| Project/Area Number |
16K19599
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Collagenous pathology/Allergology
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| Research Institution | Kobe University |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
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| Keywords | 関節リウマチ / 骨髄由来抑制細胞 / 代謝 / 骨髄由来抑制細胞（MDSC） / 骨髄由来抑制細胞 (MDSC) / 免疫学 |
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| Outline of Final Research Achievements |
Glutamine metabolism and the mechanistic mTOR pathway are activated cooperatively in the differentiation and activation of inflammatory immune cells. This study investigated how inhibiting both glutamine metabolism with DON and mTOR with rapamycin affects immune cells and the arthritis in a mouse model. We revealed that rapamycin and DON additively suppressed CD4+ T cell proliferation, and both of them inhibited Th17 cell differentiation. While DON inhibited the differentiation of dendritic cells and macrophages and facilitated that of Ly6G+ granulocytic (G)-MDSCs more strongly than did rapamycin, G-MDSCs treated with rapamycin but not DON suppressed CD4+ T cell proliferation in vitro. The combination of rapamycin and DON significantly suppressed the arthritis in SKG mice more strongly than did each monotherapy in vivo. The numbers of CD4+ T and Th17 cells in the spleen were lowest in mice treated with the combination therapy.
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| Academic Significance and Societal Importance of the Research Achievements |
関節リウマチ治療は生物学的製剤やJAK阻害剤の登場により、治療成績は格段に改善したが、2～3割の関節リウマチ患者では寛解が得られていない。我々はmTOR阻害剤のラパマイシンとグルタミン代謝阻害剤DONの併用療法で関節リウマチモデルであるSKGマウスの関節炎抑制効果を示すことができた。機序としてはCD4陽性T細胞の増殖とTh17細胞の分化を抑制することである。mTORおよびグルタミン代謝を同時に阻害することによる新しい関節リウマチの治療戦略を示すことができた。
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