, 2 of which had a few granulomas, had many more. P acnes strains from a particular site (lung, lymph node, skin or conjunctivae, and intestine) were genetically similar, more than isolates obtained from different sites. Lymph-node isolates from subjects with and without sarcoidosis differed little. Conclusion: These results suggest that P acnes normally resides in peripheral lung tissue and mediastinal lymph nodes and that the strains of P acnes isolated from sarcoid lymph nodes were not specific to sarcoidosis.

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W B SAUNDERS CO LTD  

Existence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) neutralizing antibody and treatment with recombinant GM-CSF are new topics in idiopathic pulmonary alveolar proteinosis (PAP). We have hypothesized inhaled GM-CSF is effective and neutralizing capacity of GM-CSF, not concentration of anti-GM-CSF antibody in serum reflect disease severity.
A 57-year-old female smoker with idiopathic PAP was treated with inhaled GMCSF. The response to the treatment was evaluated by diffusing capacity for carbon monoxide (DLCO), alveolar-arterial oxygen gradient ([A-a]DO2)- Conventional serum markers, including KL-6, surfactant apoprotein (SP)-A, SP-D, carcino-embryonic antigen and cytokeratin fragment 19 (CYFRA), and concentration of anti-GM-CSF antibody were examined. The neutralizing capacity of GM-CSF in serum was evaluated using a GM-CSF dependent cell line, TF-1.
Ground glass opacity disappeared at the end of the treatment. Her DLCO, [A-a]DO2 remarkably improved after treatment. The neutralizing capacity of GM-CSF declined in line with disease remission and it correlated significantly with DLCO (P = 0.0137). The concentration of anti-GM-CSF antibody had no significant relation with disease severity and serum markers including neutralizing capacity. Conventional serum markers other than CYFRA showed no significant correlation with DLCO.
Inhaled GM-CSF was effective for idiopathic PAR Serial measurement of neutralizing capacity of GM-CSF was useful to evaluate disease severity and the anti-GM-CSF antibody was proved to be a causative factor for PAR In the future, inhaled GM-CSF may replace whole lung lavage and response to GM-CSF and its optimal amount may be decided by the capacity. (C) 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.rmed.2004.08.011

Web of Science

PubMed

researchmap

記述言語：日本語   掲載種別：研究論文（国際会議プロシーディングス）  

HIV-1 infection is a major cause of worldwide epidemic of tuberculosis. There is increasing clinical evidence that coinfection with M. tuberculosis accelerates progression of AIDS. We found that, in vivo, HIV-1 load and mutation increase in involved lung segments in patients with pulmonary tuberculosis. We also reported that Mycobacterium tuberculosis stimulates HIV-1 replication by enhancing transcription on the 5′ LTR in a macrophage cell line, THP-1, in vitro. In contrast, HIV-1 replication is suppressed by M. tuberculosis infection of monocytes derived macrophages (MDM) or differentiated monocytic THP-1 cells. We observed that HIV-1 5′ LTR function was repressed in PMA differentiated THP-1 cells after co-infection with M. tuberculosis. Point mutations in C/EBP β binding domains of the HIV-1 LTR negative regulatory element (NRE) abolished promoter repression. Monocyte-derived macrophages and differentiated THP-1 cells increased expression of the 16kDa inhibitory form of C/EBP after M. tuberculosis co-infection. Bronchoalveolar lavage cells obtained from normal controls and alveolar macrophages from uninflamed lung of tuberculosis patients also expressed the 16kDa inhibitory form of C/EBP. However, alveolar macrophages from lung segments involved with pulmonary tuberculosis had markedly reduced C/EBP expression. These data suggest that 16kDa isoform of C/EBP plays an important role for the control of HIV-1 replication in macrophages. We propose derepression of HIV-1 LTR mediated transcription as one mechanism for enhanced HIV-1 replication observed in pulmonary tuberculosis. Since the cellular immune response in pulmonary tuberculosis requires lymphocyte/macrophage interaction, a model system was developed in which lymphocytes were added to AM. Contact between lymphocytes and AM reduced inhibitory C/EBP β, activated NF-κB and enhanced HIV-1 replication. If contact between lymphocytes and macrophages was prevented, inhibitory C/EBP β expression was maintained and the HIV-1 long terminal repeat (LTR) was not maximally stimulated although NF-κB was activated. Antibodies which cross-linked macrophage expressed B-7, VCAM and CD-40 were used mimic lymphocyte contact. Cross-linking antibodies abolished inhibitory C/EBP β expression
however, the HIV-1 LTR was not maximally stimulated and NF-κB was not activated. Maximal HIV-1 LTR stimulation required both lymphocyte derived soluble factors and cross-linking of macrophage expressed co-stimulatory molecules. These results demonstrate that neither contact nor soluble factor(s) are sufficient to maximally enhance HIV-1 LTR activity in macrophages. Contact between activated lymphocytes and macrophages is necessary to downregulate inhibitory C/EBP β, thereby derepressing the HIV-1 LTR. Lymphocyte derived soluble factor(s) activate NF-κB, further enhancing the HIV-1 LTR.

DOI： 10.11400/kekkaku1923.79.659

Scopus

PubMed

researchmap

記述言語：英語   出版者・発行元：W B SAUNDERS CO  

Pulmonary alveolar proteinosis (PAP) has been recognized for almost half a century. At least three separate pathophysiologic mechanisms may lead to the characteristic feature of PAP: the excessive accumulation of surfactant lipoprotein in pulmonary alveoli, with associated disturbance of pulmonary gas exchange. The prognosis for adult patients with PAP varies, but disease-specific survival rate exceeds 80% at 5 years. The survival rates for adult PAP patients seem to have increased progressively in the four decades since the initial clinical description of this condition. The last decade has brought new advances in laboratory and clinical research that are lifting a veil not only on PAP but also on general aspects of pulmonary surfactant biology and innate immune defense.

