Development of a new treatment strategy for SLE by artificially restoring epigenomic memory in helper T cells
| Project/Area Number |
20K08815
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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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| Review Section |
Basic Section 54020:Connective tissue disease and allergy-related
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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) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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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 / 濾胞制御性ヘルパーT細胞 / 末梢性ヘルパーT細胞 / エピジェネティクス / サイトカイン / ジェネティクス / ヘルパーT細胞 / ゲノム |
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| Outline of Research at the Start |
本研究では、(1) Tfh細胞の可塑性に関わるゲノム異常とエピゲノム修飾との関連、(2) Tfh細胞に特異的なスーパーエンハンサー・エピゲノム修飾とその誘導因子の同定、(3) Tfh細胞のエピゲノム制御による濾胞性制御性T細胞への形質転換の検証によって、Tfh細胞の人為的なエピゲノム制御によるT細胞の機能修復の可能性を探索する。
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| Outline of Final Research Achievements |
In SLE patients, decreased IL-2 resulted in increased Tfh cells and decreased Tfr cells. IL-2 reduction in SLE patients was associated with genetic regulation of IL-2 by the disease susceptibility gene IL21-AS1. IL-2 induced the conversion of memory Tfh cells to functional Tfr cells by epigenetic regulation via activation of STAT3/STAT5. On the other hand, Tph cells increased in SLE, and their differentiation was induced by TGF-β3 produced from tissue macrophages, unlike Tfh cells, and promoted B cell differentiation and antibody production. These results suggest that IL-2 and TGF-β3, which are involved in the differentiation of pathological T cells in SLE, are novel therapeutic targets mediated by epigenome repair.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究の結果は、SLEの病態においてT細胞の分化や機能の異常がゲノム異常により規定されるSLE特異的なエピゲノム記憶に基づく可能性を示唆する。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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Report
(4 results)
Research Products
(5 results)
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[Journal Article] TGF-β3 in differentiation and function of Tph-like cells and its relevance to disease activity in patients with systemic lupus erythematosus.2022
Author(s)
Shan Y, Nakayamada S, Nawata A, Yamagata K, Sonomoto K, Tanaka H, Satoh-Kanda Y, Nguyen MP, Todoroki Y, Nagayasu A, Ueno M, Kanda R, Fujita Y, Zhang T, Hao H, Zhou J, Ma X, Anan J, Nguyen AP, Tanaka Y.
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Journal Title
Rheumatology (Oxford).
Volume: keac646.
Issue: 7
Pages: 2464-2474
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] IL-2 drives conversion of T follicular helper cells to T follicular regulatory cells through transcriptional regulation in systemic lupus erythematosus.2021
Author(s)
Hao H, Nakayamada S, Yamagata K, Ohkubo N, Iwata S, Inoue Y, Zhang M, Zhang T, Kanda Satoh Y, Shan Y, Otsuka T, Tanaka Y.
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Journal Title
Arthritis Rheumatol.
Volume: 73
Issue: 1
Pages: 132-142
DOI
Related Report
Peer Reviewed / Open Access
