| アイテムタイプ |
学術雑誌論文 / Journal Article(1) |
| 公開日 |
2025-09-18 |
| タイトル |
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タイトル |
Granulomatous inflammatory responses are elicited in the liver of PD-1 knockout mice by de novo genome mutagenesis |
| 言語 |
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言語 |
eng |
| キーワード |
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主題Scheme |
Other |
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主題 |
PD-1 |
| キーワード |
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主題Scheme |
Other |
|
主題 |
granuloma |
| キーワード |
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主題Scheme |
Other |
|
主題 |
autoimmunity |
| キーワード |
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|
主題Scheme |
Other |
|
主題 |
genome mutation |
| キーワード |
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|
主題Scheme |
Other |
|
主題 |
self-nonself discrimination |
| 資源タイプ |
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資源タイプ |
journal article |
| アクセス権 |
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アクセス権 |
open access |
| 著者 |
Nagaretnam, Ilamangai
Kakimoto, Yoshiya
Yoneshige, Azusa
Takeuchi, Fuka
Sakimura, Takayuki
Sato, Kanato
Osaki, Yoshiro
Ishii, Yuta
Ozaki, Ai
Tamura, Masaru
Hamada, Michito
重岡, 稔章
Ito, Akihiko
石田, 靖雅
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| 抄録 |
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内容記述タイプ |
Abstract |
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内容記述 |
Introduction: Programmed death-1 (PD-1) is a negative regulator of immune responses. Upon deletion of PD-1 in mice, symptoms of autoimmunity developed only after they got old. In a model experiment in cancer immunotherapy, PD-1 was shown to prevent cytotoxic T lymphocytes from attacking cancer cells that expressed neoantigens derived from genome mutations. Furthermore, the larger number of genome mutations in cancer cells led to more robust anti-tumor immune responses after the PD-1 blockade. To understand the common molecular mechanisms underlying these findings, we hypothesize that we might have acquired PD-1 during evolution to avoid/suppress autoimmune reactions against neoantigens derived from mutations in the genome of aged individuals. Methods: To test the hypothesis, we introduced random mutations into the genome of young PD-1–/– and PD-1+/+ mice. We employed two different procedures of random mutagenesis: administration of a potent chemical mutagen N-ethyl-N-nitrosourea (ENU) into the peritoneal cavity of mice and deletion of MSH2, which is essential for the mismatch-repair activity in the nucleus and therefore for the suppression of accumulation of random mutations in the genome. Results: We observed granulomatous inflammatory changes in the liver of the ENU-treated PD-1 knockout (KO) mice but not in the wild-type (WT) counterparts. Such lesions also developed in the PD-1/MSH2 double KO mice but not in the MSH2 single KO mice. Conclusion: These results support our hypothesis about the physiological function of PD-1 and address the mechanistic reasons for immunerelated adverse events observed in cancer patients having PD-1-blockade immunotherapies. |
| 書誌情報 |
en : Discovery Immunology
巻 4,
号 1,
ページ数 14,
発行日 2024-12-25
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| 出版者 |
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出版者 |
Oxford University Press |
| ISSN |
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収録物識別子タイプ |
EISSN |
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収録物識別子 |
2754-2483 |
| 出版者版DOI |
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関連タイプ |
isReplacedBy |
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識別子タイプ |
DOI |
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関連識別子 |
https://doi.org/10.1093/discim/kyae018 |
| 出版者版URI |
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関連タイプ |
isReplacedBy |
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識別子タイプ |
URI |
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関連識別子 |
https://academic.oup.com/discovimmunology/article/4/1/kyae018/7932366 |
| 権利 |
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|
権利情報Resource |
https://creativecommons.org/licenses/by-nc/4.0/ |
|
権利情報 |
© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. |
| 著者版フラグ |
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出版タイプ |
NA |
| 助成情報 |
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助成機関名 |
Japan Society for the Promotion of Science (JSPS) |
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研究課題番号 |
21H02717 |
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研究課題番号URI |
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21H02717/ |
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研究課題名 |
若齢ＰＤ－１ノックアウトマウスに誘発される自己免疫性肝炎の研究 |
| 助成情報 |
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助成機関名 |
Japan Society for the Promotion of Science (JSPS) |
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研究課題番号 |
22K19508 |
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研究課題番号URI |
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22K19508/ |
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研究課題名 |
「自己」から逸脱し始めた老化細胞への免疫応答はＰＤ－１によって抑制されるのか？ |
| 助成情報 |
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助成機関名 |
Japan Society for the Promotion of Science (JSPS) |
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研究課題番号 |
24K22097 |
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研究課題番号URI |
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-24K22097/ |
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研究課題名 |
ＰＤ－１は「自己」から逸脱し始めた老化細胞への免疫学的拒絶応答を抑制する |
| 助成情報 |
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助成機関名 |
ONO Pharmaceutical Co., LTD |
