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Updated: Jul 1, 2025
Modeling and Evaluation of Murine Diabetic Cardiomyopathy Model
Published on: November 29, 2024
Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in
Jeremy J Racine1, John F Bachman1, Ji-Gang Zhang1
1The Jackson Laboratory, Bar Harbor, ME.
Abstract:
Myocarditis has emerged as an immune-related adverse event of immune checkpoint inhibitor (ICI) cancer therapy associated with significant mortality. To ensure patients continue to safely benefit from life-saving cancer therapy, an understanding of fundamental immunological phenomena underlying ICI myocarditis is essential. We recently developed the NOD-cMHCI/II-/-.DQ8 mouse model that spontaneously develops myocarditis with lower mortality than observed in previous HLA-DQ8 NOD mouse strains. Our strain was rendered murine MHC class I and II deficient using CRISPR/Cas9 technology, making it a genetically clean platform for dissecting CD4+ T cell-mediated myocarditis in the absence of classically selected CD8+ T cells. These mice are highly susceptible to myocarditis and acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, anti-PD-1 administration accelerates skeletal muscle myositis. Using histology, flow cytometry, adoptive transfers, and RNA sequencing analyses, we performed a thorough characterization of cardiac and skeletal muscle T cells, identifying shared and unique characteristics of both populations. Taken together, this report details a mouse model with features of a rare, but highly lethal clinical presentation of overlapping myocarditis and myositis following ICI therapy. This study sheds light on underlying immunological mechanisms in ICI myocarditis and provides the basis for further detailed analyses of diagnostic and therapeutic strategies.
Insights
A new mouse model helps researchers understand immune checkpoint inhibitor (ICI) myocarditis, a dangerous side effect of cancer therapy. This model reveals key immune responses, aiding in developing safer cancer treatments.
Area of Science:
- Immunology
- Oncology
- Cardiology
Background:
- Immune checkpoint inhibitors (ICIs) are vital cancer therapies but can cause life-threatening myocarditis.
- Understanding the immunological basis of ICI-induced myocarditis is crucial for patient safety.
- Existing models have limitations in dissecting specific immune mechanisms.
Purpose of the Study:
- To develop and characterize a novel mouse model for studying immune checkpoint inhibitor (ICI)-induced myocarditis.
- To investigate the immunological mechanisms underlying myocarditis and myositis in response to anti-PD-1 therapy.
- To provide a platform for evaluating diagnostic and therapeutic strategies for ICI-related adverse events.
Main Methods:
- Development of a genetically modified NOD mouse strain deficient in murine MHC class I and II.
- Induction of myocarditis and myositis using anti-PD-1 immune checkpoint inhibitor therapy.
- Comprehensive analysis including histology, flow cytometry, adoptive transfers, and RNA sequencing.
Main Results:
- The developed mouse model spontaneously develops myocarditis and acute heart failure following anti-PD-1 treatment.
- Anti-PD-1 administration also accelerates skeletal muscle myositis, presenting overlapping symptoms.
- Characterization of cardiac and skeletal muscle T cells revealed shared and distinct immunological features.
Conclusions:
- This novel mouse model accurately recapitulates key features of human ICI-induced myocarditis and myositis.
- The model facilitates the study of CD4+ T cell-mediated mechanisms in ICI-related cardiotoxicity.
- This research provides a foundation for developing improved strategies to manage ICI-induced myocarditis.
