Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMEDICAL RESEARCH PRESS LTD  

Antigen-presenting cells express pattern recognition receptors (PRRs), which sense pathogen-associated molecular patterns from microorganisms and lead to the induction of inflammatory responses. C-type lectin receptors (CLRs), the representative PRRs, bind to microbial polysaccharides, among which Dectin-2 and Mincle recognize mannose-containing polysaccharides. Because influenza virus (IFV) hemagglutinin (HA) is rich in mannose polysaccharides, Dectin-2 or Mincle may contribute to the recognition of HA. In this study, we addressed the possible involvement of Dectin-2 and Mincle in the viral recognition and the initiation of cytokine production. Interleukin (IL)-12p40 and IL-6 production by bone marrow-derived dendritic cells (BM-DCs) upon stimulation with HA was significantly reduced in Dectin-2 knockout (KO) mice compared to wild-type (WT) mice whereas there was no difference between WT mice and Mincle KO mice. BM-DCs that were treated with Syk inhibitor resulted in a significant reduction of cytokine production upon stimulation with HA. The treatment of BM-DCs with methyl-alpha-D-mannopyranoside (ManP) also led to a significant reduction in cytokine production by BM-DCs that were stimulated with HA, except for the A/H1N1pdm09 subtype. IL-12p40 and IL-6 synthesis by BM-DCs was completely diminished upon stimulation with HA treated with concanavalin A (ConA)-bound sepharose beads. Finally, GFP expression was detected in reporter cells that were transfected with the Dectin-2 gene, but not with the Mincle gene, when stimulated with HA derived from the A/H3N2 subtype. These data suggested that Dectin-2 may be a key molecule as the sensor for IFV to initiate the immune response and regulate the pathogenesis of IFV infection.

DOI： 10.2220/biomedres.42.53

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：DOVE MEDICAL PRESS LTD  

Purpose: Although chronic low back pain (CLBP) has profound effects on patients, society, and economy, its causes are difficult to identify. Psychogenic effects or social stress is known to affect CLBP; hence, investigation of its underlying causes requires a multifactorial approach. We determined the factors associated with CLBP by using an Internet-based survey. To prevent CLBP, we need to understand its cause and background.Patients and methods: A total of 1000 participants either with (+) or without (-) CLBP answered the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ), which assesses five domains of CLBP: low back pain, lumbar function, walking ability, social life function and mental health. We also administered a new questionnaire for participants, that comprised five different domains: Body, Lifestyle, Emotion, Diet, and Social. To evaluate psychogenic effects on CLBP, we added two original factors, namely outshout and HIE, which have not yet been studied. HIE is a traditional concept (sense) of "feeling cold" or "chilly." All participants completed both questionnaires.Results: Multivariate logistic regression analysis extracted four factors (sleep, room temperature, outshout, and HIE) that were associated with CLBP. The mental health domain was assessed using the JOABPEQ for each of these factors. The factors outshout and HIE differed between CLBP (+) and CLBP (-) patients. CLBP (-) participants also showed a difference in Sleep and HIE factors.Conclusion: Among psychogenic effects, Emotion was common to all the four extracted factors. There was no common physical divisor. Therefore, we hypothesized that acute low back pain might develop into CLBP in the presence of psychological stress or other emotional factors such as outshout or HIE. Hence, we need to consider both physical and psychogenic effects in the prevention and treatment of CLBP. Furthermore, appropriate evaluation and treatment of psychological stress may be effective in reducing CLBP.

DOI： 10.2147/JPR.S223190

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DOI： 10.4236/health.2018.105046

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Other Link： http://file.scirp.org/xml/84784.xml

Publishing type：Research paper (scientific journal)   Publisher：Scientific Research Publishing, Inc.  

DOI： 10.4236/health.2017.913130

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Publishing type：Research paper (scientific journal)   Publisher：Scientific Research Publishing, Inc.  

DOI： 10.4236/health.2017.910098

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMJ PUBLISHING GROUP  

Objective To study the effects of repetitive manual acupuncture treatment on acute stress in mice and to explore its impact on the immune system.
Methods Thirty-six mice were randomly allocated to one of four groups: control, acupuncture, stress and acupuncture+stress (n=9 each). Mice in the two acupuncture groups were given daily acupuncture treatment superficially (to skin depth) at CV6, CV12 and bilateral ST25, LR14, GB20, GB21, BL10, BL11, BL13, BL14, BL19, BL23 and BL25 for 7 days. On the eighth day mice in the stress and acupuncture+stress groups were exposed to acute stress for 2 h by confinement in a 50 mL centrifuge tube. Body temperature, blood glucose, the number and subpopulation ratios of leucocytes in the liver, spleen and thymus, natural killer (NK) cell percentage cytotoxicity and serum corticosterone and interferon gamma IFN gamma were quantified.
Results Mice exposed to stress (irrespective of acupuncture treatment) exhibited hypothermia and hyperglycaemia. However, the increase in glucose level was mitigated by repetitive acupuncture treatment (p<0.05). Percentage cytotoxicity and the level of corticosterone were significantly increased after stress but were unaffected by acupuncture. IFN gamma levels did not differ between the groups. Hepatic innate immunity in the liver appeared to be stimulated by repetitive acupuncture treatment as proportions of extrathymic T cells, NK cells and NKT cells in the liver were greatest in the acupuncture+stress group and significantly increased relative to the control group.
Conclusions Repetitive manual acupuncture mitigated stress-induced hyperglycaemia and enhanced markers of innate immunity in the liver within the range of normal homoeostasis. As long as acupuncture stimuli were appropriately applied, they did not appear to be stressful to the mice.

DOI： 10.1136/acupmed-2014-010660

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DOI： 10.4236/health.2015.77094

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Other Link： http://file.scirp.org/xml/57742.xml

Publishing type：Research paper (scientific journal)   Publisher：Scientific Research Publishing, Inc.  

DOI： 10.4236/health.2015.75070

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Other Link： http://file.scirp.org/xml/56482.xml

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMEDICAL RESEARCH PRESS LTD  

The effect of repetitive mild hyperthermia on body temperature, the autonomic nervous system, and innate and adaptive immunity was investigated using a new hyperthermia treatment system, nanomist sauna (NMS). Six healthy volunteers participated and the concentration of catecholamines and cortisol, and the frequency and function of leukocytes in the peripheral blood were investigated before and after successive 7 days of hyperthermia treatment (20 min/day, 40 degrees C, 100% relative humidity). After treatment, the blood level of adrenaline and cortisol on the 7th day was decreased compared with the 1st day, indicating the suppression of the sympathetic nervous system activity. Moreover, the frequency of CD56(+)NK, CD56(+)NKT and B cells on the 7th day tended to be increased compared with the 1st day. The frequency of HLA-DR-positive NK and NKT cells and expression of HLA-DR on B and T cells increased. The cytotoxicity of NK cells and proliferative response of B cells were also elevated. The results indicate that repetitive mild hyperthermia treatment might suppress excessive sympathetic dominance and modify immunity. Additionally, because it can provide the same effects as conventional hyperthermia treatments with minimal burden to the body, NMS may be a novel patient- and elderly-friendly hyperthermia treatment for health promotion.

DOI： 10.2220/biomedres.36.135

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHURCHILL LIVINGSTONE  

Capillary vessel flow in the base of the fingernail can be observed by microscopy. This flow is switched off under some conditions, such as coldness, surprise, and anger and is switched on again under other conditions, such as warming, relaxation, and mild exercise. In other words, capillary vessels perform two functions: switching flow on and off. It is speculated that the switch-off function is necessary to direct energy production to the glycolysis pathway, while the switch-on function is necessary for the mitochondrial pathway. This is because glycolysis takes place under anaerobic conditions, while oxidative phosphorylation in the mitochondria proceeds under aerobic conditions in the body. To switch off circulation, the negative electric charges on the surface of erythrocytes and the capillary wall may be decreased by stimulation of the sympathetic nerves and secretion of steroid hormones. Negative charge usually acts as repulsive force between erythrocytes and between erythrocytes and the capillary wall. By decreasing the negative charge, erythrocytes can aggregate and also adhere to the capillary wall. These behaviors may be related to the capillary flow switch-off function. Here, it is emphasized that the capillary vessels possess not only a switch-on function but also a switch-off function for circulation. (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.mehy.2014.03.035

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Language：English   Publisher：Biomedical Research Press  

Although growing evidence suggests a major role for T cells in the pathogenesis of primary biliarycirrhosis (PBC), the roles of natural killer (NK) and natural killer T (NKT) cells, which predominatein the liver, in the pathogenesis of PBC remain unclear. We investigated the status ofNK and NKT cells in the liver and peripheral blood samples obtained from 11 patients with asymptomaticPBC diagnosed as stage I or II (early PBC) and 7 patients with symptomatic PBCwho underwent liver transplantation (advanced PBC) using flow cytometry and immunohistochemicalstaining. The proportions of NK and NKT cells were significantly decreased in the liver ofpatients with early PBC compared with normal donors. However, the proportion of CD56+ NKTcells was increased in the liver of patients with advanced PBC. Moreover, the proportion of activatedFas ligand (FasL)-positive NKT cells was significantly increased in the liver of patients withadvanced PBC compared with early PBC (P = 0.013). We also found increased expression of FasLon lymphocytes infiltrating around the injured bile duct in advanced PBC using immunohistochemicalstaining. Our results suggest that activated NKT cells may contribute to the biliary epithelialcell death resulting in the progression of PBC.

