| Project/Area Number |
19K23863
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund |
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| Review Section |
0803:Pathology, infection/immunology, and related fields
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| Research Institution | Kyoto University |
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Principal Investigator |
Wang Bo 京都大学, iPS細胞研究所, 研究員 (80842765)
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| Project Period (FY) |
2019-08-30 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | iPSC derived T cells / immune rejection / gene editing / iPSC-derived T cells / iPSCs / Activated iPS-T cells / PVR / adoptive T cells therapy |
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| Outline of Research at the Start |
To generate a “universal” iPS cell source for T cells toward following steps: (1) generate HLA Class I null iPSC by targeting the gene B2M, which is required for HLA calss I presentation on the cell surface. (2) generate HLA Class II null iPSC by knocking out their transactivator, CIITA, which must be a matter to allo-CD4 T cells since activated T cells naturally express HLA-II. (3) Express a defined NK cell inhibitory ligand, HLA-E to inhibit NK cells. (4) Selected deleting the NK cell activating ligands to decrease the factors which activate NK cells.
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| Outline of Final Research Achievements |
Avoiding the immune rejection of transplanted T cells is central to the success of allogeneic cancer immunotherapies. One solution to protecting T-cell grafts from immune rejection involves the deletion of allogeneic factors and of factors that activate cytotoxic immune cells. Here we report the generation of hypoimmunogenic T cells derived from induced pluripotent stem cells (iPSCs) lacking β2-microglobulin, the class-II major histocompatibility complex (MHC) transactivator and the natural killer (NK) cell-ligand poliovirus receptor PVR, and expressing single-chain MHC class-I antigen E. In mouse models of CD20-expressing leukaemia or lymphoma, differentiated T cells expressing a CD20 chimeric antigen receptor largely escaped recognition by NKG2A+ and DNAM-1+ NK cells and by CD8 and CD4 T cells in the allogeneic recipients while maintaining anti-tumour potency. Hypoimmunogenic iPSC-derived T cells may contribute to the creation of off-the-shelf T cell immunotherapies.
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| Academic Significance and Societal Importance of the Research Achievements |
ユニバーサルなT細胞免疫療法を目指してT細胞に直接ゲノム編集を行うさまざまな研究が行われてきましたが、ゲノム編行うことでT細胞の能力が弱まる可能性がある。本研究はこの問題を解決する方法として、iPS細胞の段階でゲノム編集を行い、それを分化させることでT細胞の弱体化を防ぎ、かつレシピエントの免疫細胞から攻撃を受けにくいT細胞を作製することに成功した。
本研究で示した方法は、国内外で開発の進む他家iPS細胞を用いたT細胞免疫療法において、近い将来に応用される可能性があります。
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