2021/05/15 更新

写真a

トミヤマ チカコ
富山 智香子
TOMIYAMA Chikako
所属
教育研究院 医歯学系 保健学系列 准教授
医学部 保健学科 准教授
保健学研究科 保健学専攻 准教授
職名
准教授
外部リンク

学位

  • 博士(医学) ( 2006年3月   新潟大学 )

研究分野

  • ライフサイエンス / 免疫学

  • その他 / その他  / 病態検査学

経歴(researchmap)

  • 新潟大学   医学部 保健学科   准教授

    2010年10月 - 現在

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  • 新潟大学   保健学研究科 保健学専攻   准教授

    2010年10月 - 現在

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  • 新潟大学   保健学研究科 保健学専攻   准教授

    2010年10月 - 現在

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  • 新潟大学   医学部 保健学科   助教

    2008年4月 - 2010年9月

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経歴

  • 新潟大学   保健学研究科 保健学専攻   准教授

    2010年10月 - 現在

  • 新潟大学   医学部 保健学科   准教授

    2010年10月 - 現在

  • 新潟大学   保健学研究科 保健学専攻   准教授

    2010年10月 - 現在

  • 新潟大学   医学部 保健学科   助教

    2008年4月 - 2010年9月

  • 新潟大学   職員(教務系)

    2002年4月 - 2008年3月

学歴

  • 新潟大学

    - 2006年3月

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    国名: 日本国

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所属学協会

  • 日本樹状細胞研究会

    2010年4月 - 2019年12月

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  • リンパ・網内系学会

    2004年4月 - 現在

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  • 日本免疫学会

    1992年4月 - 現在

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取得資格

  • 臨床検査技師

 

論文

  • Suppressive role of hepatic dendritic cells in concanavalin A-induced hepatitis 査読

    C. Tomiyama, H. Watanabe, Y. Izutsu, M. Watanabe, T. Abo

    CLINICAL AND EXPERIMENTAL IMMUNOLOGY166 ( 2 ) 258 - 268   2011年11月

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    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  

    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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  • Repetitive manual acupuncture increases markers of innate immunity in mice subjected to restraint stress 査読

    Mayumi Watanabe, Eisuke Kainuma, Chikako Tomiyama

    ACUPUNCTURE IN MEDICINE33 ( 4 ) 312 - 318   2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元: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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  • On/off switching of capillary vessel flow controls mitochondrial and glycolysis pathways for energy production 査読

    Toru Abo, Mayumi Watanabe, Chikako Tomiyama, Yasuhiro Kanda

    MEDICAL HYPOTHESES83 ( 1 ) 99 - 100   2014年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元: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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  • Can the early bird catch the worm? Effects of the early rising on leukocyte subsets via modification of autonomic nervous system and the effect on glucose levels 査読

    Watanabe M, Ling Y, Tomiyama C, Adachi K, Mori H, Nishijo K, Abo T, Akazawa K

    Natural Science5 ( 11 ) 1133 - 1138   2013年11月

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    記述言語:英語  

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  • Research on stress-induced apoptosis of natural killer cells and the alteration of their killing activity in mouse liver 査読

    Zhen Ma, Yang Liu, Xin Zhou, Hai-Long Yu, Ming-Qi Li, Chikako Tomiyama-Miyaji, Toru Abo, Xue-Feng Bai

    World Journal of Gastroenterology19 ( 37 ) 6258 - 6264   2013年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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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  • Perioperative Immunological Differentiation in Liver Cirrhotic Patients who Underwent Living Related Liver Transplantation 査読

    Yoshinobu Sato, Chikako Tomiyama, Satoshi Yamamoto, Hiroshi Oya, Takashi Kobayashi, Hidenaka Kokai, Kohei Miura, Yuki Hirose, Katsuyoshi Hatakeyama

    HEPATO-GASTROENTEROLOGY60 ( 124 ) 666 - 668   2013年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元: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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  • Association of urinary 8-OHdG with lifestyle and body composition in elderly natural disaster victims living in emergency temporary housing 査読

    Kimie Saito, Hagiko Aoki, Naoshi Fujiwara, Masahiro Goto, Chikako Tomiyama, Yuka Iwasa

    ENVIRONMENTAL HEALTH AND PREVENTIVE MEDICINE18 ( 1 ) 72 - 77   2013年1月

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    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  

    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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  • The effects of application of an ancient type of acupuncture needle on increase in urination of hospitalized oldest-old people. 査読