DOI： 10.2220/biomedres.35.161

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Other Link： http://search.jamas.or.jp/link/ui/2015032875

Language：English  

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Aim: To investigate the stress-induced apoptosis of natural killer (NK) cells and the changes in their killing activity in mouse livers. Methods: A restraint stress model was established in mice. Flow cytometry was employed to measure the percentage of NK cells and the changes in their absolute number in mouse liver. The cytotoxicity of hepatic and splenic NK cells was assessed against YAC-1 target cells via a 4 h 51Cr-release assay. Results: The restraint stress stimulation induced the apoptosis of NK cells in the liver and the spleen, which decreased the cell number. The number and percentage of NK cells in the spleen decreased. However, the number of NK cells in the liver decreased, whereas the percentage of NK cells was significantly increased. The apoptosis of NK cells increased gradually with prolonged stress time, and the macrophage-1 (Mac-1)+ NK cells were more susceptible to apoptosis than Mac-1- NK cells. Large numbers of Mac-1- NK cells in the liver, which are more resistant to stress-induced apoptosis, were observed than the Mac-1- NK cells in the spleen. The stress stimulation diminished the killing activity of NK cells in the spleen was significantly decreased, but the retention of numerous Mac-1- NK cells in the liver maintained the killing ability. Conclusion: Significant stress-induced apoptosis was observed among Mac-1+ NK cells, but not Mac-1- NK cells in the mouse liver. Stress stimulation markedly decreased the killing activity of NK cells in the spleen but remained unchanged in the liver. © 2013 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v19.i37.6258

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PubMed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: Liver cirrhotic patients are immunological compromised hosts. Preoperative status in cirrhotic patients affects postoperative infection complications. This study investigates the perioperative immunological changes in the differentiation by MELD score. Methodology: Fifteen patients underwent LDLT and were divided two groups, Group I (n=5, MELD score >= 20) and Group II (n=10, MELD score <20). Immunological status of cirrhotic patients was analyzed for Th1, Th2, Treg and Th17 by flow cytometry using monoclonal antibody CD3/CD19,CD4/8, FoxP3, IL-17, IFN-gamma and TNF-alpha. Results: T cell decreased and increased gradually following LDLT. The preoperative T cell count of MELD score 33 patients was very low. CD4 and CD8 T cells also decreased after LDLT. The preoperative CD8(+) T cell count of MELD score 33 patients was very low. Th17 decreased and recovered gradually in the all patients after LDLT. However Th17 of MELD score 33 did not recover. IFN-gamma-producing cells in naive T cells decreased after LDLT. Preoperatively those in the Group I was lower than those in the Group II. The population of Treg decreased in the Group I, however, it increased in the Group II on 7 days after LDLT. Conclusions: The patients with MELD score >20 showed a decrease of cytotoxic immunity with both diminution and delay of CD8+ T cells and Th17 helper T cells. The cytotoxic immunity of the patients with MELD score <20 was maintained and recovered in the early period after LDLT. The patients with MELD score >20 might be at high risk of infection after LDLT.

DOI： 10.5754/hge

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Objectives Residents who lost land and houses due to disasterous heavy rainfall-related events on July 13, 2004 and the Chuetsu Earthquake on October 23, 2004 were moved to emergency temporary housing. The change in life style due to living under such conditions is assumed to increase oxidative stress level. In this study, we investigated the oxidative stress level in elderly residents of emergency temporary housing, and analyzed its association with lifestyle and body composition following these disasters.
Methods A noninvasive oxidative stress marker, urinary 8-hydroxydeoxyguanosine (8-OHdG), and body composition were measured in 73 elderly residents of emergency temporary housing.
Results In the elderly female residents, the urinary 8-OHdG level tended to decrease with time after the disasters. 8-OHdG levels were slightly higher in females than males and significantly higher among those who exercised regularly compared to those who did not, particularly in females. A weak correlation was noted between the urinary 8-OHdG level and muscle ratio in females.
Conclusions The in vivo oxidative stress level in our study cohort of elderly residents of emergency temporary housing changed following the change in life style, but remained within the normal range. The increase in oxidative stress levels of elderly females was related to menopause. A decrease in estrogen levels due to menopause inhibits its antioxidant effects, which increases 8-OHdG levels. Although it is difficult to determine, a decrease in daily stressors over time following the disaster could be a cause of the decrease in oxidative stress levels. We suggest that the close evaluation of the stress level of disaster victims is desirable, in combination with evidence of antioxidative substances and the psychosocial influence of suffering as a consequence of the disaster.

DOI： 10.1007/s12199-012-0284-8

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.4236/health.2013.57147

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMEDICAL RESEARCH PRESS LTD  

Skin rubdown using a dry towel (SRDT) to scrub the whole body is a traditional therapy for health promotion. To investigate its mechanism, 24 healthy male volunteers were studied. Body temperature, pulse rate, red blood cells (RBCs), serum levels of catecholamines and cortisol, blood gases (PO2, sO(2), PCO2 and pH), lactate and glucose, and the ratio and number of white blood cells (WBCs) were assessed before and after SRDT. After SRDT, pulse rate and body temperature were increased. PO2, sO(2) and pH were also increased and there was no Rouleaux formation by RBCs. Lactate level tended to increase, whereas that of glucose did not. Adrenaline and noradrenaline levels increased, indicating sympathetic nerve (SN) dominance with increase in granulocytes. WBC number and ratio were divided into two groups according to granulocyte ratio (<= or < 60%) before SRDT: a normal group and a SN group. Only in the SN group did the granulocyte ratio decrease and the lymphocyte ratio and number increase after SRDT. It is suggested that SRDT is a mild aerobic, systemic exercise that might affect the immune system via the autonomic nervous system.

DOI： 10.2220/biomedres.33.243

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HUMANA PRESS INC  

Cumulative evidence has shown that extrathymic T cells can be autoreactive and that B-1 cells may produce autoantibodies. These T and B-1 cells, which form part of the innate immune system, tend to be activated simultaneously when conventional T and B cells are in a suppressive state, for example, when thymic atrophy occurs by stress or involution with aging. In other words, autoreactive T cells and autoantibody-producing B cells are different from thymus-derived T cells and bone marrow-derived B cells. Activated extrathymic T cells and B-1 cells are often observed in numerous autoimmune diseases, aging, malarial infection and chronic graft-versus-host disease. It is thought that the autoreactivity of extrathymic T cells and B-1 cells may be important for the elimination of "abnormal self" tissues or cells. However, over-activation of innate lymphocytes may be related to the onset of disease or self-tissue destruction. However, it must be emphasized that the autoreactivity of innate lymphocytes is not generated by failure of the thymic pathway of T-cell differentiation or the conventional pathway of B-2 cells.

