Role of tumor microenvironment in the chronic infection HTLV-1 and the ATL development
| 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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Report
(4 results)
Research Products
(11 results)
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[Journal Article] The Nature of the HTLV-1 Provirus in Naturally Infected Individuals Analyzed by the Viral DNA-Capture-Seq Approach2019
Author(s)
Katsuya H, Islam S, Tan, Ito J, Miyazato P, Matsuo, Inada Y, Iwase, Uchiyama Yoshikazu、Hata Hiroyuki、Sato T, Yagishita N, Araya N, Ueno T, Nosaka K, Tokunaga M, Yamagishi M, Watanabe T, Uchimaru K, Fujisawa J-i, Utsunomiya A, Yamano Y, Satou Y
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Journal Title
Cell Reports
Volume: 29
Issue: 3
Pages: 724-735
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Identification and Molecular Characterization of a New HTLV-1 Enhancer2019
Author(s)
M. Matsuo, T. Ueno, P. Miyazato, H. Katsuya, S. Islam, B.J. Tan, S. Iwase, M. Tokunaga, K. Nosaka, A. Utsunomya, J. Fujisawa, Y. Satou
Organizer
19th International Conference on Human Retrovirology
Related Report
Int'l Joint Research
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[Presentation] HTLV-1ウィルスエンハンサーはウィルス遺伝子および宿主遺伝子発現の亢進を誘導する2019
Author(s)
松尾美沙希, 上野孝治, 宮里パオラ, 勝屋弘雄, タン ベンジー, ジャック ヤン, イスラム サイフル, 徳永雅仁, 野坂生郷, 宇都宮與, 藤澤順一, 佐藤賢文
Organizer
第6回日本HTLV-1学会学術集会
Related Report
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