    Watanabe M, Takano O, Tomiyama C, Guan J, Hou G, Mori H, Nishijo K, Abo T, Akazawa K

    Health5 ( 7 ) 1092 - 1098   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.4236/health.2013.57147

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  • Skin rubdown with a dry towel, 'kanpu-masatsu' is an aerobic exercise affecting body temperature, energy production, and the immune and autonomic nervous systems 査読

    Mayumi Watanabe, Osamu Takano, Chikako Tomiyama, Hiroaki Matsumoto, Takahiro Kobayashi, Nobuatsu Urahigashi, Takeo Madarame, Toru Abo

    BIOMEDICAL RESEARCH-TOKYO33 ( 4 ) 243 - 248   2012年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元: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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  • Biology of autoreactive extrathymic T cells and B-1 cells of the innate immune system 査読

    Toru Abo, Chikako Tomiyama, Hisami Watanabe

    IMMUNOLOGIC RESEARCH52 ( 3 ) 224 - 230   2012年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元: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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  • Immunosuppressive function of dendritic cells existed in the liver. 査読

    Chikako Tomiyama, Hisami Watanabe, Mayumi Watanabe, Toru Abo

    Current Research in Immunology6   1 - 7   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Cytokine profile of murine malaria: stage-related production of inflammatory and anti-inflammatory cytokines 査読

    Hanaa Y. Bakir, Chikako Tomiyama, Toru Abo

    BIOMEDICAL RESEARCH-TOKYO32 ( 3 ) 203 - 208   2011年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元: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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  • Metabolic conditions, hypothermia, and hypoxia induced by continuous stress are more often associated with carcinogenesis than known carcinogens. 査読

    Abo T, Watanabe M, Matsumoto H, Tomiyama C, Taniguchi T

    Medical Hypotheses and Research7   53 - 56   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Internal environment for growth of cancer cells in mice:hypothermia, anemia and lymphocytopenia. 査読

    Watanabe M, Matsumoto H, Tomiyama C, Akazawa K, Abo T

    Health3 ( 4 ) 238 - 244   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.4236/health.2011.34042

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  • Association of glucocorticoid with stress-induced modulation of body temperature, blood glucose and innate immunity 査読

    Eisuke Kainuma, Mayumi Watanabe, Chikako Tomiyama-Miyaji, Masashi Inoue, Yuh Kuwano, HongWei Ren, Toru Abo

    PSYCHONEUROENDOCRINOLOGY34 ( 10 ) 1459 - 1468   2009年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元: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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  • Acute stress augments innate immunity in the liver and increases hyaluronan levels in the tissues and blood of mice 査読

    Masashi Inoue, Yuh Kuwano, Chikako Tomiyama-Miyaji, Mayumi Watanabe, Eisuke Kainuma, Hongwei Ren, Jiwei Shen, Kyosuke Miyazaki, Toru Abo

    BIOMEDICAL RESEARCH-TOKYO30 ( 3 ) 157 - 163   2009年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元: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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  • Alkalization of blood pH is responsible for survival of cancer patients by mild hyperthermia 査読

    Takahiko Ohishi, Chiyoko Nukuzuma, Akira Seki, Mayumi Watanabe, Chikako Tomiyama-Miyaji, Eisuke Kainuma, Masashi Inoue, Yuh Kuwano, Toru Abo

    BIOMEDICAL RESEARCH-TOKYO30 ( 2 ) 95 - 100   2009年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元: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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  • Resistance and augmentation of innate immunity in mice exposed to starvation 査読

    Jiwei Shen, Hongwei Ren, Chikako Tomiyama-Miyaji, Mayumi Watanabe, Eisuke Kainuma, Masashi Inoue, Yuh Kuwano, Toru Abo

    CELLULAR IMMUNOLOGY259 ( 1 ) 66 - 73   2009年

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    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  

    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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  • Role of alpha-adrenergic stimulus in stress-induced modulation of body temperature, blood glucose and innate immunity 査読

    Mayumi Watanabe, Chikako Tomiyama-Miyaji, Eisuke Kainuma, Masashi Inoue, Yuh Kuwano, Hongwei Ren, Jiwei Shen, Toru Abo

    IMMUNOLOGY LETTERS115 ( 1 ) 43 - 49   2008年1月

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    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 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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  • Modulation of the endocrine and immune systems by well-controlled hyperthermia equipment. 査読

