吉村　昭彦 （ヨシムラ　アキヒコ）

Yoshimura, Akihiko

写真a

所属（所属キャンパス）

医学部 （三田）

職名

名誉教授

HP
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  • 学歴 1981年　　3月　　　京都大学理学部　卒業 1985年　　6月　　　京都大学理学研究科博士課程 修了 学位 理学博士　（京都大学・1986年） 職歴 1985 年 7月　 大分医科大学生化学教室・助手 1987 年 9月　鹿児島大学医学部 腫瘍研究施設・助手 1989 年 6月　　　　　　　同　　助教授 1989-1991　アメリカ合衆国MIT　Whiteheadホワイトヘッド研究所のLodish研に留学 1995 年 6月 久留米大学分子生命科学研究所・教授 2001年1月　九州大学生体防御医学研究所・教授 2008　年　4月　　慶應義塾大学医学部・免疫微生物学教室　教授 受賞　　　 平成10年度　日本生化学会奨励賞 平成13年度　日本免疫学会賞 平成19年度　日本生化学会柿内三郎賞 平成19年度 持田記念学術賞

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  • 当教室の研究目標は『分子の言葉で疾患を理解する』ということで、主に免疫系を中心に研究を行っています。私は若い人達が成長し、かつ私自身も刺激をうけ成長できるようなラボをつくりたいと常々思っています。科学は想像力と創造の学問です。学生と私で新しいものを生み出し世に問うていくことが私の仕事で す。その過程で学生は成長していく。私のラボの第一の使命はMD,PhDを問わず、医学生物学分野の研究者を育てることです。

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  • Significant association between joint ultrasonographic parameters and synovial inflammatory factors in rheumatoid arthritis

    Kondo Y., Suzuki K., Inoue Y., Sakata K., Takahashi C., Takeshita M., Kassai Y., Miyazaki T., Morita R., Niki Y., Kaneko Y., Yasuoka H., Yamaoka K., Yoshimura A., Takeuchi T.

    Arthritis Research and Therapy （Arthritis Research and Therapy）  21 （ 1 ）  2019年10月

    ISSN  14786354

    　概要を見る

    © 2019 The Author(s). Background: Ultrasonography (US) can directly demonstrate joint inflammation, including grayscale (GS) signs of synovial hypertrophy and power Doppler (PD) techniques to demonstrate increased blood flow and vascularization. Recently, echogenicity, especially hypoechoic synovium, has also been associated with local inflammatory activity. However, only a few studies have demonstrated correlation between histopathologic and immunopathologic evaluation and US findings. The aim of this study was to clarify whether joint US findings including synovial hypertrophy, vascularity, and echogenicity can accurately characterize synovial pathophysiology in patients with active rheumatoid arthritis (RA). Methods: A total of 44 patients with RA were included, both treated (n = 25) and untreated (n = 19) and scheduled for US examination of the knee joint with synovial fluid (SF) aspiration and two treated patients also underwent synovial biopsy. US images were quantitatively analyzed using grayscale assessment of synovial hypertrophy and PD for vascularity and echogenicity. Levels of nine SF cytokines and growth factors were also measured. Results: Both US synovial hypertrophy and PD vascularity significantly correlated with SF inflammatory cytokine levels such as IL-6, IL-8, IL-1β and IL-10 in untreated patients. Angiogenic factors, including vascular endothelial growth factor (VEGF), only correlated with PD vascularity. In the treated patients, the associations between synovial hypertrophy and any cytokines were diminished, although synovial vascularity and echogenicity correlated with IL-6 and VEGF (p < 0.05). Histopathologic analysis revealed that hypoechogenicity of the synovium correlated with marked infiltration of lymphocytes and hypervascularity. Conclusions: We demonstrated the pathophysiological origins of US findings in the joint. The degree of US vascularity of the synovium correlated with local inflammatory cytokine levels and angiogenetic factors in patients with active RA. Synovial echogenicity, and not hypertrophy, correlated with inflammation, especially in treated patients with RA.

  • miR-181a/b-1 controls thymic selection of Treg cells and tunes their suppressive capacity

    Łyszkiewicz M., Winter S., Witzlau K., Föhse L., Brownlie R., Puchałka J., Verheyden N., Kunze-Schumacher H., Imelmann E., Blume J., Raha S., Sekiya T., Yoshimura A., Frueh J., Ullrich E., Huehn J., Weiss S., Gutierrez M., Prinz I., Zamoyska R., Ziętara N., Krueger A.