DOI： 10.1016/j.ccm.2004.04.002

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Haplotype-based human genome research is important in identifying disease susceptibility genes efficiently. Although haplotype reconstruction by statistical methods is widely used, direct haplotype determination by molecular techniques has also been developed as a complementary method for statistical estimation. In this study, we demonstrate a molecular haplotyping method making use of single-strand conformation polymorphism (SSCP) gels. We identified 10 common SNPs and a dinucleotide insertion/deletion polymorphism within 2-kb region upstream of the transcription initiation site of MUM and determined haplotype structure, dividing the region into two DNA fragments. Real haplotypes were determined unambiguously by our SSCP-based analysis with fragments longer than 1 kb. Haplotypes reconstructed from diploid genotypes in the same region by the statistical methods including EM algorithm were also evaluated. Direct comparison between statistical estimation and direct determination of haplotypes revealed that major haplotypes containing multiple marker sites showing strong LD are estimated in great accuracy but that a variety of haplotypes reflecting weak LD are not reconstructed precisely enough. Our data can be helpful in implementing molecular haplotyping or statistical estimation, since usage of these methods may be determined depending on the haplotype structures. (C) 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ygeno.2004.05.008

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING ASIA  

Objective: The association of pulmonary fibrosis (PF) with myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitides has not been well documented. The aim of this study was to assess the clinicopathological characteristics of PF in patients who tested positive for MPO-ANCA.
Methodology: In this study, 31 patients (17 males and 14 females; mean age, 69 years) diagnosed as having PF with positive MPO-ANCA levels ranging from 10 to 840 EU with a mean of 112.5 EU, were evaluated clinicopathologically.
Results: Among 31 patients with PE 22 had underlying systemic diseases such as collagen vascular diseases, while nine had unknown aetiology. Evidence of glomerulonephritis was demonstrated in 14 patients. The clinical features were a history of dry cough and/or fine crackles in all 31 patients. Chest CT scans showed honeycombing in the lung bases in 26 patients. The histopathological features of the diseased lung tissues in all 11 autopsied cases were compatible with the usual interstitial pneumonia (UIP) pattern. Vasculitis was confirmed in bronchial arteries and/or pulmonary arterioles in five patients. The mortality was as high as 13 of the 31 patients. The causes of death were: deterioration of PF in five (two of whom were associated with pulmonary haemorrhage), lung cancer in two, pneumonia in four, and digestive tract bleeding in two. The survival rates in PF with MPO-ANCA-negative collagen vascular diseases, cryptogenic fibrosing alveolitis (CIA), and PF with positive MPO-ANCA, were compared. The 5-year survival rate in PF with positive MPO-ANCA was worse than in PF with MPO-ANCA-negative collagen vascular diseases and was the same for CIA.
Conclusion: Although there was no correlation between MPO-ANCA titres and the activity of PE this study demonstrated that the presence of positive MPO-ANCA was an unfavorable prognostic factor in patients with PE.

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING ASIA  

We describe a case of a patient with idiopathic pulmonary alveolar proteinosis (PAP), who had an elevated serum level of antigranulocyte-macrophage colony stimulating factor (anti-GM-CSF) antibody accompanied by T-cell receptor gene rearrangements in BAL fluid cells. Histopathological examination of the lung excluded lymphoma but revealed PAP and silicosis. There was no detectable serum anti-GM-CSF antibody in 50 outpatients with advanced silicosis who did not have PAP, suggesting that anti-GM-CSF antibody is directly linked to PAP but not to silicosis. We speculate that monoclonal expansion of a T-cell population may play a role in the production of anti-GM-CSF antibody and the development of PAP.

DOI： 10.1111/j.1440-1843.2004.00574.x

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC IMMUNOLOGISTS  

We used a PCR and sequence procedure to analyze the Ig V-H gene and the mutations in the 5' regulatory regions of BCL-6 genes in pulmonary lymphoproliferative disorders (mucosa-associated lymphoid tissue (MALT) lymphoma, HIV-related, EBV-related, and virus-negative lymphocytic interstitial pneumonia (LIP)). Eight of 20 (40%) pulmonary MALT lymphoma and 10 of 20 LIP (5 of 5 (100%) HIV-related, 2 of 5 (40%) EBV-related, and 3 of 10 (30%) virus-negative LIP) cases showed BCL-6 gene mutations. Intraclonal heterogeneity of the BCL-6 mutations was observed only in pulmonary MALT lymphoma cases whose Ig V, genes also showed intraclonal heterogeneity. Ongoing BCL-6 mutations might reflect re-entry into a germinal center pathway to further mutations. BCL-6 mutations in pulmonary MALT lymphoma and HIV-negative LIP showed some features (high transition to transversion ratio, standard polarity, and RGYW/WRCY bias) of Ig V-H gene hypermutation, leading to the view that pulmonary MALT lymphomas and HIV-negative LIP are under the influence of germinal center hypermutation mechanisms. Because BCL-6 mutations in HIV-related LIP cases did not demonstrate features of Ig V, gene hypermutation, immunological reactions in HIV-related LIP are the result of a process different from that found in HIV-negative pulmonary lymphoproliferative disorders.

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Purpose: To evaluate the possible long-term alterations of choroidal perfusion parameters in the new central macular area after macular translocation surgery.
Methods: Eleven subjects with subfoveal neovascular membrane secondary to age-related macular degeneration or degenerative myopia underwent indocyanine green angiography by using a scanning laser ophthalmoscope before and after macular translocation (mean, 10 months after surgery). Fluorescence intensity of the new central macular area over time was evaluated. Parameters derived from the intensity curves included 10% filling time, ascending slope, and maximal intensity of brightness. The 10% filling time reflects the rapidity of the early choroidal filling phase, whereas the slope of the filling of the curve shows the speed of blood entrance into the choroid. Maximal intensity of brightness indicates vascular density of the area.
Results: No statistical difference was encountered before or after macular translocation in 10% filling time (14.25 +/- 2.09 seconds versus 16.20 +/- 2.95 seconds), slope of the ascending portion of the curve (0.12 +/- 0.04 versus 0.11 +/- 0.04), and maximal intensity of brightness (0.89 +/- 0.09 versus 0.88 +/- 0.07) in the new central macular area. The rotational degree of the retina against the retinal pigment epithelium did not show any significant correlation with 10% filling time, slope, or maximal intensity of brightness.
Conclusion: Choroidal perfusion parameters in the new foveal region do not change after macular translocation surgery.

