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免疫检查点抑制剂相关心肌炎的临床前小鼠模型

Preclinical mouse models of immune checkpoint inhibitor-associated myocarditis.

作者信息

Fankhauser Reilly G, Johnson Douglas B, Moslehi Javid J, Balko Justin M

机构信息

Medical Scientist Training Program, Vanderbilt University Medical Center, Nashville, TN, USA.

Department of Medicine, Division of Hematology and Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.

出版信息

Nat Cardiovasc Res. 2025 May;4(5):526-538. doi: 10.1038/s44161-025-00640-2. Epub 2025 May 7.


DOI:10.1038/s44161-025-00640-2
PMID:40335724
Abstract

In this Review, we present a comprehensive analysis of preclinical models used to study immune checkpoint inhibitor-associated myocarditis (hereafter ICI-myocarditis), a potentially lethal immune-related adverse event. We begin by providing an overview of immune checkpoint inhibitors, highlighting how their efficacy in cancer treatment is counterbalanced by their predisposition to cause immune-related adverse events. Next, we draw from human data to identify disease features that an effective mouse model should ideally mimic. After that, we present a critical evaluation of a wide variety of existing mouse models including genetic, pharmacological and humanized models. We summarize insights gathered about the underlying mechanisms of ICI-myocarditis and the role of mouse models in these discoveries. We conclude with a perspective on the future of preclinical models, highlighting potential model improvements and research directions that could strengthen our understanding of ICI-myocarditis, ultimately improving patient outcomes.

摘要

在本综述中,我们对用于研究免疫检查点抑制剂相关心肌炎(以下简称ICI心肌炎)的临床前模型进行了全面分析。ICI心肌炎是一种具有潜在致命性的免疫相关不良事件。我们首先概述免疫检查点抑制剂,强调它们在癌症治疗中的疗效如何被其引发免疫相关不良事件的倾向所抵消。接下来,我们借鉴人类数据来确定有效小鼠模型理想情况下应模拟的疾病特征。之后,我们对包括基因模型、药理学模型和人源化模型在内的多种现有小鼠模型进行了批判性评估。我们总结了关于ICI心肌炎潜在机制以及小鼠模型在这些发现中的作用所获得的见解。我们最后展望了临床前模型的未来,强调了潜在的模型改进和研究方向,这些改进和方向可能会加强我们对ICI心肌炎的理解,最终改善患者的治疗结果。

相似文献

[1]
Preclinical mouse models of immune checkpoint inhibitor-associated myocarditis.

Nat Cardiovasc Res. 2025-5

[2]
Identification of key immune-related genes and potential therapeutic targets in immune checkpoint inhibitor-associated myocarditis.

Postgrad Med J. 2025-1-23

[3]
Central memory CD4+ T cells play a protective role against immune checkpoint inhibitor-associated myocarditis.

Cardiovasc Res. 2024-10-14

[4]
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Circ Res. 2025-2-28

[5]
Heart-Specific Immune Responses in an Animal Model of Autoimmune-Related Myocarditis Mitigated by an Immunoproteasome Inhibitor and Genetic Ablation.

Circulation. 2020-6-9

[6]
Immune checkpoint inhibitor-associated myocarditis: manifestations and mechanisms.

J Clin Invest. 2021-3-1

[7]
A Genetic Mouse Model Recapitulates Immune Checkpoint Inhibitor-Associated Myocarditis and Supports a Mechanism-Based Therapeutic Intervention.

Cancer Discov. 2021-3

[8]
Immune-checkpoint inhibitor-mediated myocarditis: CTLA4, PD1 and LAG3 in the heart.

Nat Rev Cancer. 2024-8

[9]
Immune checkpoint inhibitor-associated myocarditis: a historical and comprehensive review.

Am J Physiol Heart Circ Physiol. 2025-4-1

[10]
Insight of immune checkpoint inhibitor related myocarditis.

Int Immunopharmacol. 2024-12-25

本文引用的文献

[1]
Immune responses in checkpoint myocarditis across heart, blood and tumour.

Nature. 2024-12

[2]
Injury-induced myosin-specific tissue-resident memory T cells drive immune checkpoint inhibitor myocarditis.

Proc Natl Acad Sci U S A. 2024-10-15

[3]
Gasdermin-E-mediated pyroptosis drives immune checkpoint inhibitor-associated myocarditis via cGAS-STING activation.

Nat Commun. 2024-8-5

[4]
Programmed death of cardiomyocytes in cardiovascular disease and new therapeutic approaches.

Pharmacol Res. 2024-8

[5]
Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti-PD-1 Immune Checkpoint Inhibitor Cancer Therapy.

J Immunol. 2024-4-15

[6]
Recurrent Adrenergic Stress Provokes Persistent Myocarditis in PD-1-Deficient Mice.

JACC Basic Transl Sci. 2023-9-20

[7]
T Cells and Macrophages Drive Pathogenesis of Immune Checkpoint Inhibitor Myocarditis.

Circulation. 2024-1-2

[8]
Immune Checkpoint Inhibitors-Associated Myocarditis: Diagnosis, Treatment and Current Status on Rechallenge.

J Clin Med. 2023-12-17

[9]
Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor-associated lethal myocarditis in mice.

ESC Heart Fail. 2024-4

[10]
HLA-DQ8 Supports Development of Insulitis Mediated by Insulin-Reactive Human TCR-Transgenic T Cells in Nonobese Diabetic Mice.

J Immunol. 2023-12-15

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