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再生胸腺微小環境によるT細胞の誘導　　―γδT細胞の産生と悪性腫瘍への応用―

再生胸腺微环境诱导T细胞-γδT细胞的产生及其在恶性肿瘤中的应用-

基本信息

批准号：
21K06977
负责人：
保坂直樹
金额：
$ 2.66万
依托单位：
Kansai Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2021
资助国家：
日本
起止时间：
2021-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-21K06977/
关键词：
胸腺 γδT細胞再生

项目摘要

本研究課題ではin vitroにてマウス人工性多能性幹細胞（induced pluripotent stem cells, iPSC）から胸腺上皮細胞(thymic epithelial cells, TEC)を誘導し、胸腺微小環境を構築の下、非iPS細胞由来の造血幹細胞(hematopoietic stem cells: HSC)との共培養によりγδT細胞の誘導を試みるものである。これらのγδT細胞は腫瘍化への危険が低く、治療への応用が期待できる。本課題では特に抗腫瘍効果について調べる。方法として、まずiPSCに適宜Activin A, Fibroblast growth factor(FGF)7, FGF8, FGF10, bone morphogenetic protein (BMP) 4を加え、内中胚葉及び胚体内胚葉を経由してTECを誘導させる。次に骨髄細胞(bone marrow cells:BMC)における単核球からlineage marker陽性細胞をmagnetic beads法にて除去し、HSCとして精製する(HSC-eBMC)。これらのTECとHSC-eBMCをサイトカインの存在下に相互作用させると、γδT細胞が誘導された。副作用を調べる為に自家骨髄移植したマウスに投与したが、明らかな自己免疫疾患や腫瘍の発生は見られず長期に生存した。また担白血病腫瘍マウスに投与すると、腫瘍の抑制とともに延命効果が得られた(J Cell Mol Med. 25: 10604, 2021)。次にin vitroにて、PD-L1発現腫瘍細胞への抗腫瘍効果を調べた。誘導γδT細胞との共培養にて、PD-1抗体投与郡と非投与群とを比較した所、前者ではγδT細胞の割合が増え、かつ腫瘍細胞の割合が減る傾向にあった。またこれらの実験で使用するiPSCを肝細胞由来のものに変えても、同様のγδT細胞の誘導が見られた。

This research topic is based on the induction of artificial pluripotent stem cells (iPSC) in vitro, thymic epithelial cells (TEC), construction of thymus microenvironment, and hematopoietic stem cells (hematopoietic stem cells) derived from non-iPS cells: HSC) and co-culture and induction of γδ T cells are tested. The risk of inflammation of γδ T cells is low, and the treatment is not expected to be effective. The purpose of this topic is to adjust the anti-tumor effect. Methods: Activin A, Fibroblast growth factor (FGF) 7, FGF8, FGF10, bone morphogenetic protein (BMP) 4, Activin A, Fibroblast growth factor (FGF) 7, FGF8, FGF10, and bone morphogenetic protein (BMP) 4 were added into iPSC and endoblasts, and endomesoblasts and embryonic endodermis were induced by TEC. Bone marrow cells (BMC) are removed by the magnetic beads method, and HSC is purified (HSC-eBMC). In the presence of TEC and HSC-eBMC, it can interact with each other and induce γδ T cells. The side effects are as follows: Home-made bone grafts are used for transplantation, and long-term survival of autoimmune diseases such as swelling and ulcers is known. It is used to treat leukemia tumors and has a life-prolonging effect on the suppression of tumors and tumors (J Cell Mol Med. 25: 10604, 2021). The anti-tumor effect of PD-L1 on tumor cells has been demonstrated in vitro. Induced γδ T cells were co-cultured, PD-1 antibody-administered counties and non-administered groups were compared, former γδ T cells were cut and combined, and tumor cells were cut and combined to reduce the trend. We use iPSC to induce liver cells and induce γδ T cells.