DOI： 10.1097/00006982-200404000-00003

Web of Science

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC HEMATOLOGY  

Deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF) in mice results in pulmonary alveolar proteinosis (PAP) from impaired surfactant catabolism by alveolar macrophages (AMs). Recently, we have shown that neutralizing anti-GM-CSF autoantibodies develop specifically in patients with idiopathic pulmonary alveolar proteinosis (iPAP). Analogous to murine PAP models, it is plausible that the autoantibodies reduce GM-CSF activity, resulting in AM dysfunction and surfactant accumulation. To examine this hypothesis, we estimated the neutralizing activity of the auto-antibodies in the lungs of patients and characterized their biologic properties. GM-CSF bioactivity was completely abrogated in the bronchoalveolar lavage fluid (BALF) of patients with iPAP but not in healthy subjects. Autoantibodies were present in the alveoli in high concentrations and colocalized with GM-CSF. They recognized human GM-CSF with high avidity (K-AV = 20.0 +/- 7.5 muM) and high specificity, reacting with its superstructure and neutralizing GM-CSF activity to a level 4000 to 58 000 times the levels of GM-CSF normally present in the lung. Although target epitopes varied among patients, GM-CSF amino acids 78 to 94 were consistently recognized. Thus, autoantibodies bind GM-CSF with high specificity and high affinity, exist abundantly in the lung, and effectively block GM-CSF binding to its receptor, inhibiting AM differentiation and function. Our data strengthen the evidence associating anti-GM-CSF autoantibodies with the pathogenesis of this disease.

DOI： 10.1182/blood-2003-05-1565

Web of Science

PubMed

researchmap

記述言語：英語   出版者・発行元：MASSACHUSETTS MEDICAL SOC/NEJM  

DOI： 10.1056/NEJMra023226

Web of Science

PubMed

researchmap

記述言語：日本語   出版者・発行元：The Japanese Society of Internal Medicine  

びまん性汎細気管支炎はアジア系集団に好発する慢性炎症性呼吸器疾患である.その発症素因として,ヒト白血球抗原(human leukocyte antigen; HLA)との関連が検討されてきた.韓国人患者との対比などから,疾患感受性遺伝子の同定を試みた結果, HLA-A, B両遺伝子座間に疾患感受性遺伝子が存在する可能性が示唆され,分子遺伝学的にその候補領域の特定と感受性遺伝子の同定が進められている.

DOI： 10.2169/naika.92.1206

CiNii Article

CiNii Books

researchmap

その他リンク： https://jlc.jst.go.jp/DN/JALC/00230305043?from=CiNii

記述言語：日本語   出版者・発行元：The Japanese Society of Internal Medicine  

特発性肺胞蛋白症は末梢気道にサーファクタントが貯留する希な疾患である. 1994年,顆粒球マクロファージコロニー刺激因子(GM-CSF)欠損マウスは肺胞蛋白症を発症することが報告された.このマウスの肺胞マクロファージには分化障害があり,その結果,サーファクタントの分解が障害され,発症する.次いで,筆者らは, 99年,病原物質として患者の肺及び血液に抗GM-CSF自己抗体が大量に存在することを明らかにした.これらの成果をふまえて,近年治療法としてGM-CSFの連日投与が有効であることがわかり,我が国でもGM-CSF吸入による重症特発性肺胞蛋白症の治療研究が開始された.

DOI： 10.2169/naika.92.1279

CiNii Article

CiNii Books

researchmap

その他リンク： https://jlc.jst.go.jp/DN/JALC/00230305159?from=CiNii

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Conventional measures of the severity of alveolar proteinosis (AP) include alveolar-arterial oxygen gradient ([A - a]Do2), vital capacity (VC), and carbon monoxide transfer factor (TLCO), but alternative serological measures have been sought. Granulocyte-macrophage colony stimulating factor (GM-CSF) neutralising autoantibody is found in patients with idiopathic acquired AP. We have investigated the interrelationships between the levels of this antibody and those of surfactant protein (SP)-A and -B, lactate dehydrogenase (LDH), and conventional measures of disease severity, and the capacity of these parameters to predict the response to rhGM-CSF treatment. Methods: Blood levels of anti-GM-CSF antibodies, SP-A, SP-B, LDH, and [A - a]Do2, VC, and TLCO were measured before rhGM-CSF treatment and every 2 weeks thereafter in 14 patients with AP. Results: At baseline, high levels of anti-GM-CSF antibodies and increased SP-A and SP-B levels were seen in all patients, and LDH was raised in 83%. SP-A was highly correlated with [A - a]Do2, VC, and TLCO (p≤0.02), but other markers were not. Only a normal LDH level was predictive of a response to rhGM-CSF treatment (p=0.03). During treatment a correlation between conventional and serological variables within patients was seen only between SP-A and [A - a]Do2 (p=0.054), LDH levels and [A - a]Do2 (p=0.010), and LDH levels and VC (p=0.019). Conclusions: Of the serological parameters studied, only SP-A and LDH levels were correlated with conventional measures of disease severity, with LDH most accurately reflecting [A - a]Do2 and vital capacity. Only a normal LDH level predicted a higher likelihood of response to treatment with GM-CSF.

DOI： 10.1136/thorax.58.3.252

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

A 47-year-old man, who had been diagnosed as myelodysplastic syndrome (MDS), complained of a severe cough and a high-grade fever. Chest CT disclosed scattered small nodules and ground-glass opacities with interlobular septal thickening in both lung fields and a mass lesion in the right lower lobe. Pathological findings of the ground-glass opacities and the mass lesion obtained by video-assisted thoracoscopic surgery revealed the accumulation of eosinophilic amorphous material in the alveoli and confirmed the diagnosis of pulmonary alveolar proteinosis (PAP). Autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) in sera were below sensitivity, while the GM-CSF level was elevated in bronchoalveolar lavage fluid. He was diagnosed as secondary PAP associated with MDS.

DOI： 10.2169/internalmedicine.42.187

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：論文集(書籍)内論文   出版者・発行元：Elsevier Inc.  

