| Project/Area Number |
19K18007
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 54040:Metabolism and endocrinology-related
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| Research Institution | Osaka University |
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Principal Investigator |
Fujita Yukari 大阪大学, 医学系研究科, 寄附講座助教 (60837003)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | PD-L1の発現 / PD-L1発現 / β細胞量 / α細胞量 / 膵島炎 / Tリンパ球 / 免疫チェックポイント阻害薬 / 1型糖尿病 |
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| Outline of Research at the Start |
本研究の目的は、免疫チェックポイント阻害薬（ICI)による1型糖尿病発症機序を組織学的に明らかにし、ICI投与患者における同糖尿病の発症予測につなげるために、
①ICIの投与を受けた後に1型糖尿病を発症した患者の膵組織を用いて糖尿病発症機序の組織学的解明、②MHCテトラマー試薬を使用し、ICIの投与を受けた患者末梢血における抗原特異的Ｔ細胞の検出、③ハイリスク患者の臨床的特徴付けおよび今後の発症予測への展開
を行っていく予定である。
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| Outline of Final Research Achievements |
Pancreatic tissues from 3 patients who developed type 1 diabetes after PD-1 antibody treatment (T1D), 3 patients who did not develop type 1 diabetes despite PD-1 antibody treatment (non-T1D), and 7 patients with normal glucose tolerance (control) were used to compare pancreatic beta cell volume, islet inflammation, and PD-L1 expression. Pancreatic β-cell volume was markedly decreased in T1D. Insulitis was observed in T1D and non-T1D, but not in control. PD-L1 expression in pancreatic β-cells was markedly decreased in the PD-1 antibody-treated patients (T1D and non-T1D).
The results suggest that PD-L1 expression in pancreatic beta cells is decreased by PD-1 antibody treatment, resulting in insulitis, but other factors may be involved in whether or not type 1 diabetes develops.
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| Academic Significance and Societal Importance of the Research Achievements |
PD-1抗体の投与により、1型糖尿病非発症者においても膵β細胞のPD-L1発現が低下していることが明らかとなった。ICI関連糖尿病の最大の原因であると考えられ、PD-1抗体を投与される患者では全ての患者が1型糖尿病発症の可能性を念頭に置く必要がある。
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