    PLoS biology （PLoS biology）  17 （ 3 ）  2019年03月

    　概要を見る

    The interdependence of selective cues during development of regulatory T cells (Treg cells) in the thymus and their suppressive function remains incompletely understood. Here, we analyzed this interdependence by taking advantage of highly dynamic changes in expression of microRNA 181 family members miR-181a-1 and miR-181b-1 (miR-181a/b-1) during late T-cell development with very high levels of expression during thymocyte selection, followed by massive down-regulation in the periphery. Loss of miR-181a/b-1 resulted in inefficient de novo generation of Treg cells in the thymus but simultaneously permitted homeostatic expansion in the periphery in the absence of competition. Modulation of T-cell receptor (TCR) signal strength in vivo indicated that miR-181a/b-1 controlled Treg-cell formation via establishing adequate signaling thresholds. Unexpectedly, miR-181a/b-1-deficient Treg cells displayed elevated suppressive capacity in vivo, in line with elevated levels of cytotoxic T-lymphocyte-associated 4 (CTLA-4) protein, but not mRNA, in thymic and peripheral Treg cells. Therefore, we propose that intrathymic miR-181a/b-1 controls development of Treg cells and imposes a developmental legacy on their peripheral function.

  • Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis

    Nakamoto N., Sasaki N., Aoki R., Miyamoto K., Suda W., Teratani T., Suzuki T., Koda Y., Chu P., Taniki N., Yamaguchi A., Kanamori M., Kamada N., Hattori M., Ashida H., Sakamoto M., Atarashi K., Narushima S., Yoshimura A., Honda K., Sato T., Kanai T.

    Nature Microbiology （Nature Microbiology）  4 （ 3 ） 492 - 503 2019年03月

    　概要を見る

    © 2019, The Author(s), under exclusive licence to Springer Nature Limited. Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease and its frequent complication with ulcerative colitis highlights the pathogenic role of epithelial barrier dysfunction. Intestinal barrier dysfunction has been implicated in the pathogenesis of PSC, yet its underlying mechanism remains unknown. Here, we identify Klebsiella pneumonia in the microbiota of patients with PSC and demonstrate that K. pneumoniae disrupts the epithelial barrier to initiate bacterial translocation and liver inflammatory responses. Gnotobiotic mice inoculated with PSC-derived microbiota exhibited T helper 17 (T H 17) cell responses in the liver and increased susceptibility to hepatobiliary injuries. Bacterial culture of mesenteric lymph nodes in these mice isolated K. pneumoniae, Proteus mirabilis and Enterococcus gallinarum, which were prevalently detected in patients with PSC. A bacterial-organoid co-culture system visualized the epithelial-damaging effect of PSC-derived K. pneumoniae that was associated with bacterial translocation and susceptibility to T H 17-mediated hepatobiliary injuries. We also show that antibiotic treatment ameliorated the T H 17 immune response induced by PSC-derived microbiota. These results highlight the role of pathobionts in intestinal barrier dysfunction and liver inflammation, providing insights into therapeutic strategies for PSC.

  • Pulmonary phagocyte-derived NPY controls the pathology of severe influenza virus infection

    Fujiwara S., Hoshizaki M., Ichida Y., Lex D., Kuroda E., Ishii K., Magi S., Okada M., Takao H., Gandou M., Imai H., Hara R., Herzog H., Yoshimura A., Okamura H., Penninger J., Slutsky A., Uhlig S., Kuba K., Imai Y.