    Tomiyama-Miyaji C, Watanabe M, Ohishi T, Kanda Y, Kainuma E, Bakir HY, Shen J, Ren H, Inoue M, Tajima K, Bai X, Abo T

    Biomedical research (Tokyo, Japan)28 ( 3 ) 119 - 125   2007年6月

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  • Malaria protection in β2-microglobulin-deficient mice lacking MHC class I antigens: Essential role of innate immunity, including γδT cells. 査読

    Taniguchi T, Tachikawa S, Kanda Y, Kawamura T, Tomiyama-Miyaji C, Li C, Watanabe H, Sekikawa H, Abo T

    Immunology122   514 - 521   2007年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/j.1365-2567.2007.02661.x

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  • Relationship between diseases accompanied by tissue destruction and granulocytes with surface adrenergic receptors. 査読

    Abo T, Kawamura T, Kawamura H, Tomiyama-Miyaji C, Kanda Y

    Immunologic research37 ( 3 ) 201 - 210   2007年

  • Protection against malaria due to innate immunity enhanced by low-protein diet. 国際誌

    Anoja Ariyasinghe, Sufi Reza M Morshed, M Kaiissar Mannoor, Hanaa Y Bakir, Hiroki Kawamura, Chikako Miyaji, Toru Nagura, Toshihiko Kawamura, Hisami Watanabe, Hiroho Sekikawa, Toru Abo

    The Journal of parasitology92 ( 3 ) 531 - 8   2006年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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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  • Reasons why DBA/2 mice are resistant to malarial infection: expansion of CD3int B220+ gammadelta T cells with double-negative CD4- CD8- phenotype in the liver. 査読

    Bakir HY, Tomiyama-Miyaji C, Watanabe H, Nagura T, Kawamura T, Sekikawa H, Abo T

    Immunology117 ( 1 ) 127 - 135   2006年1月

  • Transient appearance of hepatic natural killer cells with high cytotoxicity and unique phenotype in very young mice. 査読

    Bai X, Wang S, Tomiyama-Miyaji C, Shen J, Taniguchi T, Izumi N, Li C, Bakir HY, Nagura T, Takahashi S, Kawamura T, Iiai T, Okamoto H, Hatakeyama K, Abo T

    candinavian Journal of Immunology63   273 - 281   2006年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/j.1365-3083.2006.01738.x

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  • Amelioration of acute graft-versus-host disease by NKG2A engagement on donor T cells. 国際誌

    Hiroki Kawamura, Hideo Yagita, Tetsuro Nisizawa, Nakako Izumi, Chikako Miyaji, Russell E Vance, David H Raulet, Ko Okumura, Toru Abo

    European journal of immunology35 ( 8 ) 2358 - 66   2005年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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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  • Hepatic natural killer and natural killer T cells markedly decreased in two cases of drug-induced fulminant hepatic failure rescued by living donor liver transplantation. 国際誌

    Ryoko Miyakawa, Takafumi Ichida, Satoshi Yamagiwa, Chikako Miyaji, Hisami Watanabe, Yoshinobu Sato, Hisashi Yokoyama, Chika Tsukada, Yuiko Ishimoto, Satoshi Sugahara, Xiu Hua Yang, Toru Abo, Hitoshi Asakura

    Journal of gastroenterology and hepatology20 ( 7 ) 1126 - 30   2005年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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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  • Protection against malaria by anti-erythropoietin antibody due to suppression of erythropoiesis in the liver and at other sites. 査読

    Tsubata S, Ebe K, Kawamura T, Ishimoto Y, Tomiyama-Miyaji C, Watanabe H, Sekikawa H, Aoyagi Y, Abo T

    Immunol Cell Biol83 ( 6 ) 638 - 42   2005年

  • Age-dependent variation in the proportion and numer of intestinal lymphocyte subsets, especially natural killer T cells, double-positive CD4+ CD8+ cells and B220+ T cells, in mice. 査読

    Ishimoto Y, Tomiyama-Miyaji C, Watanabe H, Yokoyama H, Ebe K, Tsubata S, Aoyagi Y, Abo T

    Immunology113 ( 3 ) 371 - 377   2004年

  • Comparative characterization of double-positive CD4+CD8+ cells in the thymus and small intestine of mice. 査読

    Ebe K, Tomiyama-Miyaji C, Yokoyama H, Ishimoto Y, Tsubata S, Nagura T, Li C, Bai X, Kawamura T, Watanabe H, Aoyagi Y, Abo T

