Yoshimura, Akihiko

写真a

Affiliation

School of Medicine (Mita)

Position

Professor Emeritus

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  • Education: Undergraduate: 1976-1980 Kyoto University, Kyoto, Japan Biology and Chemistry B.S. awarded 3/80 Graduate: 1980-1985 Kyoto University, Kyoto, Japan Department of Biophysics Ph.D. awarded 3/86 Research Appointment: 1985-1987 Assistant Professor Oita Medical School, Oita, Japan 1987-1989 Assistant Professor Cancer Research Institute Kagoshima University, Kagoshima, Japan 1989-1991 Postdoctoral Research Fellow Whitehead Institute for Biomedical Research, MIT Cambridge, MA, USA 1989-1995 Associate Professor, Kagoshima University, Kagoshima, Japan 1995-2000 Professor, Insutitute of Life Science, Kurume University Kurume, Japan 2001-2008 Professor, Medical Institute of Bioregulation, Kyushu University Fukuoka, Japan 2008- present Professor, Department of Microbiology and Immunology, Keio University of Medicine Award Japan Biochemistry Society Award 1998 Japan Immunology Society Award 2001 Mochida Memorial Award 2007 Kakiuchi Samuro Award (Japan Biochemical Society) 2007

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Message from the Faculty Member 【 Display / hide 】

  • 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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Papers 【 Display / hide 】

  • 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 )  2019.10

    ISSN  14786354

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    © 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 )  2019.03

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    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 2019.03

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    © 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 2019.02

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    © 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 )  2018.12

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    © 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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Papers, etc., Registered in KOARA 【 Display / hide 】

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Reviews, Commentaries, etc. 【 Display / hide 】

  • 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 2019.03

    ISSN  00280836

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    © 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 2019.01

    ISSN  00280836

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    © 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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Research Projects of Competitive Funds, etc. 【 Display / hide 】

  • Elucidation of the molecular mechanism of memory T cell exhaustion and development of its reprogramming method

    2022.06
    -
    2024.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 挑戦的研究（萌芽）, Principal investigator

  • Brain inflammation and repair mechanism by adaptive immunity

    2021.07
    -
    2026.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (S), Principal investigator

  • T cell reprogramming by metabolic and epigenetic modification

    2018.06
    -
    2021.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Challenging Research (Pioneering), Principal investigator

  • Immune systems involved in the resolution of inflammation and tissue repair

    2017.05
    -
    2022.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (S), Principal investigator

  • Stem Cell Memory T細胞の創出と応用

    2016.04
    -
    2019.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Challenging Exploratory Research, Principal investigator

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Awards 【 Display / hide 】

  • ベストティーチャー賞

    2014, 慶應義塾大学医学部

  • 持田記念学術賞

    2007, 持田財団

  • 日本生化学会柿内三郎賞

    2007, 日本生化学会

  • 日本免疫学会賞

    2001, 日本免疫学会

  • 日本生化学会奨励賞

    1998, 日本生化学会

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Courses Taught 【 Display / hide 】

  • MICROBIOLOGY AND IMMUNOLOGY

    2024

  • MICROBIOLOGY

    2024

  • PHYSIOLOGY OF HUMAN BODY

    2023

  • MICROBIOLOGY AND IMMUNOLOGY: SEMINAR

    2023

  • MICROBIOLOGY AND IMMUNOLOGY: PRACTICE

    2023

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Courses Previously Taught 【 Display / hide 】

  • microbiology and immunology

    Keio University

    2015.04
    -
    2016.03
    , 

    Spring Semester, Laboratory work/practical work/exercise, Lecturer outside of Keio, 2h, 110people

    antibody production, Gram staining, virus titration

  • microbiology and immunology

    Keio University

    2015.04
    -
    2016.03
    , 

    Spring Semester, Lecture, Within own ｆaculty, 8h, 110people

    immunological disease, bacteria, virus

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