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Noninvasive Assessment of Cardiac Abnormalities in Experimental Autoimmune Myocarditis by Magnetic Resonance Microscopy Imaging in the Mouse
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A Genetic Mouse Model Recapitulates Immune Checkpoint Inhibitor-Associated Myocarditis and Supports a Mechanism-Based
Spencer C Wei1, Wouter C Meijers2, Margaret L Axelrod2
1Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas. jallison@mdanderson.org spencer.wei@gmail.com javid.moslehi@vumc.org.
Cancer Discovery
|December 1, 2020
Summary
Immune checkpoint inhibitors (ICI) can cause myocarditis. A new mouse model shows CTLA4 and PD-1 loss causes heart inflammation, and CTLA4-Ig (abatacept) can treat this ICI-related myocarditis.
Area of Science:
- Immunology
- Cardiology
- Oncology
Background:
- Immune checkpoint inhibitors (ICIs) targeting CTLA4 or PD-1/PD-L1 have revolutionized cancer treatment.
- However, ICIs can cause immune-related adverse events, notably myocarditis.
Purpose of the Study:
- To develop a preclinical mouse model for studying ICI-associated myocarditis.
- To investigate the functional interaction between CTLA4 and PD-1 in myocarditis development.
- To evaluate the therapeutic potential of CTLA4-Ig (abatacept) in mitigating ICI-induced myocarditis.
Main Methods:
- Generation of a mouse model with monoallelic loss of Ctla4 and complete absence of Pdcd1.
- Assessment of survival, cardiac function (ECG), and myocardial histology.
- Evaluation of therapeutic efficacy using CTLA4-Ig (abatacept).
Main Results:
- The developed mouse model exhibits premature death due to T cell and macrophage infiltration of the myocardium and severe ECG abnormalities, mimicking human ICI-myocarditis.
- CTLA4 and PD-1 exhibit a gene dosage-dependent interaction in myocarditis pathogenesis.
- Treatment with CTLA4-Ig (abatacept) ameliorated disease progression in the mouse model.
Conclusions:
- A robust preclinical model for ICI-associated myocarditis has been established.
- CTLA4 and PD-1 functionally interact, contributing to myocarditis development, particularly with combination ICI therapy.
- CTLA4-Ig (abatacept) shows promise in attenuating ICI-induced myocarditis, supporting its clinical investigation.
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