    Biomed Res25 ( 4 ) 201 - 207   2004年

  • Characterization of extrathymic CD8 alpha beta T cells in the liver and intestine in TAP-1 deficient mice. 国際誌

    Chika Tsukada, Chikako Miyaji, Hiroki Kawamura, Ryoko Miyakawa, Hisashi Yokoyama, Yuiko Ishimoto, Shinobu Miyazawa, Hisami Watanabe, Toru Abo

    Immunology109 ( 3 ) 343 - 50   2003年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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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  • Expansion of unconventional T cells with natural killer markers in malaria patients. 国際誌

    Hisami Watanabe, Anura Weerasinghe, Chikako Miyaji, Hiroho Sekikawa, Sinichi Toyabe, M Kaiissar Mannor, Sufi Reza M Morshed, Ramesh C Halder, Jun Kobayashi, Hiromu Toma, Yoshiya Sato, Kuni Iwai, Hiroki Matsuoka, Toru Abo

    Parasitology international52 ( 1 ) 61 - 70   2003年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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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  • Immunopotentiation of intraepithelial lymphocytes in the intestine by oral administrations of beta-glucan. 国際誌

    Chika Tsukada, Hisashi Yokoyama, Chikako Miyaji, Yuiko Ishimoto, Hiroki Kawamura, Toru Abo

    Cellular immunology221 ( 1 ) 1 - 5   2003年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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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  • AIM inhibits apoptosis of T cells and NKT cells in Corynebacterium-induced granuloma formation in mice. 査読

    Kuwata.K, Watanabe.H, Jing.S-Y, Yamamoto.T, Tomiyama-Miyaji.C, Abo.T, Miyazaki.T, Naito.M

    Am. J. Pathol ( 162 ) 837 - 847   2003年

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  • Enforced expression of Bcl-2 restores the number of NK cells, but does not rescue the impaired development of NKT cells or intraepithelial lymphocytes, in IL-2/IL-15 receptor beta-chain-deficient mice. 国際誌

    Masahiro Minagawa, Hisami Watanabe, Chikako Miyaji, Katsuhiro Tomiyama, Hideki Shimura, Akiko Ito, Masaaki Ito, Jos Domen, Irving L Weissman, Kazuhiro Kawai

    Journal of immunology (Baltimore, Md. : 1950)169 ( 8 ) 4153 - 60   2002年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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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  • Unconventional NK1.1(-) intermediate TCR cells as major T lymphocytes expanding in chronic graft-versus-host disease. 国際誌

    Ryoko Miyakawa, Chikako Miyaji, Hisami Watanabe, Hisashi Yokoyama, Chika Tsukada, Hitoshi Asakura, Toru Abo

    European journal of immunology32 ( 9 ) 2521 - 31   2002年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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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  • Mechanisms underlying the activation of cytotoxic function mediated by hepatic lymphocytes following the administration of glycyrrhizin. 国際誌

    Chikako Miyaji, Ryoko Miyakawa, Hisami Watanabe, Hiroki Kawamura, Toru Abo

    International immunopharmacology2 ( 8 ) 1079 - 86   2002年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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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  • Leukocyte accumulation and changes in extra-renal organs during renal ischemia reperfusion in mice. 国際誌

    Shinobu Miyazawa, Hisami Watanabe, Chikako Miyaji, Osamu Hotta, Toru Abo

    The Journal of laboratory and clinical medicine139 ( 5 ) 269 - 78   2002年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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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共同研究・競争的資金等の研究

  • 脂質代謝と肝樹状細胞を組合せた自己免疫性肝炎の早期診断法の開発

    研究課題/領域番号:17K08977  2017年04月 - 2020年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    富山 智香子, 尾関 百合子, 佐藤 英世