DOI： 10.1007/s12026-012-8324-4

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Concanavalin A (Con A)-induced hepatitis is a mouse model of acute autoimmune hepatitis. The aim of this study was to investigate the role of hepatic dendritic cells (DC) in the immune modulation of tissue damage. Almost all hepatic DC were plasmacytoid DC (CD11c(+) I-Alow B220(+)); however, conventional DC were CD11c(+) I-Ahigh B220(-). At an early stage (3-6 h) after Con A administration, the number of DC in both the liver and spleen decreased, increasing thereafter (12-24 h) in parallel with hepatic failure. The hepatic CD11c(+) DC population contained many CD11b-cells, while the majority of splenic CD11c(+) DC were CD11b(+). After Con A administration, the proportion of I-A(+) and CD11b(+) cells within the CD11c(+) DC population tended to increase in the liver, but not in the spleen. Similarly, expression of the activation markers CD80, CD86 and CD40 by CD11c(+) DC increased in the liver, but not in the spleen. Next, adoptive transfer of DC isolated from the liver and spleen was performed 3 h after Con A administration to examine the immunomodulatory function of DC. Only hepatic DC had the ability to suppress hepatic failure. Analysis of cytokine production and subsequent identification of the effector cells showed that hepatic DC achieved this by suppressing the production of interleukin (IL)-12 and IL-2, rather than modulating effector cell function.

DOI： 10.1111/j.1365-2249.2011.04458.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMEDICAL RESEARCH PRESS LTD  

Balance between inflammatory and anti-inflammatory cytokines may be important in malaria presentation and outcome. To clarify cytokine interactions that produce pathology of malaria and control infection, C57BL/6 mice were infected with 10(4) parasitized RBCs from a non-lethal strain of Plasmodium yoelii. Kinetics was monitored showing the course of parasitemia, and cytokines were determined by RT-PCR from liver and spleen tissues. Inflammatory cytokines such as interferon-gamma (IFN gamma), interleukin (IL)-12, IL-6, tumor necrosis factor-alpha (TNF alpha) and anti-inflammatory cytokines, including IL-4 and IL-10, were investigated as key molecules that interact with immune cells in the activation of the immune responses. The production of IFN gamma mRNA was found to be higher on day 7 than on day 21 after infection, and IL-12 and IL-6 showed higher expression in the liver than in the spleen. Though TNF alpha was highly expressed on day 14 after infection and on day 21 in the liver, such expression was decreased on day 21 in the spleen. Anti-inflammatory cytokines showed high expression in both the liver and spleen. The results suggest that a relative balance between inflammatory and anti-inflammatory cytokines is crucial and that the increase of inflammatory cytokine levels during the acute phase of malaria may reflect an early and effective immune response. The counteraction effect of anti-inflammatory cytokines is thought to play a role in limiting progression from uncomplicated malaria to severe life-threatening complications.

DOI： 10.2220/biomedres.32.203

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DOI： 10.4236/health.2011.34042

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

To know the details of the mechanism on stress-associated responses, attention was first focused on body temperature and blood glucose after stress. Mice were exposed to restraint stress for 6 h. Under this condition, hypothermia (39 degrees C -> 33 degrees C) and hyperglycemia 11150 mg/dl -> 350 mg/dl) were induced. Reflecting a stress-associated response, an increase of serum corticosterone (200 ng/ml -> up to 600 ng/ml) was observed. It was examined whether an administration of glucocorticoid induced a similar response. An injection of hydrocortisone (5.0 and 10.0 mg/mouse) simultaneously induced hypothermia and hyperglycemia. The effect on immunoparameters by an injection of hydrocortisone was examined. Although immunosuppression was seen as thymic atrophy and a decrease in the proportion of B cells in the liver, extrathymic T cells and NKT cells were found to be stress-resistant lymphocyte populations, especially in the liver. HSP70 mRNA was indicated to increase in the adrenal glands in response to the hydrocortisone injection. At( these responses, including hypothermia, hyperglycemia and immunomodulation, induced by the hydrocortisone injection were suppressed by pre-administration of a glucocorticoid receptor antagonist (RU-486). These results suggest that glucocorticoid is one of the important mediators of the stress-associated responses. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.psyneuen.2009.04.021

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Language：English   Publisher：WILEY-BLACKWELL  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMEDICAL RESEARCH PRESS LTD  

The effect of acute stress oil the immune system was examined ill mice. Restraint stress decreased the number of lymphocytes in the liver, whereas the number of lymphocytes remained unchanged in the spleen and thymus. In the liver, the decrease in number appeared at 1.5 h and fell to a third of the control level at 3 h. The proportions of IL-2R beta(+)TD3(int) cells, NKT cells, CD44(+) T cells and B cells were changed in the liver. The absolute numbers of IL-2R beta(+)CD3(int) cells, NKT cells and CD3(+)CD44(+) cells remained constant ill the liver under the stress, while those of total T cells and NK cells decreased. The levels of hyaluronan (HA) in Various tissues and sera were then examined. The expression of hyaluronan binding protein (HABP) was found to increase in the skin, liver and kidney as shown by immunohistochemical staining. An increase of HA in sera due to stress was seen at 3 h. The present results Suggest that the activation of CD44(+) T cells and unconventional T cells (i.e., innate immunity) in the blood and the elevated levels of HA (ligand for CD44) in the tissues and blood are crucial responses to acute stress exposure.

DOI： 10.2220/biomedres.30.157

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMEDICAL RESEARCH PRESS LTD  

The effect of mild hyperthermia on venous blood pH was examined in 6 cancer patients. Mild hyperthermia was induced by continuation of a rectal temperature of 39.5 degrees C for 30 min. All 6 patients were diagnosed as suffering from advanced cancer with or without surgery and chemotherapy pretreatrnents. In Cases I to 5, but not Case 6, venous blood pH was alkalized up to pH 7.7 by this mild hyperthermia and the effect was reproduced depending on the application of hyperthermia. At this time, alkalized pH was accompanied by increased PO, and decreased PCO(2) in the blood. These patients showed good physical conditions and improved clinical data. On the other hand, hyperthermia could not be continued in Case 6 due to his worsened physical condition. The present data suggest that mild hyperthermia is a useful method to improve circulation failure, physical condition and clinical data.

DOI： 10.2220/biomedres.30.95

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Mice were exposed to starvation for 3 days. Body temperature and various parameters were examined. By starvation, body temperature, blood glucose and ACTH decreased, especially on days 2 and 3. The level of corticosterone increased at this time. On the other hand, the number of lymphocytes yielded by the liver, spleen and thymus decreased from day 1 to 3. The change of the distribution of lymphocyte subsets was unique because NK NKT and extrathymic T cells were stress-resistant in the liver. Conventional T and B cells were stress-sensitive. Reflecting the increased proportion of NK and NKT cells, NK and NKT activities were augmented. The increased proportion of NKT cells produced both IFN gamma and IL-4 (Th0-type profile). The proportion and some functions of granulocytes and macrophages increased on Day I after starvation. These results suggest that starvation has a potential to increase the functions of unconventional lymphocytes and myeloid cells. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.cellimm.2009.05.015

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Mice were exposed to restraint stress for 3 h. During this period, low body temperature (hypothermia, 39 degrees C -> less than 37 degrees C) and high blood glucose levels (hyperglycemia, 150 mg/dl -> up to 220 mg/dl) were simultaneously induced. Reflecting a stress-induced phenomenon, blood levels of catecholamines increased at that time. Administration of adrenaline (alpha-stimulus), but neither noradrenaline (alpha but less than adrenaline) nor isoproterenol (beta), induced a similar stress-induced pattern of body temperature and blood glucose variations. This a-adrenergic effect was confirmed using alpha- and beta-blockers in adrenaline-induced hypothermia and hyperglycemia. By applying this alpha-stimulus, the effect on immunoparameters was then investigated. Stress-resistant lymphocyte populations were found to be NK cells, extrathymic T cells and NKT cells, especially in the liver. Functional assays showed that both NK-cell cytotoxicity and NKT-cell cytotoxicity were augmented by alpha-stimulus. These results suggest that alpha-stimulus is one of the important factors in the stress-induced phenomenon and that it eventually produces hypothermia, hyperglycemia and innate-immunity activation seen during stress. (C) 2007 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.imlet.2007.09.010

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Authorship：Lead author   Language：English   Publisher：Biomedical Research Press  

Since high levels of hyperthermia induce immunosuppression to a certain extent (<I>i.e.</I>, granulocytosis and lymphocytopenia) in patients, we applied mild hyperthermia in volunteers using equipment enabling well-controlled hyperthermia. Restricted control of rectal temperature at 39.4 (± 0.2)°C for 30 min was conducted and various parameters of the body were examined. The most prominent change observed during exposure to hyperthermia was elevated levels of pH and PO<SUB>2</SUB> in the blood, even in the venous blood. A transient elevation of ACTH, cortisol and growth hormone in the blood was also seen during this time. In parallel with this phenomenon, the number of total lymphocytes and those of its subsets (especially CD57<SUP>+</SUP> or CD56<SUP>+</SUP> NK cells and NKT cells) increased. More interestingly, the proportion of HLA-DR (MHC class II antigens) increased in NK and NKT cells, and their intensity on the surface of CD20<SUP>+</SUP> B cells increased. These results suggest that mild hyperthermia is important for modulation of the functions of the circulatory, endocrine and immune systems.

