| Project/Area Number |
17K10010
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Collagenous pathology/Allergology
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| Research Institution | University of Occupational and Environmental Health, Japan |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | 全身性エリテマトーデス / 濾胞性ヘルパーT細胞 / 免疫フェノタイプ / エピジェネティクス / JAK阻害薬 / 形質芽細胞 / 免疫フェノタイピング / 内科 / 免疫学 / トランスレーショナルリサーチ |
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| Outline of Final Research Achievements |
We have used an immunophenotyping approach to categorize patients with SLE into distinct subgroups by comprehensive multicolor flow cytometric analysis. We identified three distinct subgroups based on T cell heterogeneity, including a T cell-independent group, a T follicular helper (Tfh) cell-dominant group and a T regulatory (Treg) cell-dominant group. The percentage of patients who were resistant to immunosuppressive treatment was highest among the Tfh cell-dominant group. In vitro analysis demonstrated that IL-12-mediated co-activation of STAT1 and STAT4 alters histone modification, resulting in development of pathogenic Tfh-Th1-like cells. Finally, Tfh/Th1 differentiation was inhibited by selective TYK2 inhibitors. Collectively, our data indicated that the IL-12-TYK2-STAT pathway is a candidate for new therapeutic target for SLE.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究の結果により、SLEの病態においてT細胞ダイナミズムによるheterogeneityが存在することが明らかとなった。SLEの病態に関与するTfh細胞への分化偏向はJAK-STAT経路を介したエピジェネティクス機序で制御されており、これらを標的とした創薬はSLEの治療抵抗性難治性病態への新たな治療戦略に有望である。本研究は、免疫難病であるSLEへの疾患特異的治療の開発に重要な示唆を与え、医療および社会の発展に資するものである。
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