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    自己免疫性肝炎(autoimmune hepatitis: AIH)は、50代以降の女性に多く発症する慢性肝炎であると共に、近年、男性患者や重症患者の増加がみられるようになってきた。そのため、AIHの発症・病態進展要因には性差だけでなく複合的な因子が考えられる。そこで、我々は昨年度マウスに卵巣摘出術(ovariectomy; OVX)を行い、低エストロゲン状態がAIH肝障害とDCへ与える影響について検討を行った。その結果、OVXによりAIH肝障害は有意に増悪し、肝障害時の標的臓器である肝では、siglec-H+PDCA-1+B220+形質細胞様樹状細胞(plasamacytoid dendritic cells; pDC)の減少傾向、I-A+F4/80+通常型樹状細胞(conventional dendritic cells; cDCs)の有意な増加を認めたことを報告した。そこで、今年度も昨年に引き続き低エストロゲン状態で変化の見られたDC分画機能とDCによる刺激が影響するT細胞分画・機能について検討を行った。その結果、OVXしたマウスのAIH肝障害時の肝DCはTNF-αおよびIL-12産生量が増加した一方、IL-10産生減弱を認めた。また、肝臓のT細胞については、CD4+T細胞、CD8+T細胞共にOVXによりCD69発現が増強し、AIH肝障害時にはより加速した。さらに、血中のIFN-γ、TNF-α、およびIL-4産生量も増加した。以上のことから、AIH肝障害は低エストロゲン状態で増悪し、その免疫学的機序として1)pDCの減少と機能的減弱、2)cDCの増加とTNF-αによる直接的肝細胞障害の増強、3)活性化T細胞の増加による肝障害の増強が推察された。

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  • 女性ホルモンと肝樹状細胞の変化が自己免疫性肝炎発症へ与える影響について

    研究課題/領域番号:26460643  2014年04月 - 2017年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    富山 智香子, 渡邉 香奈子, 渡部 久実

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    配分額:4940000円 ( 直接経費:3800000円 、 間接経費:1140000円 )

    エストロゲンの低下する中年女性に自己免疫性肝炎は好発する。そこで、エストロゲンの増減が自己免疫性肝炎の発症及び進展にどのように影響するかについて、肝樹状細胞に焦点を当てて検討した。その結果、エストロゲンはエストロゲン受容体α鎖を介して肝形質細胞様樹状細胞のIL-10産生を増加させ自己免疫性肝障害を抑制した。一方、エストロゲン受容体阻害および閉経により抑制作用が減弱したと同時に、肝骨髄系樹状細胞が活性化し、IL-12p70およびTNFα産生が増大し肝障害増悪を誘導した。

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  • 性差に基づいた自己免疫性肝炎の発症と肝内樹状細胞との関連性について

    研究課題/領域番号:23510345  2011年 - 2013年

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    富山 智香子, 井筒 ゆみ, 渡部 久実

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    配分額:3900000円 ( 直接経費:3000000円 、 間接経費:900000円 )

    自己免疫性肝炎は、妊娠や閉経など性ホルモンの変動で誘発されることが報告されているが、その発症機構について解明に至っていない。このことから、エストロゲンの自己応答性への影響について自己免疫性肝炎モデルを用いて樹状細胞に焦点を当てて検討した。その結果、エストロゲン投与により自己免疫性肝障害が抑制され、これらマウス肝内にCD274陽性で未熟な樹状細胞の増加を認めた。また、これら肝内樹状細胞のみにIL-10産生能の増強を認め、血清中のIL-12量が減少していた。以上から、エストロゲン暴露によって肝内に増加した抑制能を持つ樹状細胞が、自己免疫性肝障害を抑制する可能性が示唆された。

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  • 統合医療による「冷え」の解明とその予防

    研究課題/領域番号:19K10727  2019年04月 - 2022年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    渡邉 真弓, 王 財源, 富山 智香子, 武田 時昌

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

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  • 結核ワクチン開発を指向した抗酸菌特有の翻訳後修飾付加ポリペプチドの抗原性検証

    研究課題/領域番号:19K07536  2019年04月 - 2022年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    尾関 百合子, 富山 智香子

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

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  • 原発被災市町村復興の担い手となる壮年期男性への生活と健康に関する支援方法の構築

    研究課題/領域番号:18K02058  2018年04月 - 2022年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    岩佐 有華, 齋藤 智子, 富山 智香子, 西方 真弓