DOI： 10.2220/biomedres.28.119

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Doctoral thesis   Publisher：新潟医学会  

Concanavalin A(Con A)投与により誘導される肝傷害はT細胞依存性であることは古くから知られている。しかし、肝臓には自然免疫を担うNK細胞やNKT細胞が他の臓器に比べて最も多く存在し、特異な免疫応答の場であることも明らかとなってきた。Con A肝炎モデルマウスにおいては、肝傷害のエフェクター細胞としてのT細胞、NKT細胞、Kupffer細胞、liver sinusoidal endothelial cells(LSEC)や好中球の役割、およびその機能亢進が報告されている。しかし、肝樹状細胞(DC)は肝移植におけるトレランス誘導に重要な役割を果たしていることが明らかとなり注目を浴びているが、Con A肝炎での動態は不明である。本研究では、正常マウスの肝臓より効率よくDC分画を採取する方法を確立すると共に、自己免疫性あるいは劇症肝炎モデルとして使われるCon A投与マウスの肝DCの性状と機能について解析した。その結果、正常の肝臓にはI-A-CD11clowのplasmacytoid(形質細胞様)DCが優位に存在し、その抗原提示能が低いことが明らかとなった。Con A肝炎では肝DCの総数が減少すると共に、I-A+CD11chigh CD205+のmyeloid系DCの割合が増加すること、I-A-CD11clow DC中の補助シグナル分子であるCD80とCD86の発現低下を認めた。ケモカインのmRNA発現については肝、および脾DCでCCL17が増強し、CpG刺激によるサイトカイン産生能については、MCP-1の増加、およびIL-10の低下が肝DCに特徴的であった。これらの解析から、肝傷害における病態形成への肝DCの役割の一端を明らかにできた。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2007&ichushi_jid=J00990&link_issn=&doc_id=20070511020005&doc_link_id=%2Fdg3nigta%2F2007%2F012101%2F005%2F0025-0037%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2007%2F012101%2F005%2F0025-0037%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/j.1365-2567.2007.02661.x

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DOI： 10.1007/BF02697370

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Mice were fed ad libitum with a normal diet (25% protein) or low-protein diets (0-12.5% protein) for a wk and then infected with a nonlethal or lethal strain of Plasmodium yoelii, that is, blood stage infection. The same diet was continued until recovery. Mice fed with a normal diet showed severe parasitemia during nonlethal infection, but survived the infection. They died within 2 wk in the case of lethal infection. However, all mice fed with low-protein diets survived without apparent parasitemia (there were small peaks of parasitemia) in cases of both nonlethal and lethal strains. These surviving mice were found to have acquired potent innate immunity, showing the expansion of NK1.1 -TCRint cells and the production of autoantibodies during malarial infection. Severe combined immunodeficiency (scid) mice, which lack TCRint cells as well as TCRhigh cells, did not survive after malarial infection of lethal strain of P. yoelii, even when low-protein diets were given. These results suggest that low-protein diets enhanced innate immunity and inversely decreased conventional immunity, and that these immunological deviations rendered mice resistant against malaria. The present outcome also reminds us of our experience in the field study of malaria, in which some inhabitants eventually avoided contracting malaria even after apparent malarial infection.

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DOI： 10.1111/j.1365-2567.2005.02273.x

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DOI： 10.1111/j.1365-3083.2006.01738.x

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Acute graft-versus-host disease (aGVHD) remains a major complication of allogeneic bone marrow transplantation, which is caused by donor T cells specific for host alloantigens. In a murine model, we found that donor T cells expressed a natural killer cell inhibitory receptor, CD94/NKG2A, during the course of aGVHD. Administration of an anti-NKG2A mAb markedly inhibited the expansion of donor T cells and ameliorated the aGVHD pathologies. These results suggested that the CD94/NKG2A inhibitory receptor expressed on host-reactive donor T cells can be a novel target for the amelioration of aGVHD.

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The human liver contains significant numbers of innate immune cells, such as natural killer (NK) cells and natural killer T (NKT) cells, which express both T-cell receptors and NK-cell receptors simultaneously. It has been suggested that the innate immune system plays a crucial role in the liver. In this report, the distribution of NK and NKT cells in the liver and peripheral blood of two patients with drug-induced fulminant hepatic failure (FHF) who had undergone living donor liver transplantation was examined. In both the liver and peripheral blood, the proportions of NK and NKT cells markedly decreased compared with those in healthy donors. It was also revealed that, unlike murine NKT cells, human CD56(+) T cells and CD57(+) T cells did not constitutively express CD28, which is one of the important costimulatory molecules on T cells. Additionally, the residual CD56(+) T cells and CD57(+) T cells in the patients expressed more CD28 than in controls. This result suggests that NKT cells might be more activated in FHF. Although the accumulation of further cases is required, it is suggested that both NK and NKT cells might be involved in hepatic injury in FHF.

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DOI： 10.1111/j.1440-1711.2005.01385.x

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DOI： 10.1111/j.1365-2567.2004.01961.x

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Language：English   Publisher：Biomedical Research Press  

This study focused on double-positive (DP) CD4⁺8⁺ cells in both the intestine and thymus. In normal mice, the proportion of DP cells in the intestine increased with aging, while that of DP cells in the thymus remained unchanged. When mice were exposed to restraint stress for 18 h, intestinal DP cells were resistant to restraint stress, while thymic DP cells were sensitive to such stress in terms of apoptotic properties. Intestinal intraepithelial lymphocytes (IEL) and thymocytes were then cultured and the number of living cells were analyzed. The number of DP cells in the thymus decreased prominently in <i>in vitro</i> culture. Interestingly, a similar phenomenon was found in intestinal DP cells in <i>in vitro</i> culture. When thymocytes were isolated from mice exposed to restraint stress, these DP cells were found to become sensitive to apoptosis in <i>in vitro</i> culture. Phenotypic characterization revealed that DP cells in the intestine were CD3⁺CD25⁻CD44⁺CD69⁺, while those in the thymus were CD3⁻CD25⁺CD44⁻CD69⁻. These results suggest that DP cells in the intestine were more mature than those in the thymus and that DP cells of IEL and thymus were generated as primitive T cells in phylogeny but later developed along independent pathways at each site.

DOI： 10.2220/biomedres.25.201

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Missing self which lacked the expression of MHC class I antigens was prepared in irradiated B6.Ly5.1 mice (H-2^b) which had undergone bone marrow transplantation (BMT) (depleted of T cells) of TAP-1 (−/−) (Ly5.2, H-2^b) mice. Donor cells (Ly5.2⁺) and recipient cells (Ly5.1⁺) were identified by Ly5 markers. For purposes of comparison, syngeneic (B6.Ly5.2 mice) BMT and allogeneic (BALB/c mice, H-2^d) BMT were also conducted. In the case of missing self cells, the ratio of expanding donor cells increased in the liver, spleen and bone marrow on days 14 and 21 after BMT. Such donor cells were mainly NK cells and NKT cells, especially in the liver. The interacting recipient lymphocytes were NKT cells at the early stage (day 7). However, the major lymphocytes became IL-2Rβ⁺CD3^int cells which lacking NK1.1 at the fulminant stage (days 14 and 21). At this time, granulocytes expanded prominently. Since IL-2Rβ⁺CD3^int cells (NK1.1⁻) lacked cytotoxicity, the suppression of expanding donor cells might be mediated by granulocytes. Granulocytes were activated by inflammatory cytokines. These results suggest that in addition to NK1.1-expressing cells (e.g., NK and NKT cells), IL-2Rβ⁺CD3^int cells lacking NK1.1 may be also the lymphocyte subset which recognizes MHC class I-deficient self.

