Elucidation of the pathogenic mechanism of autoimmune pituitary diseases

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K20933
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0904:Internal medicine of the bio-information integration and related fields
• Research Institution: Kyoto University (2022); Kobe University (2021)
• Principal Investigator: KANIE Keitaro 京都大学, iPS細胞研究所, 研究員 (90905829)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Keywords: iPS細胞 / 下垂体機能低下症 / 自己免疫疾患 / 自己免疫性下垂体疾患 / 自己免疫性下垂体炎 / キラーT細胞 / 細胞傷害性T細胞

Outline of Final Research Achievements

Few models using induced pluripotent stem cells (iPSCs) have been reported for autoimmune diseases. Anti-pituitary-specific transcription factor (PIT)-1 hypophysitis is caused by autoimmunity against PIT-1-expressing anterior pituitary cells, and cytotoxic T cells (CTLs) play an essential role in the disease. Using tissues expressing the same human leukocyte antigen (HLA) is essential for establishing a T cell-mediated autoimmune disease model; therefore, we used patient-derived iPSCs. First, we cloned PIT-1-specific CTLs and determined the set of epitopes and T cell receptors. Then we analyzed the cytotoxicity of the iPSC-derived pituitary cells in co-culture with CTLs. Activation of CTLs and PIT-1-positive cell-specific cytotoxicity were observed only in co-culture of iPSC-derived pituitary cells and PIT-1-specific CTLs. Furthermore, we determined specific T cell receptors and HLA haplotypes. Specific cytotoxicity was inhibited by immunosuppressive agents.

Free Research Field

自己免疫性下垂体疾患

Academic Significance and Societal Importance of the Research Achievements

一部の自己免疫疾患では、その発症に特異的なキラーT細胞の関与が示唆されているが、特異的抗原の同定および病原性キラーT細胞の単離は困難であった。本研究では、①患者末梢血液より病原性をもつキラーT細胞を単離する方法を開発し、②自己免疫性下垂体炎の患者由来iPS細胞を利用した疾患モデルを作成した。