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Mouse Models for Graft Arteriosclerosis
Published on: May 14, 2013
A humanized HLA-DR4 mouse model for autoimmune myocarditis
M Emrah Şelli1, Anita C Thomas1, David C Wraith2
1University of Bristol, School of Clinical Sciences, UK; Bristol Heart Institute, Bristol Royal Infirmary, Bristol BS2 8HW, UK.
Insights
A new mouse model mimics human autoimmune myocarditis, a cause of heart failure. Treatment with specific peptides improved cardiac function, offering potential for new therapies targeting autoimmune heart disease.
Area of Science:
- Immunology
- Cardiology
- Genetics
Background:
- Myocarditis, a leading cause of heart failure in young adults, is linked to autoimmunity against human cardiac α-myosin (hCAM) and the human major histocompatibility II (MHCII) DR4 allele.
- Understanding the mechanisms of hCAM-induced myocarditis is crucial for developing effective treatments.
Purpose of the Study:
- To develop a humanized mouse model for studying hCAM-induced autoimmune myocarditis.
- To evaluate the therapeutic potential of hCAM-derived peptides in this model.
Main Methods:
- Development of a mouse model using human HLA-DR4 transgenic mice lacking mouse MHCII genes, immunized with hCAM.
- Assessment of immune responses (T-cell proliferation, antibody titers), cardiac function (echocardiography), and cardiac histology.
- Treatment of the model with hCAM-derived peptides.
Main Results:
- Immunization induced splenic T-cell proliferation, increased antibody titers, cardiac inflammation, and impaired cardiac function (reduced cardiac output and fractional shortening).
- Treatment with hCAM-derived peptides significantly preserved ejection fraction and fractional shortening.
- Prolonging the experiment led to mortality, but cardiac dilatation and fibrosis were not observed at the initial time point.
Conclusions:
- The developed humanized mouse model effectively replicates key features of hCAM-induced autoimmune myocarditis.
- hCAM-derived peptides show therapeutic promise for preserving cardiac function in autoimmune cardiomyopathy.
- This model serves as a valuable platform for refining peptide-based treatments for autoimmune heart conditions.
Abstract:
Myocarditis, the principal cause of dilated cardiomyopathy and heart failure in young adults, is associated with autoimmunity to human cardiac α-myosin (hCAM) and the DR4 allele of human major histocompatibility II (MHCII). We developed an hCAM-induced myocarditis model in human HLA-DR4 transgenic mice that lack all mouse MHCII genes, demonstrating that immunization for 3weeks significantly increased splenic T-cell proliferative responses and titres of IgG1 and IgG2c antibodies, abolished weight gain, provoked cardiac inflammation and significantly impaired cardiac output and fractional shortening, by echocardiography, compared to adjuvant-injected mice. Neither cardiac dilatation nor fibrosis occurred at this time point but prolonging the experiment was associated with mortality. Treatment with mixtures of hCAM derived peptides predicted to have high affinity for DR4 significantly preserved ejection fraction and fractional shortening. Our new humanized mouse model of autoimmune cardiomyopathy should be useful to refine hCAM-derived peptide treatment.