DOI： 10.2220/biomedres.25.209

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C57BL/6 (B6) female mice were injected with 10⁷ splenocytes of B6 male mice to immunize male H-Y antigens. This stimulation induced a slight increase in the proportions of CD3^intIL-2Rβ⁺ cells, CD3^intNK1.1⁺ cells (i.e., NKT cells), and CD4⁺T cells in the liver and spleen. However, cytotoxic activity against male H-Y antigens was not detected in hepatic and splenic lymphocytes. When these <i>in vivo</i> primed hepatic or splenic lymphocytes were cultured <i>in vitro</i> with irradiated splenocytes of male mice (i.e., mixed lymphocyte reaction, MLR), potent cytotoxicity against male H-Y antigens was induced. Unprimed (<i>in vivo</i>) hepatic and splenic lymphocytes did not acquire such activity even by <i>in vitro</i> stimulation. If the primed mice were <i>in vivo</i> stimulated again with male lymphocytes, such cytotoxicity was not obtained. In other words, <i>in vivo</i> priming and <i>in vitro</i> culture stimulation were both required for the induction of cytotoxicity. Phenotypic characterization and cell-depletion study using normal B6 mice and NKT-deficient mice revealed that effector cells were both CD8⁺NK1.1⁻TCR^int and CD8⁺NK1.1⁺TCR^int cells. These results suggest that recognition of H-Y antigens and effector function against H-Y antigens may be events of innate immunity similar to the case of other self-related antigens.

DOI： 10.2220/biomedres.25.93

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TAP-1 deficient (-/-) mice cannot transport MHC class I antigens onto the cell surface, which results in failure of the generation of CD8+ T cells in the thymus. In a series of recent studies, it has been proposed that extrathymic T cells are generated in the liver and at other extrathymic sites (e.g. the intestine). It was therefore investigated whether CD8+ extrathymic T cells require an interaction with MHC class I antigens for their differentiation in TAP-1(-/-) mice. Although CD8+ thymically derived T cells were confirmed to be absent in the spleen as well as in the thymus, CD8 alpha beta+ T cells were abundant in the livers and intestines of TAP-1(-/-) mice. These CD8+ T cells expanded in the liver as a function of age and were mainly confined to a NK1.1-CD3int population which is known to be truly of extrathymic origin. Hepatic lymphocytes, which contained CD8+ T cells and which were isolated from TAP-1(-/-) mice (H-2b), responded to neither mutated MHC class I antigens (bm1) nor allogeneic MHC class I antigens (H-2d) in in vitro mixed lymphocyte cultures. However, the results from repeated in vivo stimulations with alloantigens (H-2d) were interesting. Allogeneic cytotoxicity was induced in liver lymphocytes in TAP-1(-/-) mice, although the magnitude of cytotoxicity was lower than that of liver lymphocytes in immunized B6 mice. All allogeneic cytotoxicity disappeared with the elimination of CD8+ cells in TAP-1(-/-) mice. These results suggest that the generation and function of CD8+ extrathymic T cells are independent of the existence of the MHC class I antigens of the mouse but have a limited allorecognition ability.

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Immunological states during human malarial infection were examined. In parallel with parasitemia and anemia, granulocytosis was induced in the blood of patients, especially those infected with Plasmodium (P.) falciparum. At that time, the level of lymphocytes remained unchanged or slightly increased in the blood. However, the distribution of lymphocyte subsets was modulated, showing that the proportion of CD56(+)T cells, CD57(+)T cells, and gammadeltaT cells (i.e. all unconventional T cells) had increased in patients infected with P. falciparum or P. vivax. This phenomenon occurred at the early phase of infection and disappeared in the course of recovery. The data from patients with multiple attacks of P. vivax infection showed that there was no augmentation of these responses. In adult cases, the increase in the proportion of unconventional T cells seemed to closely parallel disease severity. However, all these responses were weak in children, even those infected with P. falciparum. In conjunction with accumulating evidence from mouse malaria experiments, the present results suggest that the immunological state induced by malarial infection might mainly be an event of unconventional T cells and that the immunological memory might not be long-lasting, possibly due to the properties of unconventional T cells.

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Mice were orally administered with beta-glucan, isolated from baker's yeast, daily for one week (25mg/day/mouse) and several immunoparameters in the digestive tract were examined. The most prominent change was an increase in the number of intraepithelial lymphocytes (IEL) in the intestine, although the number of lymphocytes in the liver remained unchanged. The absolute number of both alphabetaT cells and gammadeltaT cells expressing CD8 antigens increased among IEL in the intestine. Primarily, liver lymphocytes showed a spontaneous production of Type 0 cytokine (simultaneous production of IFNgamma and IL-4) while IEL did not produce any cytokines without stimulation. However, mice administered with beta-glucan produced Type 1 cytokine, namely, production of IFNgamma alone. These results suggest that beta-glucan may be an important potentiator for mucosal immunity in the digestive tract.

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IL-2/IL-15Rbeta-deficient mice display impaired development of NK cells, NKT cells, and intraepithelial lymphocytes of the intestine and skin. To determine the role of survival signals mediated by IL-2/IL-15R in the development of these innate lymphocytes, we introduced a bcl-2 transgene into IL-2/IL-15Rbeta-deficient mice. Enforced expression of Bcl-2 restored the number of NK cells in IL-2/IL-15Rbeta-deficient mice, but the rescued NK cells showed no cytotoxic activity. The numbers of NKT cells and intestinal intraepithelial lymphocytes did not increase significantly, and skin intraepithelial lymphocytes remained undetectable in the bcl-2 transgenic IL-2/IL-15Rbeta-deficient mice. These results indicate an essential role of IL-2/IL-15R-mediated survival signals in the development of NK cells, but they also show that additional nonsurvival signals from IL-2/IL-15R are necessary for innate lymphocyte development.

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Chronic graft-versus-host disease (GVHD) accompanying autoimmune disease was induced in (C57BL/6xDBA/2) F(1) mice (H-2(b/d)) by an injection of splenic T cells of parental DBA/2 origin (H-2(d)). In parallel with the onset of proteinuria, an expansion of lymphocytes was induced in the liver and kidney, showing a peak at 2 weeks after the onset of disease. The majority of lymphocytes were of recipient origin (H-2(b/d)). The main lymphocyte subset among T cells at the pre-onset stage and after the onset of disease was CD8(+) NK1.1(-) CD3(int) cells (of extrathymic, hepatic origin) in both the liver and kidney. NK1.1(-) CD3(int) cells confer primarily neither NK-like nor NKT-like cytotoxicity. No induction of these types of cytotoxicity was observed in these mice with the expansion of NK1.1(-) CD3(int) cells. This raised the possibility that granulocytes induced in the liver and kidney might be associated with tissue damage. The present results suggest that, similarly to the case of autoimmune-prone mice with genetic background (e.g. MRL-lpr/lpr mice and BXSB mice), NK1.1(-) CD3(int) cells of extrathymic, hepatic origin might be crucial lymphocytes involved in the induction of the autoimmune-like disease in mice with chronic GVHD, in conjunction with Bcells (e.g. B-1 cells).

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Stronger neo-minophagen C (SNMC), a glycyrrhizin (GL) preparation, has been used for the treatment of chronic viral hepatitis. It has been reported that a single administration of SNMC induced the activation of hepatic lymphocytes in number and function in animal studies. However, it is still unknown how SNMC augments the cytotoxic function and why such augmentation of cytotoxicity occurs in the liver and other organs. In this study, SNMC was daily injected into mice (2 mg GL/day/mouse) for 2 weeks. A significant augmentation of cytotoxicity mediated by NK cells, NKT cells and TNFalpha was demonstrated mainly in the liver. The presence of TNFalpha-mediated cytotoxicity in the liver was demonstrated for the first time. In contrast to CD8+ cytotoxic T cells (CD8+ CTL), all these cytotoxicities were preexistent in lymphocytes without the immunization of a specific antigen or alloantigens. NK cytotoxicity was mediated by a perforin system, while NKT cytotoxicity was mediated by a Fas ligand system. The present results suggest that the entire cytotoxic function mediated by hepatic lymphocytes was simultaneously augmented by SNMC.