This chapter describes novel activities of erythromycin and its derivatives that include erythromycin treatment in diffuse panbronchiolitis, inhibition of chloride channel, modulation of bacterial function, and the effects of macrolides on cytokine or chemokine expression. Fourteen-membered ring macrolides, such as erythromycin and oleandomycin exhibit antimicrobial activity. In order to study the structure-activity relationships of macrolides, the macrolides are screened as the acceleration of gastrointestinal motor stimulating activity (GMSA). Three of the new macrolides, EM201, EM522, and EM574 strongly inhibit the proliferation of T lymphocytes and differentiation of monocytic cells. Thus, these results suggest that the antimicrobial effect, GMSA, the inhibition of cytokines releasing from lymphocyte and macrophage, and the inhibition of water and mucous secretions from epithelial cells can be a result of the different structural factors of macrolides. Development of new derivatives exhibiting anti-inflammatory actions without bactericidal activity are required, because low-dose and long-term erythromycin therapy induces the formation of macrolide-resistant bacterial strains. © 2003 Elsevier Inc. All rights reserved.

DOI： 10.1016/B978-012526451-8/50013-8

Scopus

researchmap

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ROCKEFELLER UNIV PRESS  

HIV-1 replication is markedly upregulated in alveolar macrophages (AM) during pulmonary tuberculosis (TB). This is associated with loss of an inhibitory CCAAT enhancer binding protein beta (C/EBPbeta) transcription factor and activation of nuclear factor (NF)-kappaB. Since the cellular immune response in pulmonary TB requires lymphocyte-macrophage interaction, a model system was developed in which lymphocytes were added to AM. Contact between lymphocytes and AM reduced inhibitory C/EBPbeta, activated NF-kappaB, and enhanced HIV-1 replication. If contact between lymphocytes and macrophages was prevented, inhibitory C/EBPbeta expression was maintained and the HIV-1 long terminal repeat (LTR) was not maximally stimulated although NF-kappaB was activated. Antibodies that cross-linked macrophage expressed B-7, and vascular cell adhesion molecule and CD40 were used to mimic lymphocyte contact. All three cross-linking antibodies were required to abolish inhibitory C/EBPbeta expression. However, the HIV-1 LTR was not maximally stimulated and NF-kappaB was not activated. Maximal HIV-1-LTR stimulation required both lymphocyte-derived soluble factors, and crosslinking of macrophage expressed costimulatory molecules. High level HIV-1-LTR stimulation was also achieved when IL-1beta, IL-6, and TNF-beta were added to macrophages with crosslinked costimulatory molecules. Contact between activated lymphocytes and macrophages is necessary to down-regulate inhibitory C/EBPbeta, thereby derepressing the HIV-1 LTR. Lymphocyte-derived cytokines activate NF-kappaB, further enhancing the HIV-1 LTR.

DOI： 10.1084/jem.20011614

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Chronic obstructive pulmonary disease (COPD) is due to interactions between cigarette smoke exposure and other risk factors. Genetic variations of human beta-defensin-1 (hBD-1), an endogenous antimicrobial peptide in the airway, were investigated in 60 patients and 213 healthy volunteers by single-strand conformation and restriction fragment length polymorphism analysis and DNA sequencing. Four nucleotide variations in the 5' and 3' untranslated regions and two nonsynonymous substitutions in the coding region were identified. Of these, a newly found Ile38 variant was observed in 15.0% of patients but only in 2.8% of healthy individuals and was significantly associated with the disease (OR = 6.1, 95% confidence intervals 2.0-18.3, P=0.0012). More than 80% of those with Ile38 experienced sputum production for more than 3 months during the follow-up period. Genetic variations in hBD-1 may define a high-risk subgroup of COPD where the component of chronic bronchitis is predominant. (C) 2002 Elsevier Science (USA).

DOI： 10.1006/bbrc.2002.6395

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

We used a denaturing gradient gel electrophoresis (DGGE) procedure with 40-nucleotide guanine- and cytosine-rich sequences in the polymerase chain reaction (PCR) and sequencing analysis to analyze the T cell antigen receptor (TCR)-Vgamma gene repertoire of infiltrating T lymphocytes in pulmonary lymphoproliferative disorders. Six of 15 low-grade mucosa-associated lymphoid tissue (MALT) lymphomas and 8 of 15 cases of lymphocytic interstitial pneumonia (LIP) showed some oligoclonal bands for TCR-Vgamma genes on DGGE. Sequencing analysis demonstrated plural oligoclonal TCR-Vgamma clones among the oligoclonal PCR products on DGGE, leading to the conclusion that conventional antigen-specific oligoclonal expansions may play some role in the pathogenesis of pulmonary lymphoproliferative disorders. The frequency of oligoclonal, infiltrating T cell expansions in human immunodeficiency virus (HIV)-related LIP (100%) was significantly higher than in low-grade pulmonary MALT lymphomas (40%) or,in HIV-negative LIP (30%). Because recent evidence demonstrates that the V3 loop in the proviral amino acid sequences of mononuclear cells from bronchoalveolar lavage is more homogeneous than those from peripheral blood, this homogeneity might result in oligoclonal expansions of infiltrating T lymphocytes as a consequence of ongoing reactions against lung-specific viral strains.

DOI： 10.1164/ajrccm.165.2.2101141

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Idiopathic pulmonary alveolar proteinosis (PAP) has recently been recognised as a disease of impaired alveolar macrophage function caused by neutralising anti-granulocyte-macrophage colony-stimulating (anti-GM-CSF) autoantibodies. Subcutaneous recombinant human GM-CSF is a novel treatment for PAP, but its mechanism of action is unclear. Methods: Clinical, functional, and bronchoalveolar lavage (BAL) findings were prospectively evaluated in a patient with PAP treated with daily subcutaneous GM-CSF 8 μg/kg for 12 weeks. Results: Treatment resulted in improvements in dyspnoea, lung function, and peak cycle ergometry performance. In serum and BAL fluid the titre of anti-GM-CSF autoantibodies was raised at baseline and markedly reduced on treatment. At baseline the BAL fluid cellular profile showed a decrease in the absolute number and the percentage of macrophages (50%) and an increase in lymphocytes (45%), predominantly CD4+. This cellular distribution remained unchanged after 6 and 12 weeks of treatment while macrophages became morphologically normal and functionally improved. Extracellular proteinaceous material completely disappeared. Conclusions: Clinically successful treatment of PAP with GM-CSF was associated with a profound reduction in GM-CSF neutralising autoantibodies, improvement in alveolar macrophage morphology and function, but persistent BAL lymphocytosis.