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    本年度は、原発災害により被災し長期の避難生活を送る壮年期男性(以下、被災群)と被災していない壮年期男性(以下、非被災群)の睡眠とストレスを比較することを目的に、非被災群10名の睡眠とストレスに関するデータ収集を行い、その結果を分析した。
    客観的睡眠状態はActigraphを、主観的睡眠状態はピッツバーグ睡眠質問票(以下,PSQI)を用いてデータ収集を行った。Actigrapでは、Sleep Minutes(睡眠時間),Sleep Efficiency(睡眠効率),Sleep Latency(入眠潜時),Wake after Sleep Onset(中途覚醒時間)の測定を行った。
    主観的ストレス状態は精神健康調査票(以下,GHQ28)を,客観的ストレス状態は唾液ストレスバイオマーカー(α-Amylase,Cortisol,Chromogranin A, s-IgA)を用いてデータ収集を行った。
    今回収集した非被災群のデータを、以前に収集した被災群のデータ(仮設住宅居住時及び復興住宅居住時)と比較するためにMann-Whitney の U検定を用いて分析した(p<0.05)。
    その結果、非被災群と復興住宅居住時の被災群では、睡眠とストレスに有意差は認められなかった。一方で、非被災群と仮設住宅居住時の被災群では、PSQI総得点(p=0.039)及びPSQI下位尺度睡眠時間(p=0.006)及びSleep Latency(p=0.034)において有意差が認められた。
    これらのことから、原発災害により長期の避難生活を送る壮年期男性の仮設住宅居住時の睡眠は被災し避難していない一般の壮年期男性と比較して、有意に悪いことが明らかになった。

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  • 精神機能と免疫機能の相関研究

    研究課題/領域番号:16K01786  2016年04月 - 2020年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    七里 佳代, 富山 智香子, 渡邉 真弓

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    配分額:4810000円 ( 直接経費:3700000円 、 間接経費:1110000円 )

    本研究の平成30年度の研究実績の概要を報告する。
    平成29年度報告書での「今後の推進方策」に記したとおり、「精神的健常群」の精神医学的データを収集・解析して学会発表した(Efficiency of defensive functioning scale:Correlation to Beck's Depression Inventory,13th World congress on Healthcare & Technolpgies,Dublin,Ireland,2018.6.14-15)。本年度は続編を発表予定である(14th World congress on Healthcare & Technolpgies,London,UK,2019.7.22-23)。
    平成28年度中に得られていた「精神症状発現群」の生体情報検査データの診断別解析の結果では、自閉スペクトラム症群と適応障害群について、末梢体表温度が低く、末梢の血流循環が低い傾向が示された。自閉スペクトラム症群では顆粒球、NK細胞、NKT細胞が関わる自然免疫増強傾向がうかがえた。自然免疫増強傾向はストレスホルモン反応性との関連が報告されているが、自閉スペクトラム症群ではストレスホルモンであるコルチゾールとアドレナリンは低下しており、ストレスホルモン反応性とは関連性が低いと考えられた。一方、セロトニンとNk細胞の関連性についてはうつ病者におけるSSRI投与後のNK細胞活性の上昇が報告されており、自閉スペクトラム症群におけるNK細胞の増加傾向にセロトニンが関与している可能性が示唆された。
    また「精神症状発現群」の伝統医学的検査データ(舌診)の分析結果では、自閉スペクトラム症群の舌像は様々であった。適応障害群では「点刺」が多い傾向が認められ、精神的ストレスが関係して発生するとされる中医理論に合致していた。

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  • 結核菌の新しいヒト免疫抑制機構の解明とその解除による新規制御法の開発

    研究課題/領域番号:16K08774  2016年04月 - 2019年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    尾関 百合子, 富山 智香子

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    配分額:4940000円 ( 直接経費:3800000円 、 間接経費:1140000円 )

    結核は、最大級の細菌感染症であり、結核菌はその起因菌である。結核菌は一旦感染が成立するとヒト体内から排除されることなく、無症候感染というかたちで潜伏する(潜在性結核)。無症候感染者は人類の1/3に及び、年率約1%で発症するが、HIV感染、糖尿病など免疫抑制を伴う負荷は、発症リスクを上昇させる。このことは、宿主免疫応答が結核の発症と潜在化に多大に関与することを示している。本研究では結核菌の宿主に対する免疫抑制機構の一端を明らかにするとともに、それを解除する方法を見いだし、ワクチン開発の可能性を示した。

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  • 原発災害により超長期に応急仮設住宅に避難する被災者の特徴と支援プログラムの構築

    研究課題/領域番号:15K11929  2015年04月 - 2018年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    岩佐 有華, 青木 萩子, 齋藤 智子, 西方 真弓, 村松 芳幸, 富山 智香子

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    配分額:4940000円 ( 直接経費:3800000円 、 間接経費:1140000円 )

    東日本大震災に関連した福島第一原子力発電所事故による長期の避難生活が,住民の睡眠や精神健康に影響することが明らかになっており,心身への影響が懸念されている.そこで今回,長期に避難生活を送る壮年期男性の睡眠とストレスについて,仮設住宅居住時と復興住宅居住時でのそれぞれの実際を明らかにすることを目的に研究を行った.
    その結果,応急仮設住宅居住時と復興住宅居住時の比較において,客観的睡眠と客観的ストレスに有意な変化は認められなかったが,主観的睡眠と主観的ストレスは復興住宅居後,有意に悪化していることが明らかになった.

