| 研究課題/領域番号 |
21K08152
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| 研究機関 | 名古屋大学 |
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研究代表者 |
コーチン ビタリー 名古屋大学, 医学系研究科, 特任助教 (30648001)
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| 研究期間 (年度) |
2021-04-01 – 2024-03-31
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| キーワード | GPRC5A / irAEs / ICIs / Autoimmune antibody / Cytotoxic T cells |
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| 研究実績の概要 |
Immune Related Adverse Events (irAEs) restrain ICIs use. The irAEs are caused by ICI-induced autoimmune reaction against self-tissues by self-directed antibody (Ab) and/or autoimmune T cells. We found GPRC5A-derived peptide epitope presented by HLA-A24 specifically in lung and currently investigating whether autoreactive T cells and/or Ab to GPRC5A may be responsible for the inflammation and damage in lung tissue of patients that underwent treatment with ICI.
We used plasma samples from patients who developed irAEs in lung (IP) (30) and those who didn’t(36). Samples from healthy donors(30) were used as controls.
Average level of anti-GPRC5A Ab by ELISA in patients was significantly higher than the Ab level in controls. Patients with irAEs had slightly higher Ab level than those without.
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
The objective of the first year (2021-2022) was successfully completed by the optimization of the anti-GPRC5A Ab assay method (ELISA) as well as a pilot screening of a limited number of patients plasma samples that developed/didn't develop irAEs upon ICI treatment.
We have optimized the immunization protocol to induce and assay the peptide/MHC-restricted cytotoxic T cells (CTLs) using ELISpot. We are going to apply the method to induce CTLs directed against GPRC5A self-peptide presented in HLA-A24-restricted manner in HLA-A24 transgenic (Tg) MHC-KO mice. Breeding of the HLA-A24-Tg MHC-KO mice for the experiments is a rather laborious and time-consuming process.
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| 今後の研究の推進方策 |
We are going to increase the number of patients plasma samples to confidently verify whether the anti-GPRC5A Ab level would be associated with irAEs in lung tissue.
We are going to use GPRC5A synthetic peptide in conjunction with the Freund's adjuvant to immunize HLA-A24-Tg MHC-KO mice treated with ICIs to mimic patients treatment conditions. Amino acid sequence of the GPRC5A epitope presented by HLA-A24 in humans is conserved in its murine homolog. Therefore upon induction of self-reactive cellular immune response in HLA-A24-Tg MHC-KO mice we are going to probe whether such induced CTLs would attack HLA-A24-expressing lung tissue causing inflammation and damage similar to irAEs.
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| 次年度使用額が生じた理由 |
Several mass spectrometry experiments were planned this fiscal year. However, establishing primary cancer cell lines to be used for the analyses took longer than expected. Therefore some mass spectrometry experiments were postponed to the next fiscal year. Breeding of the HLA-A24-Tg MHC-knockout mice seems to take longer compared to WT animals. They did not expand to enough numbers this year. Therefore, I postponed some immunization experiments to the next fiscal year.
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