DOI： 10.1136/thorax.57.3.277

Scopus

PubMed

researchmap

記述言語：日本語   出版者・発行元：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.24.5_416_1

CiNii Article

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

Alveolar proteinosis (AP) is characterized by excessive surfactant accumulation, and most cases are of unknown etiology. Standard therapy for AP is whole-lung lavage, which may not correct the underlying defect. Because the hematopoietic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is required for normal surfactant homeostasis, we evaluated the therapeutic activity of CM-CSF in patients with idiopathic AP. Fourteen patients received 5 mug/kg/d CM-CSF for 6 to 12 wk with serial monitoring of the alveolar-arterial oxygen gradient ([A-a]Do(2)), diffusing capacity of carbon monoxide, computed tomographic scans, and exercise testing. Patients not responding to 5 mug/kg/d CM-CSF underwent stepwise dose escalation, and responding patients were retreated at disease recurrence. Stored pretreatment sera were assayed for CM-CSF-neutralizing autoantibodies. According to prospective criteria, five of 14 patients responded to 5 mug/kg/d GM-CSF, and one of four patients responded after dose escalation (20 mug/kg/d). The overall response rate was 43% (mean improvement in [A-a]Do(2) = 23.2 mm Hg). Responses lasted a median of 39 wk, and were reproducible with retreatment. CM-CSF was well-tolerated, with no late toxicity seen. The only treatment-related factor predictive of response was CM-CSF-induced eosinophilia (p = 0.01). Each of 12 patients tested had GM-CSF-neutralizing autoantibodies present in pretreatment serum. We conclude that GM-CSF has therapeutic activity in idiopathic AP, providing a potential alternative to whole-lung lavage.

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

The two-step polymerase chain reaction (PCE) and sequencing analysis was used to analyze the immunoglobulin heavy chain variable (Ig V-H) genes of open-chest biopsy or autopsy samples from five patients with Epstein-Barr virus-negative human immunodeficiency virus (HIV)-related lymphoid interstitial pneumonia (LIP), and the results were compared with those for Ig V-H genes from five HIV-negative LIP patients. The findings of this study are consistent with the different immunological situations of HIV-related and HIV-negative LIP. (a) The Ig V(H)3 subgroup was underexpressed in three of five cases of HIV-related LIP. In contrast, none of the HIV-negative cases showed this abnormality. Because the Ig V(H)3 subgroup encodes the largest portion of Ig V-H genes, a depletion of B cells expressing Ig V(H)3 genes reflects a major alteration in the B-cell compartment (b) All HIV-related LIP cases demonstrated two or three oligoclonal populations. HIV-negative cases showed minor monoclonal or polyclonal populations, but not oligoclonal ones. These oligoclonal populations suggest the coexistence of several occult clonal B-cell populations in HIV-related LIP. (c) Some oligoclonal clones in HIV-related LIP showed mutated framework regions not demonstrated in HIV-negative clones. This degree of variation exceeds the usual mutation rate for frameworks, suggesting a role for framework residues in antigen binding. (d) The frequency of D-D fusions of minor oligoclonal clones (HIV-related LIP) is higher than that of minor monoclonal clones (HIV-negative LIP). Such D-D fusions may enhance the probability of expression of antibodies capable of binding HIV glycoproteins.

Web of Science

researchmap

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Scopus

PubMed

researchmap

記述言語：日本語   出版者・発行元：Japanese Leprosy Association  

HIV-1 infection is a major cause of worldwide epidemic of tuberculosis. HIV-1 infection, even in its early stages, markedly reduces effective immune response to M. tuberculosis. In Japan, the cumulative number of the patients reported is 131 by the end of 1999 with 10 to 20 annual new cases. Most of Japanese cases are advanced AIDS patients with low CD4 number less than 100/ml. The peak of Japanese patient age is 40 to 60 years old, whereas that of foreigners is 20-30 years old, suggesting that most Japanese cases are recurrent tuberculosis. There is increasing clinical evidence that coinfection with M. tuberculosis accelerates progression of AIDS. We found that, in vivo, HIV-1 load and mutation increase in involved lung segments in patients with pulmonary tuberculosis. The promotion of HIV-1 production is not only due to activated translocation of a nuclear factor, NF-kB, but also due to reduced inhibitory factor, C/EBPb 16 kD which binds to HIV LTR and represses the transcription of HIV-1..

DOI： 10.5025/hansen.69.87

CiNii Article

CiNii Books

researchmap

その他リンク： http://search.jamas.or.jp/link/ui/2001000064

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japan Lung Cancer Society  

Objective: To analyze the mechanisms responsible for the increasing incidence of lung cancer in the fibrotic lung. Methods: Platelet-derived growth factor (PDGF)-B, PDGF-receptor-β, proliferating cell nuclear antigen (PCNA), c-erbB-2, c-myc (9E10,6E10), p53, p21 and p27 were evaluated immunohistochemically in lung tissues obtained from 12 patients with lung cancer associated with idiopathic interstitial pneumonia (IIP), 5 patients with acute exacerbation of IIP, 6 patients with interstitial pneumonia associated with collagen vascular diseases (IP-CVD), 5 patients with primary lung cancer and 5 normal controls. Additionally, the messenger ribonucleic acids (mRNAs) for PDGF-B were investigated by in situ hybridization. Results: PDGF-B, PDGF-receptor-β, PDGF-BmRNA, PCNA, c-erbB-2, 9E10, 6E10, p53, p21 and p27 stained positively in metaplastic cells or alveolar type II cells in lung tissues in patients with early-active stage IIP, IP-CVD and primary lung cancer but not in cases with late-inactive stage IIP or in normal controls. The expression rate of p53 and p21 correlated closely in IIP and IP-CVD but not in primary lung cancer. Conclusions: These results suggest that metaplastic cells or alveolar type II cells frequently observed in the active region of fibrotic lung tissues may have the potential to undergo malignant transformation, leading to lung cancer.

