2020 Fiscal Year Final Research Report

Elucidation of novel rejection mechanism after HLA-matched transplantation using allogeneic iPS cells

Research Project

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Project/Area Number	20K20391
Project/Area Number (Other)	18H05385 (2018-2019)
Research Category	Grant-in-Aid for Challenging Research (Pioneering)
Allocation Type	Multi-year Fund (2020) Single-year Grants (2018-2019)
Review Section	Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
Research Institution	Hiroshima University
Principal Investigator	Ohdan Hideki 広島大学, 医系科学研究科(医), 教授 (10363061)
Co-Investigator(Kenkyū-buntansha)	大平真裕広島大学, 病院(医), 助教 (30397947) 田原裕之広島大学, 病院(医), 助教 (30423354) 井手健太郎広島大学, 病院(医), 講師 (50511565) 田中友加広島大学, 医系科学研究科(医), 准教授 (90432666)
Project Period (FY)	2018-06-29 – 2021-03-31
Keywords	iPS細胞 / 他家細胞移植 / HLA一致 / SIRPα / 拒絶反応 / 免疫制御 / 自然免疫 / 獲得免疫
Outline of Final Research Achievements	The Signal regulatory protein α (SIRPα) -CD47 system is known as a self-tolerant mechanism for macrophages and dendritic cells. In this study, we elucidated that SIRPα gene polymorphisms act as an HLA-independent allorecognition mechanism, and that allogeneic cells derived from HLA3-locus iPS cells are targets of innate immune response. The activation pathway of T cells that operates after allogeneic cell transplantation is classified into direct recognition and indirect recognition pathways. Rejection that can be avoided by HLA-matched allogeneic transplantation is limited to those via the direct recognition pathway. In this study, we elucidated the mechanism by which hepatic sinusoidal endothelial cells specifically tolerate the T cell response to minor tissue-compatible antigens that elicit an immune response through the indirect recognition pathway.
Free Research Field	外科学一般
Academic Significance and Societal Importance of the Research Achievements	HLA3座一致iPS細胞由来の他家細胞移植においても、SIRPα遺伝子多型によりHLA非依存性のアロ認識機構が作動して拒絶反応が惹起され、抗SIRPα抗体によりその応答が回避し得る可能性が示された。この成果は、新規拒絶機構の解明と克服法の開発に繋がる。マイナー組織適合抗原に対するT細胞応答による拒絶反応を、肝類洞内皮細胞への抗原パルスによって回避できれば、免疫抑制薬を使用することなく移植されえたHLA3座一致iPS細胞由来の他家細胞永久生着させることが期待できる。以上の成果は、HLA一致iPS細胞由来の他家細胞移植における新たな免疫制御法として、再生医療への応用に期待できる。