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Multiorgan failure is a life threatening complication in patients with ischemic acute renal failure (ARF). However, little is known about the underlying multiorgan system cellular immunity in ischemic ARF. We therefore studied the dynamics of cells accumulating in the kidneys and other organs in mice and analyzed the characteristics of the accumulated cells. We prepared a unilateral renal ischemia/reperfusion injury (IRI) model in C57BL/6 or C3H/He mice. At 1 to 3 hours after renal ischemia, increased accumulations of neutrophils and intermediate T cells were observed in the clamped kidney, but the same phenomena were also observed in the nonclamped kidney, liver, and spleen. After 24 hours, these cell numbers had returned to preischemic levels, but remained elevated for a longer period in the clamped kidney. The intermediate T cells that accumulated in the kidney and liver in the IRI mice expressed higher Vbeta chains specific to forbidden clones than in the control mice. Moreover, the accumulated intermediate T cells in the IRI liver had cytotoxic activity against both tumor cells and syngeneic thymocytes. In the clamped kidney, the accumulated intermediate T cells had less cytotoxic activity against tumor cells; however, the expression of the Fas ligand (FasL) increased, indicating a cell-mediated tissue injury via the Fas/FasL system. Histopathologically, an influx of neutrophils and lymphocytes was observed not only in the clamped kidney but also in the hepatic sinusoids concomitantly with liver dysfunction. These findings indicate that a systemic cellular immune response, including intermediate T cells, affects multiple organs during ischemic ARF, which may play an important role in the development of multiorgan failure.

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Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/s0008-8749(02)00525-7

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Mice were infected with Plasmodium (P.) yoelii blood-stage parasites. Both the liver and spleen were the sites of inflammation during malarial infection at the beginning of day 7. The major expanding cells were found to be NK1.1(-) intermediate alphabetaTCR (alphabetaTCR(int)) in the liver and spleen, although the population of NK1.1(+) alphabetaTCR(int) cells remained constant or slightly increased. These TCR(int) cells are of extrathymic origin or are generated by an alternative intrathymic pathway and are distinguished from conventional T cells of thymic origin. During malarial infection, the population of conventional T cells did not increase at all. TCR(int) cells purified from the liver of mice which had recovered from P. yoelii infection protected mice from malaria when they were transferred into 6.5-Gy-irradiated mice. Interestingly, the immunity against malaria seemed to disappear as a function of time after recovery, namely, mice which had recovered from malaria 1 year previously again became susceptible to malarial infection. The present results suggest that TCR(int) cells are intimately associated with protection against malarial infection and, therefore, that mice which had recovered from malaria 1 year previously lost such immunity.

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Lipopolysaccharide (LPS) is known to bind to several receptors on macrophages, including CD14 and macrophage scavenger receptor class A types I and II (MSR-A), and stimulates macrophages to release various inflammatory mediators. MSR-A recognizes a broad range of polyanionic ligands such as chemically modified lipoproteins, LPS of Gram-negative bacteria, and lipoteichoic acid of Gram-positive bacteria, suggesting a role in host defence. In this study, mice lacking MSR-A were used to elucidate the role of MSR-A in endotoxin shock. Peritoneal macrophages from MSR-A-deficient (MSR-A(-/-)) mice bound less remarkably to LPS than those from wild-type (MSR-A(+/+)) mice and the binding activity of MSR-A(+/+) macrophages to LPS was reduced by the addition of an anti-MSR-A antibody. Clearance of LPS in serum was retarded in MSR-A(-/-) mice after intraperitoneal administration of LPS. LPS-induced expression of cytokines in the liver was similar in MSR-A(+/+) and MSR-A(-/-) mice, but levels of interleukin (IL)-1beta expression and serum IL-1beta were lower in MSR-A(-/-) mice. Administration of large doses of LPS resulted in a higher mortality of MSR-A(+/+) mice and pretreatment with an IL-1 receptor antagonist reduced the mortality. Thus, MSR-A-mediated macrophage activation plays a negative role in protecting mice from endotoxin shock by enhancing IL-1beta production by macrophages.

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The immune system in centenarians was characterized as elevated levels in the proportion and number of granulocytes, NK cells, and extrathymic T cells (including NKT cells) in the peripheral blood. Conventional T cells, abundant in youth, were decreased in proportion and number. In addition to this numerical change in centenarians, the function was significantly altered in comparison with that in middle-aged subjects. The phagocytic function and cytokine production of granulocytes in centenarians increased whereas the production of superoxides from granulocytes decreased. This tendency was almost the same in both healthy and unhealthy centenarians. IFN gamma production by NK and extrathymic T cells in centenarians seemed to be augmented and resulted in an elevated level of serum IFN gamma. Possibly due to the effect of this endogenous IFN gamma, the proportion of CD64(+) (Fc gamma RI) cells among granulocytes was elevated. The expansion of CD64 antigens on granulocytes is known to be regulated by IFN gamma and to be associated with their induction of phagocytosis. These results suggest that the immune system of centenarians is not merely impaired, but altered in terms of the number and functions of granulocytes, NK cells, NKT cells.

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Many clinicians have believed that H2-blockers and proton pump inhibitors ameliorate gastric ulcers via their antacid function. We examined the effects of these antacids on granulocytes. Gastric ulcer patients were administered an H2-blocker or proton pump inhibitor for a week and the number of granulocytes and the superoxide production were examined. To determine the trafficking of granulocytes, mice were exposed to restraint stress for 24 hr. The H2-blocker decreased the number of granulocytes, while the proton pump inhibitor suppressed their superoxide production in humans and mice. The major function of H2-blockers and proton pump inhibitors in curing gastric ulcers seems to be their suppressive effects on granulocytes. In this case, stress accelerates the trafficking of granulocytes from the bone marrow to the gastric mucosa. If we demonstrate a role for granulocytes in gastric ulcer formation, an gap in the acid-pepsin theory and the Helicobacter pylori theory is filled in.

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Beige mice lack natural killer (NK) cytotoxicity, although NK cells are normally present. In recent studies, NK T cells have been newly identified. We therefore examined the number and function of NK T cells in beige mice. The number of NK T cells was at a normal level in the liver of beige mice. NK cytotoxicity was decreased in the liver of these mice, whereas NK T cytotoxicity was intact. When immunochemical staining for perforin was conducted, the majority of NK cells and the minority of NK T cells in beige mice carried a giant granule, containing perforin, in the cytoplasm. In the case of control B6 mice, the majority of NK cells and the minority of NK T cells had multiple, dispersed granules containing perforin. These results suggest that NK T cytotoxicity is unaffected by the beige mutation, owing to their cytotoxicity being mediated without the secretion system of perforin.

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When mice were exposed to restraint stress for 12 or 24 h, severe lymphopenia was induced in all immune system organs, including the liver and the thymus. However, in adrenalectomized mice, this response was completely absent. Phenotypic characterization revealed that interleukin (IL)-2Rbeta+CD3int cells (i.e. extrathymic T cells) with CD4+ phenotype and the NK1.1+ subset of CD3int cells (i.e. NKT cells) in the liver as well as the mature conventional T cells in the thymus were resistant to such stress. In adrenalectomized mice, there was no significant change in the distribution of lymphocyte subsets in all tested organs before stress. Interestingly, the number of lymphocytes in the liver and spleen and the proportion of NKT cells in the liver rather increased after stress in these adrenalectomized mice. Therefore, endogenous steroid hormones were indicated to be important in the induction of immunosuppressive states after stress. Among stress associated cytokines, the secretion of tumour necrosis factor (TNF)-alpha was completely suppressed while that of IL-6 was partially suppressed in adrenalectomized mice. These results suggest that endogenous steroid hormones are important for the induction of the stress associated immunosuppression and that NKT cells are resistant to stress, namely, resistant to exposure to endogenous steroid hormones.

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Numerous studies on the cytokine production profile in Leishmania major infected susceptible and resistant mice have been carried out to elucidate the mechanisms of healing or non-healing of this infection. However, many methods may have failed to detect the actual cytokine production in the inflammatory foci. To overcome this problems, the ELISPOT assay was used to examine the spontaneous production of IL-4 and IFN-gamma in vitro by mononuclear cells from the spleen, lymph nodes and liver in L. major-infected susceptible BALB/c and resistant C57BL/6 mice. None of these mononuclear cells spontaneously produced IFN-gamma in either mouse strains in vitro in the absence of the corresponding antigen(s). However, liver mononuclear cells from infected BALB/c mice spontaneously produced IL-4 in vitro in as early as 2 weeks after the infection, but this was not observed in C57BL/6 mice. The IL-4 producing liver lymphocytes consisted of CD4+ and/or gammadelta+ T cells and uncharacterized cells. These results suggest that liver lymphocytes play some role in the establishment of Th2 prevalence in susceptible BALB/c mice, based on the importance of IL.4 production in the early phase of L. major infection in establishing Th2 dominance in this parasite susceptible mouse.