DOI： 10.2482/haigan.40.725

Scopus

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1086/302786

CiNii Article

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ROCKEFELLER UNIV PRESS  

Idiopathic pulmonary alveolar proteinosis (I-PAP) is a rare disease of unknown etiology in which the alveoli fill with lipoproteinaceous material. We report here that I-PAP is an autoimmune disease with neutralizing antibody of immunoglobulin G isotype against granulocyte/macrophage colony-stimulating factor (GM-CSF). The antibody was found to be present in all specimens of bronchoalveolar lavage fluid obtained from 11 I-PAP patients but not in samples from 2 secondary PAP patients, 53 normal subjects, and 14 patients with other lung diseases. It specifically bound GM-CSF and neutralized bioactivity of the cytokine in vitro. The antibody was also found in sera from all I-PAP patients examined but not in sera from a secondary PAP patient or normal subjects, indicating that it exists systemically in I-PAP patients. As lack of GM-CSF signaling causes PAP in congenital cases and PAP-like disease in murine models, our findings strongly suggest that neutralization of GM-CSF bioactivity by the antibody causes dysfunction of alveolar macrophages, which results in reduced surfactant clearance.

Web of Science

researchmap

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

The bacteria isolated from the patients with lower respiratory tract infections were collected by institutions located throughout Japan, since 1981. Ikemoto et al. have been investigating susceptibilities of these isolates to various antibacterial agents and antibiotics, and analyzed some characteristics of the patients and isolates from them each year. Results obtained from these investigations are discussed. In these 17 institutions around the entire Japan, 512 strains of presumably etiological bacteria were isolated mainly from the sputa of 440 patients with lower respiratory tract infections during the period from October in 1997 to September in 1998. MICs of various antibacterial agents and antibiotics were determined against 100 strains of Staphylococcus aureus, 81 strains of Streptococcus pneumoniae, 85 strains of Haemophilus influenzae. 71 strains of Pseudomonas aeruginosa (non-mucoid strains), 27 strains of Pseudomonas aeruginosa (mucoid strains), 33 strains of Moraxella subgenus Branhamella catarrhalis, 17 strains of Klebsiella pneumoniae etc., and the susceptibilities of these strains were assessed except for those strains that died during transportation. S. aureus strains for which MICs of oxacillin (MPIPC) were higher than 4 micrograms/ml (methicillin-resistant S. aureus: MRSA) accounted for 55.0%. The frequency of the drug resistant bacteria decreased comparing to the previous year's 67.3%. Arbekacin (ABK) and vancomycin (VCM) showed the most potent activities against MRSA. Imipenem (IPM) and panipenem (PAPM) of carbapenems showed the most potent activities with MIC80S of 0.063 microgram/ml against S. pneumoniae. The frequency of penicillin (PC)-intermediate S. pneumoniae (PISP)+PC-resistant S. pneumoniae (PRSP) had decreased gradually, that is, in 1995 the frequency of it was 40.3%, but that was 30.9% in 1997. Against H. influenzae and M.(B.) catarrhalis, all the drugs showed good activities. But the sensitive strains of them against ceftazidime (CAZ) had decreased in 1997, compared those in 1995 and 1996. Meropenem (MEPM), IPM and tobramycin (TOB) showed the most potent activity against P. aeruginosa (mucoid strains). And TOB and ciprofloxacin (CPFX) showed the most potent activities against P. aeruginosa (non-mucoid strains). All drugs except ampicillin (ABPC) were more active against K. pneumoniae in 1997 than that in 1996. Also, we investigated year to year changes in the characteristics of patients, their respiratory infectious diseases, and the etiology. The examination of age distribution indicated that the proportion of patients with ages over 70 years was 45.5% of all the patients showing a slight increase year by year. About the proportion of diagnosed diseases, not so particular changes were recognized as follows: Bacterial pneumonia and chronic bronchitis were the most frequent with 33.6% and 29.1%, respectively. Number of strains isolated from patients before administration of antibiotics were more than those after administration of them in chronic bronchitis, but these had reversed in bacterial pneumonia. The tendency in bacterial pneumonia had been acknowledged since 1995. The increase of S. aureus and P. aeruginosa (both mucoid and non-mucoid strains) isolated after administration of antibiotics, has suggested the decrease of the susceptibility of these strains against antibiotics. Administration of antibiotics has changed the results of the frequency of isolation of bacterial species. Bacterial isolations before administration of antibiotics were as follows: S. pneumoniae 24.5%, H. influenzae 21.4%, S. aureus 18.4% and P. aeruginosa 12.2%. The frequencies of S. aureus decreased after antibiotics administration over 15 days, but the frequencies of P. aeruginosa was not affected. The frequencies of P. aeruginosa was 47.8% after administration over 15 days. From patients administered antibiotics of penicillins and cephems. S. aureus was mainly detected with 31.7-58.3%, and from patients administere

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

After allogeneic bone marrow transplantation (allo-BMT), recipient alveolar macrophages (AM) are gradually replaced by AM of the donor origin. An influx of mononuclear phagocytes of donor origin to the lung is responsible for the repopulation, but the detailed kinetics remain unclear. We therefore studied 24 BMT recipients who underwent bronchoalveolar lavage (BAL) from 24 to 83 days after BMT. AM cell number, size
morphology, proliferating ability, and genotype of AM were measured. Before day 50, the number and size of AM in BAL fluid were similar to those of normal nonsmokers. However, after day 50, the mean number of AM increased threefold and the mean cell size decreased due to the increase of small AM. These small cells are presumably of donor origin based on DNA fingerprinting analysis and based on fluorescence in situ hybridization for the Y chromosome in a sex- mismatched case. Immunohistochemistry and cell cycle analysis demonstrated that the increase in AM number coincided with a remarkable increase of AM expressing proliferating cell nuclear antigen, suggesting that small AM are proliferating. This is the first report representing that augmented proliferation of donor AM in situ may contribute to the reconstitution of AM population after BMT.