    Nature Microbiology （Nature Microbiology）  4 （ 2 ） 258 - 268 2019年02月

    　概要を見る

    © 2018, The Author(s), under exclusive licence to Springer Nature Limited. Crosstalk between the autonomic nervous system and the immune system by means of the sympathetic and parasympathetic pathways is a critical process in host defence. Activation of the sympathetic nervous system results in the release of catecholamines as well as neuropeptide Y (NPY). Here, we investigated whether phagocytes are capable of the de novo production of NPY, as has been described for catecholamines. We show that the synthesis of NPY and its Y1 receptor (Y1R) is increased in phagocytes in lungs following severe influenza virus infection. The genetic deletion of Npy or Y1r specifically in phagocytes greatly improves the pathology of severe influenza virus infection, which is characterized by excessive virus replication and pulmonary inflammation. Mechanistically, it is the induction of suppressor of cytokine signalling 3 (SOCS3) via NPY–Y1R activation that is responsible for impaired antiviral response and promoting pro-inflammatory cytokine production, thereby enhancing the pathology of influenza virus infection. Thus, direct regulation of the NPY–Y1R–SOCS3 pathway on phagocytes may act as a fine-tuner of an innate immune response to virus infection, which could be a therapeutic target for lethal influenza virus infection.

  • IL-6, IL-17 and Stat3 are required for auto-inflammatory syndrome development in mouse

    Oike T., Kanagawa H., Sato Y., Kobayashi T., Nakatsukasa H., Miyamoto K., Nakamura S., Kaneko Y., Kobayashi S., Harato K., Yoshimura A., Iwakura Y., Takeuchi T., Matsumoto M., Nakamura M., Niki Y., Miyamoto T.

    Scientific Reports （Scientific Reports）  8 （ 1 ）  2018年12月

    　概要を見る

    © 2018, The Author(s). Auto-inflammatory syndrome, a condition clinically distinct from rheumatoid arthritis, is characterized by systemic inflammation in tissues such as major joints, skin, and internal organs. Autonomous innate-immune activation is thought to promote this inflammation, but underlying pathological mechanisms have not been clarified nor are treatment strategies established. Here, we newly established a mouse model in which IL-1 signaling is conditionally activated in adult mice (hIL-1 cTg) and observed phenotypes similar to those seen in auto-inflammatory syndrome patients. In serum of hIL-1 cTg mice, IL-6 and IL-17 levels significantly increased, and signal transducer and activator of transcription 3 (Stat3) was activated in joints. When we crossed hIL-1 cTg with either IL-6- or IL-17-deficient mice or with Stat3 conditional knockout mice, phenotypes seen in hIL-1 cTg mice were significantly ameliorated. Thus, IL-6, IL-17 and Stat3 all represent potential therapeutic targets for this syndrome.

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  • NR4A transcription factors limit CAR T cell function in solid tumours

    Chen J., López-Moyado I., Seo H., Lio C., Hempleman L., Sekiya T., Yoshimura A., Scott-Browne J., Rao A.

    Nature （Nature）  567 （ 7749 ） 530 - 534 2019年03月

    ISSN  00280836

    　概要を見る

    © 2019, The Author(s), under exclusive licence to Springer Nature Limited. T cells expressing chimeric antigen receptors (CAR T cells) targeting human CD19 (hCD19) have shown clinical efficacy against B cell malignancies 1,2 . CAR T cells have been less effective against solid tumours 3–5 , in part because they enter a hyporesponsive (‘exhausted’ or ‘dysfunctional’) state 6–9 triggered by chronic antigen stimulation and characterized by upregulation of inhibitory receptors and loss of effector function. To investigate the function of CAR T cells in solid tumours, we transferred hCD19-reactive CAR T cells into hCD19 + tumour-bearing mice. CD8 + CAR + tumour-infiltrating lymphocytes and CD8 + endogenous tumour-infiltrating lymphocytes expressing the inhibitory receptors PD-1 and TIM3 exhibited similar profiles of gene expression and chromatin accessibility, associated with secondary activation of nuclear receptor transcription factors NR4A1 (also known as NUR77), NR4A2 (NURR1) and NR4A3 (NOR1) by the initiating transcription factor NFAT (nuclear factor of activated T cells) 10–12 . CD8 + T cells from humans with cancer or chronic viral infections 13–15 expressed high levels of NR4A transcription factors and displayed enrichment of NR4A-binding motifs in accessible chromatin regions. CAR T cells lacking all three NR4A transcription factors (Nr4a triple knockout) promoted tumour regression and prolonged the survival of tumour-bearing mice. Nr4a triple knockout CAR tumour-infiltrating lymphocytes displayed phenotypes and gene expression profiles characteristic of CD8 + effector T cells, and chromatin regions uniquely accessible in Nr4a triple knockout CAR tumour-infiltrating lymphocytes compared to wild type were enriched for binding motifs for NF-κB and AP-1, transcription factors involved in activation of T cells. We identify NR4A transcription factors as having an important role in the cell-intrinsic program of T cell hyporesponsiveness and point to NR4A inhibition as a promising strategy for cancer immunotherapy.

  • Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery

    Ito M., Komai K., Mise-Omata S., Iizuka-Koga M., Noguchi Y., Kondo T., Sakai R., Matsuo K., Nakayama T., Yoshie O., Nakatsukasa H., Chikuma S., Shichita T., Yoshimura A.

    Nature （Nature）  565 （ 7738 ） 246 - 250 2019年01月

    ISSN  00280836

    　概要を見る

    © 2019, Springer Nature Limited. In addition to maintaining immune tolerance, FOXP3 + regulatory T (T reg ) cells perform specialized functions in tissue homeostasis and remodelling 1,2 . However, the characteristics and functions of brain T reg cells are not well understood because there is a low number of T reg cells in the brain under normal conditions. Here we show that there is massive accumulation of T reg cells in the mouse brain after ischaemic stroke, and this potentiates neurological recovery during the chronic phase of ischaemic brain injury. Although brain T reg cells are similar to T reg cells in other tissues such as visceral adipose tissue and muscle 3–5 , they are apparently distinct and express unique genes related to the nervous system including Htr7, which encodes the serotonin receptor 5-HT 7 . The amplification of brain T reg cells is dependent on interleukin (IL)-2, IL-33, serotonin and T cell receptor recognition, and infiltration into the brain is driven by the chemokines CCL1 and CCL20. Brain T reg cells suppress neurotoxic astrogliosis by producing amphiregulin, a low-affinity epidermal growth factor receptor (EGFR) ligand. Stroke is a leading cause of neurological disability, and there are currently few effective recovery methods other than rehabilitation during the chronic phase. Our findings suggest that T reg cells and their products may provide therapeutic opportunities for neuronal protection against stroke and neuroinflammatory diseases.

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競争的研究費の研究課題 【 表示 ／ 非表示 】

  • メモリーT細胞の疲弊化の分子機構の解明とそのリプログラム法の開発

    2022年06月
    -
    2024年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 吉村 昭彦, 挑戦的研究（萌芽）, 補助金,  研究代表者

  • 獲得免疫による脳内炎症の制御および修復機構の解明

    2021年07月
    -
    2026年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 吉村 昭彦, 基盤研究(S), 補助金,  研究代表者

  • 代謝とエピゲノム改変によるT細胞リプログラミング法の開発

    2018年06月
    -
    2021年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 吉村　昭彦, 挑戦的研究(開拓), 補助金,  研究代表者

  • 炎症の終息と組織修復に関与する免疫細胞システムの解明

    2017年05月
    -
    2022年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 吉村　昭彦, 基盤研究(S), 補助金,  研究代表者

  • Stem Cell Memory T細胞の創出と応用

    2016年04月
    -
    2019年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 吉村　昭彦, 挑戦的萌芽研究, 補助金,  研究代表者

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受賞 【 表示 ／ 非表示 】

  • ベストティーチャー賞

    2014年, 慶應義塾大学医学部

  • 持田記念学術賞

    2007年, 持田財団

  • 日本生化学会柿内三郎賞

    2007年, 日本生化学会

  • 日本免疫学会賞

    2001年, 日本免疫学会

  • 日本生化学会奨励賞

    1998年, 日本生化学会

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担当授業科目 【 表示 ／ 非表示 】

  • 微生物学・免疫学

    2024年度

  • 微生物学

    2024年度

  • 人体の生理

    2023年度

  • 微生物学・免疫学演習

    2023年度

  • 微生物学・免疫学実習

    2023年度

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  • 微生物学免疫学

    慶應義塾

    2015年04月
    -
    2016年03月
    , 

    春学期, 実習・実験, 兼担, 2時間, 110人

    抗体産生，グラム染色、ウイルス検定

  • 微生物学免疫学

    慶應義塾

    2015年04月
    -
    2016年03月
    , 

    春学期, 講義, 専任, 8時間, 110人

    免疫疾患、細菌、ウイルス　

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