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BACKGROUND/AIMS: We recently reported the adult mouse liver to contain c-kit+ stem cells that can give rise to multilineage leukocytes. This study was designed to determine whether or not adult mouse liver stem cells can generate intraepithelial T cells in the intestine as well as to examine the possibility that adult liver c-kit+ stem cells originate from the fetal liver. METHODS: Adult liver mononuclear cells, bone marrow (BM) cells, liver c-kit+ cells or bone BM c-kit+ cells of BALB/c mice were i.v. transferred into 4 Gy irradiated CB17/-SCID mice. In other experiments, fetal liver cells from Ly5.1 C57BL/6 mice and T cell depleted adult BM cells from Ly5.2 C57BL/6 mice were simultaneously transferred into irradiated C57BL/6 SCID mice (Ly5.2). At 1 to 8 weeks after cell transfer, the SCID mice were examined. RESULTS: Not only BM cells and BM c-kit+ cells but also liver mononuclear cells and liver c-kit+ cells reconstituted gamma delta T cells, CD4+ CD8+ double-positive T cells and CD8 alpha+beta- T cells of intestinal intraepithelial lymphocytes of SCID mice. Injection of a mixture of fetal liver cells from Ly5.1 C57BL/6 mice and adult BM cells from Ly5.2 C57BL/6 mice into Ly5.2 C57BL/6 SCID mice induced both Ly5.1 and Ly5.2 T cells, while also generating c-kit+ cells of both Ly5.1 and Ly5.2 origins in the liver. CONCLUSIONS: Adult mouse liver stem cells were able to generate intestinal intraepithelial T cells of the SCID mice, and it is thus suggested that some adult liver stem cells may indeed be derived from the fetal liver.

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It is known that ALY/Nsc Jcl-aly/aly (aly/aly) mice that congenitally lack lymph nodes fall victim to Sjögren syndrome as a function of age. We investigated how TCRint cells of extrathymic origin and TCRhigh cells of thymic origin are distributed in various organs of these mice. Although the distribution of T-cell subsets was not different between control aly/+ and aly/aly mice in youth in any of the tested organs, the proportion of TCRint cells in the liver and spleen of aly/aly mice increased with aging. Usually, TCRint cells in the liver comprise a half-and-half mixture of a NK1. 1(+) subset (i.e., NKT cells) and a NK1.1(-) subset. In constrast, almost all expanding TCRint cells in various immune organs of aly/aly mice were found to be NK1.1(-). A large proportion of lymphocytes, including NK cells and TCRint cells, were also present in the salivary glands of aly/aly mice. Interestingly, these TCRint cells in the salivary glands contained an NK1.1(+) subset (i.e., NKT cells) that used an invariant chain of Valpha14Jalpha281 for TCRalphabeta (>50%). Moreover, gammadeltaT cells that used Vgamma 1, 2, 4/Vdelta 1, 4, 6 mRNAs, different from those of gammadeltaT cells in the liver and intestine, were abundant. Possibly reflecting the in situ generation of these T cells in the salivary glands, the expression of RAG-2 mRNA was evident by the RT-RCR method. These results suggest that (i) inflammatory lymphocytes that evoke Sjögren syndrome in aly/aly mice are NK cells or TCRint cells (both NK1.1(+) and NK1.1(-) subsets) and (ii) TCRint cells in the salivary glands might be generated in situ.

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Analysis of double mutant mice of the p53 and scid genes, which have a combination of cell cycle checkpoint/apoptosis and DNA repair defects, shows that the latter defect synergistically enhances lymphoma development with loss of the former function. These mice lack the ability to eliminate lymphocytes predisposed to neoplastic transformation resulting from faulty antigen receptor gene rearrangement. Here we examine the cooperativity in double heterozygotes of p53 and scid in which normal development of lymphocytes is not impaired. MSM mice carrying a p53-knockout allele were crossed with BALB/c mice heterozygous for the scid locus and 129 offspring were obtained. They were subjected to gamma-ray irradiation, 84 thymic lymphomas being generated. The tumors and host mice were genotyped of p53 and scid. Among 42 mice developing p53-deficient lymphomas, scid/+ and +/+ genotypes did not provide difference in onset and latency. Besides, allelic loss of the Scid gene occurred at a high frequency in those lymphomas but the loss exhibited no allelic bias. The results suggest that the scid/+ genotype is not a modifier of loss of p53 function in the double heterozygotes.

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Estrogen was administered to B6 (NK1.1+ strain), BALB/c (Mls-1b2a, V beta 3+ cells being forbidden clone), or (B6 x BALB/c) F1 mice (1 mg/mouse). On days 3 and 10, the number of cells yielded by the liver doubled, whereas that yielded by the thymus decreased prominently. The numbers of cells in the spleen, bone marrow, and blood were unchanged. c-kit+ stem cells, which give rise to multilineage cells, were present in the liver and bone marrow. The proportion of such c-kit+ cells in the liver increased while that in the bone marrow decreased on day 3. Therefore, the absolute number of c-kit+ stem cells increased severalfold in the liver and clusters of lymphoid cells became visible in the parenchymal space. At that time, the expression of recombination activating gene-1 and -2 mRNAs became prominent. Reflecting these phenomena, the number and proportion of IL-2R beta+ CD3int cells (i.e., primordial T cells) increased in the liver on days 3 and 10. An increase in the number of proportion of such CD3int cells was seen even in the thymus and uterus. In parallel with the increase of CD3int cells, the proportion of granulocytes also increased in various organs on day 3. Forbidden clones were present in either the NK1.1+ or the NK1.1- subset of CD3int cells in (B6 x BALB/c) F1 mice treated with estrogen and liver mononuclear cells in such mice acquired potent cytotoxicity against syngeneic thymocytes. These results reveal that estrogen has the ability to potentiate the generation of self-reactive T cells and granulocytes in the liver and other organs.

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The immune system in the aged is a very interesting subject for study. In this study, analysis was extended to extrathymic T cells as well as NK cells and "conventional" T cells (i.e., thymus-derived T cells) in terms of their constitution and function in both healthy and unhealthy centenarians. Middle-aged persons were used as controls. Healthy and unhealthy centenarians showed lower levels in the proportion and absolute number of lymphocytes. The major change in the constitution of lymphocyte subsets was increased levels in the proportion of NK cells (CD56+/CD57+) and extrathymic T cells (CD3+CD57+). Inversely, conventional T cells decreased in proportion and function (i.e., proliferative response to mitogen). Although NK cells increased in centenarians, NK activity by whole lymphocytes and the purified NK fraction decreased. The difference between healthy and unhealthy centenarians was small in all parameters, the only difference being a lower level of expression of CD56 antigens on CD57+ T cells in unhealthy centenarians. These results indicate that there is a major shift in lymphocyte population from conventional T cells to NK cells and extrathymic T cells with aging. Concerning the age-associated increases in CD56+ T and CD57+ T cells, these cells correspond to NK1+ T cells in mice.

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Livers of the adult mice contain c-kit+ stem cells that can reconstitute thymocytes, multiple lineage cells, and bone marrow (BM) stem cells. Transfer of 1 x 10(7) hepatic mononuclear cells (MNC) and 5 x 10(4) hepatic c-kit+ cells of BALB/c mice induced DP thymocytes within a week in four Gy-irradiated CB17/-SCID mice, but 2 wk were required for BM cells or BM c-kit+ cells to produce DP thymocytes. Moreover, B cell-depleted BM cells or liver MNC of SCID mice that had been rescued by hepatic MNC of BALB/c mice again reconstituted thymus and B cells of other irradiated SCID mice. CD3- IL-2R beta- populations of both BM cells and hepatic MNC of C57BL/6 (B6) mice could generate T cells with intermediate TCR (mostly NK1.1-) in the liver of irradiated B6 SCID mice before thymic reconstitution (extrathymic T cells). Furthermore, transfer of liver c-kit+ cells of B6-Ly 5.1 mice into irradiated B6 SCID (Ly5.2) mice revealed that liver c-kit+ cells can reconstitute myeloid and erythroid lineage cells. These results strongly suggest that the liver contains pluripotent stem cells and serves an important hematopoietic organ even into adulthood.

