| Project/Area Number |
18K07152
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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 49060:Virology-related
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| Research Institution | Kansai Medical University |
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Principal Investigator |
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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: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | HTLV-1 / ヒト化マウス / 白血病 / PD-1 / 免疫チェックポイント / 細胞障害性T細胞 / CADM1 / Th1 / T-bet / IFN-γ / Ki67 / Granzyme B / ATL / 感染モデル / がん微小環境 |
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| Outline of Final Research Achievements |
To examine the role of PD-1/PD-L1 co-inhibitory signaling in ATL development, we analyzed the effect of anti-PD-1 antibody on the leukemic growth of T-cells in HTLV-1 infected humanized mouse, in which the human immune system against HTLV-1 infection is functionally established.
HTLV-1 infection of humanized mice induced hundreds fold increase of CD4 T-cells and most of infected mice died in 2 months, although the number of CD8 T-cells was similarly elevated in parallel with the overgrowth of CD4 T-cells. Administration of anti-PD-1 antibody substantially retarded the increase of CD4 T-cells as well as CD8+ T-cells in PBL and prolonged the survival of infected mice. Since most of CD8 T-cells in the infected mouse was found to be infected with HTLV-1, the co-inhibitory signals induced by the antigen non-specific activation of CD8 T-cells possibly suppress the anti-HTLV-1 immunity and the blocking of PD-1/PD-L1 pathway could have restored the immunity.
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| Academic Significance and Societal Importance of the Research Achievements |
ヒト免疫系が再構築されたヒト化マウスの系で、抗PD-1抗体の投与がHTLV-1感染細胞の腫瘍性増殖を抑制したことから、ヒト化マウスが免疫チェックポイントシグナル制御を介したATL発症予防法の開発に有用な実験系を提供することが示された。また、ヒト化マウス脾臓内において増殖したCD8T細胞の多くにHTLV-1の感染が観察され、抗HTLV-1宿主免疫への影響が示唆されたことから、HTLV-1感染初期のヒトにおけるCD8T細胞のHTLV-1感染、およびその抗HTLV-1宿主免疫ヘの関与に注目することで、ATL発症の初期過程の理解に新たな方向性を与えるものと期待される。
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