| Project/Area Number |
18K08381
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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 Tsukuba |
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Principal Investigator |
Tsuboi Hiroto 筑波大学, 医学医療系, 講師 (80580505)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | IgG4関連疾患 / ケモカイン / CCL18 / CCL8 / CCR8 / モデルマウス / シェーグレン症候群 / 口唇唾液腺 |
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| Outline of Final Research Achievements |
We analyzed the pathogenic roles and therapeutic potential of chemokine CCL18-CCR8, which is the receptor for CCL18, signal in IgG4-related disease. CCL18 producing macrophages, dendritic cells, plasmacytes, and B cells were increased in affected organs of IgG4-related disease. Interestingly, CCL18 specifically enhanced IgG4 production by peripheral blood mononuclear cells stimulated with CD40L, IL-4, IL-10, and IL-21 in vitro assays. Moreover, we showed that LATY136F knock in mouse (LAT mice), which is one of the model mice for IgG4-related disease, had enhanced CCL8 (functional analogue of human CCL18)-CCR8 axis. Importantly, anti-CCL8 neutralizing antibody could improve the inflammatory cells infiltration and fibrosis in the salivary glands of the LAT mice.
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| Academic Significance and Societal Importance of the Research Achievements |
IgG4関連疾患におけるCCL18-CCR8シグナルの病態形成における役割と治療標的の可能性をはじめて明らかにした。今後CCL18-CCR8経路を標的とした新規治療戦略の有効性を、疾患モデルマウスを用いてin vivo、ヒト細胞を用いてin vitroで検証する予定である。本研究成果は、IgG4関連疾患の病態に基づく疾患特異的新規治療戦略の構築に繋がる有意義なものと考えられる。本経路を標的とした治療戦略の実用化は、ステロイド減量後の再燃が多いIgG4関連疾患の再燃予防やステロイドの更なる減量に寄与できる可能性が期待される。
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