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  • 応急仮設住宅居住高齢者のストレス応答反応,環境,眠りの関連と包括的睡眠ケアの構築

    研究課題/領域番号:24593191  2012年04月 - 2016年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    齋藤 君枝, 青木 萩子, 藤原 直士, 富山 智香子, 岩佐 有華

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    配分額:5460000円 ( 直接経費:4200000円 、 間接経費:1260000円 )

    東日本大震災後、応急仮設住宅居住に居住する高齢被災者に対し、睡眠障害とその関連要因を検討した。睡眠の悪化は体調、受診状況が有意に関連していた。また、抑うつの有無と睡眠の質、睡眠困難、体重の減少が関連していた。生活環境では居室、風呂、トイレ、買い物の不便が睡眠に影響していた。避難に伴う心身の不調や疾患、生活環境が睡眠の悪化に影響を及ぼすと考えられた。包括的睡眠ケアには、早期からの睡眠障害のスクリーニング、情報収集の継続、ハイリスク者に対する定期的なアウトリーチ、多職種による連携介入が必要である。

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  • 臓器移植における再生間葉系肝幹細胞門脈内投与による新たな免疫寛容誘導法の確立

    研究課題/領域番号:21390356  2009年 - 2012年

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    佐藤 好信, 安保 徹, 松田 康伸, 富山 智香子

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    配分額:17420000円 ( 直接経費:13400000円 、 間接経費:4020000円 )

    本研究の全体構想は、これまでの臨床研究の成果を基に、臨床生体臓器移植におけるOperational Toleranceを誘導するメカニズムを解析しさらに肝幹細胞を中心とした再生医療を応用したスーパードナー抗原による新たな方法論を確立することである。基礎的検討としては、ヒト肝組織特に障害肝のductularreactionの存在する領域にCD133+NCAM+ human hepatic stem/progenitor細胞の存在が確認された。特に障害の程度が高い程、その存在は明らかであった。しかし正常肝組織での肝幹細胞の確認はできなかった。やはり肝幹細胞は肝に何らかの障害がもたらされて初めて誘導されるものと考えられた。ドナー抗原の門脈内投与の免疫学的検討においては、免疫寛容誘導症例でFoxP3^+/CD4^+CD25^+調節性T細胞の割合が有意に増加しており、免疫寛容に関与していることが判明した。また肝障害度(MELDスコアー)別に移植前後の免疫学的検討を行ったが、MELDスコアー20以上の症例では、調節性T細胞が有意となっており肝障害度別に免疫状態を把握する事により移植後免疫抑制剤の使用方法を調整できることが判明した。

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  • 自己免疫性肝炎における肝樹状細胞に着目した早期診断とその病態解明

    研究課題/領域番号:19790394  2007年 - 2009年

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    富山 智香子, 渡部 久実

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    配分額:3610000円 ( 直接経費:3100000円 、 間接経費:510000円 )

    自己免疫性肝炎の発症機序と早期特異的診断法の基礎的研究のために、モデルマウスの肝内樹状細胞の動態について検討を行った。その結果、モデルマウスの肝では活性化骨髄系樹状細胞が増加し、多量な炎症性サイトカイン産生を認めた。また、この肝障害を制御するには肝臓内の形質細胞様樹状細胞が部分的に必要である事が明らかとなった。さらに肝障害抑制には調節性T細胞も一部関連する可能性があり、血中においてTh2サイトカイン産生を認めた。このことから、自己免疫性肝炎における肝障害のコントロールには肝臓内の形質細胞様樹状細胞と制御性T細胞の連携が必要であり、これらをもとにした自己免疫性肝炎の早期発見及び新たな治療方法への基盤作成の可能性が示唆された。

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  • マラリア原虫感染におけるNKT-肝樹状細胞による免疫抑制機構

    研究課題/領域番号:16017290  2004年 - 2005年

    日本学術振興会  科学研究費助成事業 特定領域研究  特定領域研究

    渡部 久実, 富山 智香子

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    配分額:7000000円 ( 直接経費:7000000円 )