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Mice deficient in granulocyte-macrophage colony stimulating factor (GM-CSF) develop pulmonary alveolar proteinosis (PAP). We found that bronchoalveolar lavage fluid (BALF) from 11 patients with idiopathic pulmonary alveolar proteinosis (IPAP) suppressed the growth of peripheral blood monocytes and TF-1 cells, a cell line dependent on either GM-CSF or interleukin-3 (IL-3), The inhibitory effect of PAP-BALF occurred only when TF-1 cells were cultured with GM-CSF but not when cultured with IL-3, suggesting that PAP-BALF contains a factor that specifically interferes with GM-CSF function, I-125-GM-CSF binding to TF-1 cells was prevented in the presence of BALF from IPAP patients, Furthermore, crosslinking of I-125-GM-CSF to IPAP-BALF produced two major bands on SDS-PAGE; these bands were not observed in normal BALF. These data suggest that IPAP is caused by expression of binding factor(s) which inhibit GM-CSF function in the lung. (C) 1999 Federation of European Biochemical Societies.

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We have previously observed that HIV-1 replication is suppressed in uninflamed lung and increased during tuberculosis. In vitro THP-1 cell- derived macrophages inhibited HIV-1 replication after infection with Mycobacterium tuberculosis. Suppression of HIV-1 replication was associated with inhibition of the HIV-1 long terminal repeat (LTR) and induction of ISGF-3, a type I interferon (IFN)-specific transcription factor. Repression of the HIV-1 LTR required intact CCAAT/enhancer binding protein (C/EBP) sites. THP-1 cell-derived macrophages infected with M. tuberculosis, lipopolysaccharide, or IFN-β induced the 16-kD inhibitory C/EBPβ isoform and coincidentally repressed HIV-1 LTR transcription. C/EBPβ was the predominant C/EBP family member produced in THP-1 macrophages during HIV-1 LTR repression. In vivo, alveolar macrophages from uninflamed lung strongly expressed inhibitory 16-kD C/EBPβ, but pulmonary tuberculosis abolished inhibitory C/EBPβ expression and induced a novel C/EBP DNA binding protein. Therefore, in vitro, proinflammatory stimulation produces an IFN response inhibiting viral replication by induction of a C/EBPβ transcriptional repressor. THP-1 cell-derived macrophages stimulated with type I IFN are similar to alveolar macrophages in the uninflamed lung in vivo. In contrast, the cellular immune response in active pulmonary tuberculosis disrupts this innate immunity, switching C/EBP expression and allowing high level vital replication.

DOI： 10.1084/jem.188.7.1255

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Society of Internal Medicine  

We prospectively examined the survival rate of 67 chronic obstructive pulmonary disease (COPD) and 74 late sequelae of pulmonary tuberculosis (TB seq) patients to clarify whether nocturnal oxy hemoglobin desaturation (NOD) could be one of the independent factors determining their mortality. The sleep monitoring of arterial oxygen saturation (SpO2) and pulmonary function tests were assessed in all patients at the time of registration. Forty % of COPD and 24% of TB seq died as the direct result of deterioration of chronic respiratory failure during the 7-year observation period. Cox's proportional hazards analysis showed that NOD was an independent prognostic factor in both groups, and this was especially prominent when evaluated in terms of sleep lowest SpO2 in COPD and 85% desaturation time in TB seq. No significant prognostic factor was observed among age, vital capacity percent predicted (%VC), forced expiratory volume in one second (FEV1.0%) and partial pressure of carbon dioxide (PaCO2). We conclude that the degree of NOD can affect mortality in COPD and TB seq.

DOI： 10.2169/internalmedicine.37.354

Scopus

PubMed

researchmap

CiNii Article

CiNii Books

researchmap

記述言語：日本語   出版者・発行元：The Japanese Society of Internal Medicine  

後天性免疫不全症候群(AIDS)の流行に伴ない,合併する結核感染の増加が問題となっている.進行が速いばかりでなく,治療後も日和見感染の頻度が増加し,予後を悪化させることが指摘されている.また,肺外結核が多く,症状が非特異的で, X線像も非定型的であるため,見逃がされやすい.喀痰からの菌の検出率が低く,ツベルクリン反応もエイズの進行とともに陰性化するという問題がある.治療は,感受性菌であれば通常の化学療法によく反応するが,耐性菌の合併も増加しているので注意を要する.ハイリスクグループにはINHによる予防が勧められている.

DOI： 10.2169/naika.85.129

CiNii Article

CiNii Books

researchmap

その他リンク： http://search.jamas.or.jp/link/ui/1996142971

担当区分：筆頭著者  

researchmap

CiNii Article

researchmap

記述言語：英語  

DOI： 10.1006/clin.1995.1032

Web of Science

researchmap

その他リンク： http://orcid.org/0000-0003-4843-1427

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Thoracic Society  

This study investigated the relationship between the clinical features of sarcoidosis and the level of peripheral blood gamma-delta (γδ) T cells. Both the mean percentage of T cells and the mean cell number of γδ T cells in the peripheral blood were significantly higher in patients with clinically active sarcoidosis than in patients with inactive sarcoidosis or active tuberculosis and in normal subjects (active sarcoidosis: 18.9 ± 17.2%, 142 ± 130.4 cells/μl, n = 29
inactive sarcoidosis: 7.0 ± 3.7%, 48.7 ± 35.0 cells/μl, n = 16
active tuberculosis: 4.3 ± 3.2%, 47.9 ± 36.6 cells/μl, n = 19
control subjects: 5.0 ± 1.9%, 77.6 ± 37.7 cells/μl, n = 12). γδ T cells were significantly elevated in patients with sarcoidosis for 2 yr or more or those with Stage III radiographs. The level of γδ T cells, however, showed no correlation to the serum angiotensin-converting enzyme, a marker of active granuloma formation. γδ T cells were scarcely seen in bronchoalveolar lavages and in biopsy specimens, suggesting that these cells did not increase at the sites of inflammation. These findings suggest that increased levels of γδ T cells in the peripheral blood occur in active, long-term sarcoidosis, but that they are not directly related to granuloma formation.

