| 研究課題/領域番号 |
21K08152
|
|---|
| 研究種目 |
基盤研究(C)
|
| 配分区分 | 基金 |
|---|
| 応募区分 | 一般 |
|---|
| 審査区分 |
小区分53030:呼吸器内科学関連
|
|---|
| 研究機関 | 名古屋大学 |
|---|
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)
|
|---|
| 研究期間 (年度) |
2021-04-01 – 2025-03-31
|
| 研究課題ステータス |
交付 (2023年度)
|
| 配分額 *注記 |
4,030千円 (直接経費: 3,100千円、間接経費: 930千円)
2023年度: 1,170千円 (直接経費: 900千円、間接経費: 270千円)
2022年度: 1,430千円 (直接経費: 1,100千円、間接経費: 330千円)
2021年度: 1,430千円 (直接経費: 1,100千円、間接経費: 330千円)
|
|---|
| キーワード | GPRC5A / irAEs / ICIs / autoimmune Ab / cytotoxic T cells / irAEs, / Autoimmune antibody / Cytotoxic T cells / Lung-related irAEs / Immune checkpoint |
|---|
| 研究開始時の研究の概要 |
We are trying to elucidate the mechanisms that drive the immune-mediated recognition and killing of cancer cells as well as autoimmune damage to normal/healthy cells (immune-related adverse events, irAEs) by cytotoxic T lymphocytes activated upon immune checkpoint inhibitor (ICI) therapy. Understanding the mechanisms that underlie the development of the irAE-based autoimmune lung damage in ICI-treated patients will shed light on the ways to improve immunotherapy efficiency and for better managing of irAEs.
|
| 研究実績の概要 |
Immune Related Adverse Events (irAEs) restrain ICIs use. The irAEs are caused by ICI-induced autoimmunity against self-tissues by auto-antibody (Ab) or self-reacting T cells. We found GPRC5A-derived peptide epitope presented by HLA-A24 specifically in human lung cells 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 who underwent treatment with ICIs.
We use HLA-A24-transgenic mice (A24-Tg) as a model. We have confirmed that lung tissue of the A24-Tg animals express HLA-A24 and can process and present GPRC5A-derived peptide epitope identical to the one in human cells.
|
| 現在までの達成度 (区分) |
現在までの達成度 (区分)
3: やや遅れている
理由
The objective of the third year (2023-2024) was completed by numerous attempts to induce self-reacting CTLs using immunization of homozygous A24-Tg mice with mouse self-GPRC5A peptide. We used a number of protocols that varied in immunization intervals (ranging from 10 to 20 days), different combination of ICI antibody (and-PD-1 and/or anti-CTLA-4), and age of mice (young vs. old). We observed a tendency for a higher number of immune cell infiltrates (so called LNLS, lymph node-like structures) in the H/E-stained FFPE lung tissue specimens of mice immunized and treated with and-PD-1 and -CTLA-4 Ab. However, we couldn’t isolate self-reacting CTLs using these immunization schemes.
|
| 今後の研究の推進方策 |
It seems that congenic expression of GPRC5A in mice precludes induction of self-reacting CTLs as they are removed during negative selection process in thymus. We are currently developing GPRC5A knock-out (KO) / A24-Tg mice to address this issue by using CRISPR gene editing. Such GPRC5A-KO/A24-Tg mice should have intact precursor CD8+ CTLs directed against the GPRC5A epitope. Theoretically such CTLs could be easily induced upon immunization. Upon their induction, they can be expanded and adoptively transferred to A24-Tg mice with intact (wild type) GPRC5A gene, thus turning into self-reactive CTLs. We will investigate whether these CTLs would attack HLA-A24-expressing lung tissue causing inflammation and damage similar to irAEs in patients.
|