    【目的】マラリア感染における宿主の免疫抑制現象、特にT細胞応答の抑制はマウスモデルやマラリア患者の解析からよく知られていた。その原因として、regulatory T細胞の誘導、helper T細胞のアポトーシスや抗原提示細胞の機能不全などが報告されているが、近年樹状細胞(DC)の成熟阻害や機能変化が注目されてきている。本研究では、ネズミマラリア原虫P.yoelli17XNL(非致死株)を用い、感染防御能の増強とは相反する現象である免疫抑制機構を肝DCの動態から解明し、ワクチントライアルへの基礎的知見を得ることを目的とした。
    【成果と考察】正常マウス肝ではplasmacytoid DC(pDC)抗原(PDCA-1)を強発現するCD11c^<low>I-A^-DCが優位を占め、CpG刺激によりIFN-α産生が強く誘導されることから、pDCであることが確認できた。脾ではCD205陽性のCD11c^<high>I-A^+DC(myeloid DC:mDC)が優位を占める。感染急性期(Day7)において、肝及び脾のCD11c^<low>I-A^-B220^+DCが著しく増加し、CD86の強発現が認められたが、PDCA-1抗原の発現は低下しIFN-αの産生も低下した。一方、肝及び脾のCD11c^<high>I-A^+DCは減少した。このようなDCサブセットの表面抗原変化は、血中から原虫が排除される感染後期(Day25以降)から回復してきた。致死株感染マウスでは、非致死株感染と同様にCD11c^<low>I-A^-DCでのPDCA-1抗原の発現低下だけでなく両DCサブセットでのB220とCD86抗原の発現も低下し、両者の間に明らかな差異が認められた。CpG刺激による炎症性サイトカインであるIL-12、IL-10やTNFαの産生能は、感染の有無にかかわらず肝臓及び脾臓のCD11c^<high>I-A^+DCで高く、CD11c^<low>I-A^-DCではいずれも低値を示した。これらの結果から、マラリア原虫感染に伴ない肝DCの性状が変化し、また、原虫株による違いも見られることが明らかとなった。すなわち、肝のmDC分画は感染によりIL-12やTNFα産生を誘導することにより感染防御を担うNKT細胞の活性化に関与し、一方、pDC分画ではIFN-α産生能の低下に伴いウイルス感染防御能等が低下するものと考えられた。

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  • 生体肝移植における樹状細胞とNKT細胞の動態による拒絶発見とその制御機講の解析

    研究課題/領域番号:15790275  2003年 - 2004年

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    富山 智香子

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    配分額:3500000円 ( 直接経費:3500000円 )

    本研究課題において、得られた成果を以下に示す。
    1.ヒト生体部分肝移植での移植片拒絶と移植肝内樹状細胞とNKT細胞との関連性
    ヒト正常肝内樹状細胞(dendritic cells : DC)は表面マーカー上成熟型、逆に末梢血内DCは未熟型であることを前年度に報告している。また、生体肝移植におけるトレランス誘導には移植肝内CD28^+CD56^+T細胞の減少とdonor type CD56^+T細胞のキメリズムの長期形成が重要であることを我々のグループは報告している。今回、肝移植におけるトレランス誘導と肝および末梢血の樹状細胞との関連性を調べるために、生着している症例と拒絶反応を起こした症例とでその違いについて検討を行った。その結果、移植肝内では拒絶反応を起こした症例は生着している症例と比べ、成熟型DCの割合の減少を認めた。しかし、末梢血ではDC全体の割合が増加傾向にあるものの、正常と同様に未熟型DCが多かった。このことから、成熟型である肝DCがトレランスを誘導し、移植片生着に重要な働きをしていることが示唆された。またこのことから、移植肝内のDCの性状を調べることにより、拒絶反応の早期発見の可能性も示唆された。
    2.マウス肝樹状細胞の機能解析
    マウス肝DCは脾と比べ、表面マーカー的、および機能的にみて未熟型が多く存在すると考えられることを前年度報告した。今回は、機能解析としてDCの自然免疫で働いている重要な分子であるToll-like receptor(TLR)に着目し、またDCとT,B細胞間のinteractionに糖鎖が関係していることが近年報告され始めてきているため、この点について解析を行った。その結果、肝DCは脾と比べ、TLR2およびTLR3の低発現という特徴が見られた。糖鎖については、ジ-N-アセチルキトビオース、およびN-アセチルガラクトサミンの高結合性が見られた。

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