DOI： 10.1164/ajrccm.149.4.8143064

Scopus

PubMed

researchmap

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

To elucidate the involvement of human γδ T cell receptor (TcR)+ cells in mycobacterial infection, we examined the kinetics of these cells in skin lesions of human lepromin reaction. The majority of CD3+ cells two days after induction of the lepromin reaction were αβ TcR+, while γδ TcR+ cells accounted for only 4.4±1.4% of the CD3+ cells. On day 21, the incidence of γδ TcR+ cells was greater (16.0±2.1%), although αβ TcR+ cells remained the predominant population. These kinetics of αβ TcR+ cells and γδ TcR+ cells contradict the 'early response, self-surveillance' hypothesis for γδ TcR+ cells in mice. Most of the γδ TcR+ cells in this study of the lepromin reaction were Vδ1- Vδ2+ Vδ9+, and some of them proliferated in the skin lesions, suggesting that γδ TcR+ cells in the lesions may respond to mycobacterial antigens and may play an active part in the lepromin reaction. However, these γδ TcR+ cells were not correlated with granuloma formation, the size of necrotic areas, mycobacterial content, or the incidence of CD4+ cells and CD8+ cells. © 1993.

DOI： 10.1016/0165-2478(93)90145-R

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: There have been many reports that γδ T-cell receptor (TCR)+ cells respond to mycobacterial antigens in vitro, but there is little available information on human γδ TCR+ cells in clinical conditions. Objective: Our purpose was to investigate the distribution and involvement of human γδ TCR+ cells in granulomatous skin lesions. Methods: The incidence and V-region gene expression of human γδ TCR+ cells was examined in granulomatous skin diseases, including cutaneous tuberculosis and leprosy, by immunohistochemical procedures. Results: γδ TCR+ cells in the dermis were increased in most patients with borderline lepromatous leprosy, and they were less frequently found in lepromatous leprosy and erythema nodosum leprosum. Other granulornatous skin lesions, including sarcoidosis, contained only a few γδ TCR+ cells. The γδ TCR+ cells that were found to be increased in this study were mostly δ TCS1-, BB3+, Tiγ A+ (Vδ1-, Vδ2+, Vγ9+). Conclusion: The γδ TCR+ cells in human granulomatous skin lesions may respond to some mycobacterial antigens, but they do not appear to be directly involved in granuloma formation. © 1993, American Academy of Dermatology, Inc.. All rights reserved.

DOI： 10.1016/0190-9622(93)70007-G

Scopus

PubMed

researchmap

記述言語：日本語   出版者・発行元：The Japan Society for Clinical Immunology  

DOI： 10.2177/jsci.15.669

CiNii Article

researchmap

その他リンク： http://search.jamas.or.jp/link/ui/1993205103

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The effect of human lung conditioned medium (HLCM) on the DNA synthesis in cultured human alveolar macrophages (HAM) was evaluated. The medium from human lung cultured for 3 days (3d-HLCM) promoted the DNA synthesis as well as the recombinant human GM-CSF does. On the other hand, that cultured for six days (6d-HLCM) did not promote the DNA synthesis but strongly suppressed GM-CSF induced DNA synthesis in HAM. This growth inhibitory effect was also observed when several macrophage like cell lines were cultured with 6d-HLCM. Partial purification of an inhibitory factor on gel permeation HPLC revealed two distinct peaks of activity with molecular weights of 38 kd and 110 kd. © 1991 Academic Press, Inc.

DOI： 10.1016/S0006-291X(05)81324-5

Scopus

PubMed

researchmap

researchmap

researchmap

記述言語：日本語   出版者・発行元：Japan Society of Sarcoidosis and other Granulomatous Disorders  

DOI： 10.14830/jssog1987.10.148

CiNii Article

researchmap

researchmap

DOI： 10.1097/00004728-198907000-00033

CiNii Article

CiNii Books

researchmap

researchmap

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：科学評論社  

CiNii Article

CiNii Books

researchmap

記述言語：日本語   出版者・発行元：(一社)日本輸血・細胞治療学会  

生後4ヵ月未満児は得られる採血量が少ないことから、自動輸血検査装置や試験管法では不規則抗体検査が困難である。このため、当院では検体量が試験管法の約1/4と少量の検体で検査可能なMicro Typing Systemを採用している。2007年1月から2016年12月までの10年間においてMicro Typing Systemでは不規則抗体検査依頼のあった生後4ヵ月未満児554件中、552件(99.6%)で検査可能であった。症例の内訳では55.4%が先天性心疾患の症例であった。また、検査可能であった552件中、不規則抗体が16件(2.9%)で陽性判定であった。そのうちの14件は母親からの移行抗体、1件は移行抗体が疑われた抗E、1件は自然抗体と考えられるIgM型の抗Mであった。さらに実際に358件に赤血球輸血が実施され、その内230件(64.2%)に輸血後の不規則抗体検査が行われたが、輸血後に生後4ヵ月未満児が不規則抗体を産生した症例は認められなかった。ほぼ全例に不規則抗体スクリーニング検査を可能とするMicro Typing Systemは乳児への輸血療法の安全性確保の観点において有用である。(著者抄録)

CiNii Article

researchmap

記述言語：日本語  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語  

researchmap

記述言語：日本語  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本輸血・細胞治療学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本輸血・細胞治療学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本輸血・細胞治療学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本輸血・細胞治療学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語   出版者・発行元：先端医学社  

CiNii Article

CiNii Books

researchmap

記述言語：日本語  

J-GLOBAL

researchmap

記述言語：日本語  

J-GLOBAL

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY  

Web of Science

researchmap

記述言語：日本語  

J-GLOBAL

researchmap

記述言語：日本語  

J-GLOBAL

researchmap

記述言語：日本語  

J-GLOBAL

researchmap

記述言語：日本語   出版者・発行元：(一社)日本輸血・細胞治療学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

researchmap

記述言語：日本語  

J-GLOBAL

researchmap

記述言語：日本語  

J-GLOBAL

researchmap

記述言語：日本語  

J-GLOBAL

researchmap

記述言語：日本語  

J-GLOBAL

researchmap

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

Web of Science

researchmap

記述言語：日本語  

J-GLOBAL

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

Web of Science

researchmap

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

Web of Science