Study of the mechanism in the development of destructive thyroiditis induced by anti-PD-1 antibody

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08976
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Nagoya University
• Principal Investigator: Iwama Shintaro 名古屋大学, 医学部附属病院, 講師 (00733536)
• Co-Investigator(Kenkyū-buntansha): 有馬 寛 名古屋大学, 医学系研究科, 教授 (50422770)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 甲状腺炎 / PD-1 / 免疫チェックポイント

Outline of Final Research Achievements

Anti-PD-1 antibodies (PD-1-Ab) often cause destructive thyroiditis (DT). However, the T cell subsets involved in this situation remain unclear. PD-1-Ab injections after immunization with thyroglobulin induced DT. DT was completely prevented by previous depletion of CD4 T cells. The frequencies of central and effector memory CD4 T cell subsets were increased in mice with DT compared with controls. CD4 T cells expressed granzyme B in thyroid glands in mice with DT. Adoptive transfer of CD4 T cells from cervical lymph nodes in mice developing DT caused destruction of thyroid follicular architecture in the recipient mice. Flow cytometric analyses showed that the frequencies of central and effector memory CD4 T cells expressing the cytotoxic marker CD27 were higher in peripheral blood collected from patients with DT induced by PD-1-Ab versus those without. These data suggest a critical role for cytotoxic memory CD4 T cells in the pathogenesis of DT induced by PD-1-Ab.

Free Research Field

内分泌学

Academic Significance and Societal Importance of the Research Achievements

免疫チェックポイント阻害薬は細胞傷害作用を有するCD8陽性T細胞の活性化を介して抗腫瘍作用を発揮するが、免疫機序の関与する有害事象（irAEs）の発生が問題となっている。本研究より、抗PD-1抗体による破壊性甲状腺炎の発症には細胞傷害作用を示すCD4陽性T細胞が必須の役割を果たしていることが明らかとなった。本結果は、現在広く使用されている抗PD-1抗体による副作用の機序の解明およびその予防法の確立に繋がる成果と考えられる。