PubMed

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

It is well established that IL-7 supports the earliest differentiation of both T and B cells in fetal and adult life. On the other hand, mature lymphocyte subsets tend to decrease the response to IL-7 in case of T and B cells. In a recent study, NK1.1+ T cells in the thymus are also found to efficiently respond to IL-7 and express IL-7 receptors (IL-7R). This population is generated through an alternative intrathymic pathway. A similar population, namely, T cells with intermediate levels of TCR (i.e., int TCR cells) are known to be generated through extrathymic pathways. In this respect, the proliferative response to IL-7 and the expression of IL-7R in int TCR cells of various organs were compared. Whole liver MNC and isolated int TCR cells from the liver were found to proliferate in response to IL-7. Moreover, a considerable population of int TCR cells in both the liver and thymus were found to carry a higher density of IL-7R on the surfaces than high TCR cells. More precisely, the intensity of IL-7R on int TCR cells in the thymus was the highest but those on int TCR cells in other organs were slightly lower (i.e., int TCR cells in the thymus greater than int TCR cells in the liver greater than high TCR cells). Taken together with the result of expression of IL-7 mRNA by hepatocytes and thymic tissues, it is concluded that IL-7 is one of the most important growth factors for int TCR cells both in the liver and thymus.

PubMed

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Language：English   Publishing type：Research paper (scientific journal)  

Glycyrrhizin (GL), a plant extract, has been evaluated for its inhibitory effect on HIV replication in vitro and for its improvement of clinical symptoms in HIV-infected patients. In this study, we used GL in a murine AIDS model (MAIDS) to evaluate these effects. C57BL/6 mice were inoculated with LP-BM5 murine leukemia virus to cause MAIDS. Treatment with GL supplemented with glycine and cysteine (Stronger Neo-Minophagen C, SNMC) was then begun on day 0 or 4 wks after virus inoculation. SNMC was administered three times a week for up to 19 wks. Immunological abnormalities were monitored with respect to the surface phenotype identified by two-color staining for CD3 and IL-2 receptor beta-chain. All mice infected with the virus alone developed MAIDS and died by 14 wks after infection. The immunopathogenesis was estimated to be an abnormal expansion of intermediate CD3 cells (i.e., extrathymic T cells) as well as other types of lymphocytes. SNMC did not change the total mortality rate. However, some mice that began the treatment on day 0 or 4 wks after infection survived 3 wks longer. Splenomegaly and lymphadenopathy in such mice were suppressed. These mice showed normal phenotypic features and normal responses to Con A. These results suggest that SNMC is effective in some MAIDS mice in preventing the progression of disease. When lymphocytes isolated from the liver, spleen and lymph nodes of diseased mice were cultured in vitro, they showed a spontaneous proliferation. Interestingly, such proliferation was inhibited by addition of liver lymphocytes, but not splenic lymphocytes, obtained from normal or SNMC-treated mice. Since liver lymphocytes contains intermediate CD3 cells with autoreactivity, they may possibly suppress the progression of disease.

PubMed

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Language：English   Publishing type：Research paper (scientific journal)  

Experiments to date have revealed a population of T cells that carry intermediate (int) levels of TCR (or CD3) and express IL-2R beta-chain (IL-2R beta) in mouse liver. Such int TCR cells also reside in other immune organs, although in low numbers. On the other hand, NK1.1+ T cells with int TCR do reside in the thymus and other peripheral organs. To determine the relationship of two types of cells, we characterized int CD3 cells and NK1.1+ T cells throughout the organs in terms of the phenotype, V beta repertoire, and morphology. Although both IL-2R beta+ T cells and NK1.1+ T cells are classified as int CD3 cells, NK1.1+ T cells are present within int CD3 cells. The majority of int CD3 cells in the liver and thymus were NK1.1+, whereas the minority of such cells in the spleen, lymph nodes, and bone marrow were NK1.1+. Among int CD3 cells, double-negative (DN) CD4-8- cells and/or CD4+ were abundant in NK1.1+ subset, whereas CD8+ cells were generally abundant in NK1.1- subset. Self-reactive V beta+ clones estimated by the M1s system were distributed to both NK1.1+ and NK1.1- subsets. High CD3 cells in the thymus and other organs contained neither DN cells nor forbidden clones. Int CD3 cells had the morphology of granular or agranular lymphocytes carrying perforin. Among int CD3 cells, NK1.1+ subset had a higher level of perforin-positive cells than NK1.1- subset. These results clearly demonstrate the relationship between int TCR cells and NK1.1+ T cells in various organs.

PubMed

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Language：Japanese   Publisher：(株)医学書院  

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Authorship：Lead author   Language：Japanese   Publisher：(株)アークメディア  

成体肝は骨髄と同様な造血幹細胞ばかりでなく,T細胞をより早く分化させる前駆細胞をも有し,そこから局所でint TCR細胞やNKT細胞を分化させ得ると考えられた.又,これらの細胞の出現にはMHC class I或いはその関連分子の何らかの関与が示唆される

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Language：Japanese   Publisher：(株)アークメディア  

マクロファージスカベンジャー受容体(MSR-A)はlipopolysaccharide受容体の一つとして機能し,MSR-Aを介したシグナルはマクロファージ活性化機構に関与する

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Authorship：Lead author   Language：Japanese   Publisher：(株)医学書院  

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Authorship：Lead author   Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：新潟医学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=1998&ichushi_jid=J00990&link_issn=&doc_id=19990513390003&doc_link_id=%2Fdg3nigta%2F1998%2F011211%2F004%2F0671-0675%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F1998%2F011211%2F004%2F0671-0675%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：日本臨床免疫学会  

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Language：Japanese   Publisher：(株)ニュー・サイエンス社  

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Language：Japanese   Publisher：(株)ミノファーゲン製薬  

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Authorship：Lead author   Language：Japanese   Publisher：(株)メディカルレビュー社  

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Language：Japanese   Publisher：(株)ミノファーゲン製薬  

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Language：Japanese   Publisher：(株)文光堂  

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Language：Japanese   Publisher：(株)ミノファーゲン製薬  

著者等の解析で,intTCR細胞中にはNK1.1+細胞サブセット(NK1+T細胞)とNK1.1-細胞サブセットが存在し,しかもその細胞構成が異なることが明らかにされた.intTCR細胞とNK1+T細胞は,細胞表面形質,分布,形態,細胞障害活性,禁止クローンの存在など,いずれも類似しており,NK細胞と胸腺由来のconventional T細胞の中間に位置するリンパ球であるといえる.一方,肝臓は独自の造血幹細胞を有し,胸腺外分化T細胞を分化・成熟させることも明らかとなってきた.また,腸管の基底部(crypt lamina propria)には腸管上皮内リンパ球の前駆細胞が見いだされている.このように,胸腺外分化T細胞の前駆細胞がそれぞれの器官に存在することから,胸腺のみがT細胞分化の場であるという考えは大きく変わりつつある

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Language：English   Publisher：Niigata University  

CiNii Article

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/1997127564

Language：Japanese   Publisher：(株)ミノファーゲン製薬  

マウス白血病ウイルス(LP-BM5)によるマウスAIDS(MAIDS)モデルを用い,SNMCの投与効果の評価を試みた.ウイルス感染マウスは全て発症し,感染14週迄に死亡した.SNMCを投与した感染マウスの一部に長く生存したマウスがみられたが,死亡率に有意差は認められなかった.又,これらの長期生存マウスでは,脾腫及び全身のリンパ節腫脹が抑制され,細胞表面マーカー及びCon Aに対する反応も正常であった.又,感染マウスの肝,脾,リンパ節のリンパ球をin vitroで培養すると,これらのリンパ球は自発的増殖を示したが,それらに正常マウス又はSNMC単独投与マウスの肝リンパ球を加えた時のみ,このリンパ球の増殖が抑えられた

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Event date： 2005.12

Language：Japanese  

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Event date： 2005.5

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Event date： 2004.7

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Event date： 2003.12

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Event date： 2003.11

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2003&ichushi_jid=J00990&link_issn=&doc_id=20040130440058&doc_link_id=%2Fdg3nigta%2F2003%2F011711%2F058%2F0661-0661%26dl%3D2&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2003%2F011711%2F058%2F0661-0661%26dl%3D2&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_5.gif

Event date： 2001.12

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Event date： 1993.10

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