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J Mol Cell Cardiol. 2017 Jun;107:22-26. doi: 10.1016/j.yjmcc.2017.04.003. Epub 2017 Apr 18.

A humanized HLA-DR4 mouse model for autoimmune myocarditis.

Author information

1
University of Bristol, School of Clinical Sciences, UK; Bristol Heart Institute, Bristol Royal Infirmary, Bristol BS2 8HW, UK.
2
University of Bristol, School of Clinical Sciences, UK; Bristol Heart Institute, Bristol Royal Infirmary, Bristol BS2 8HW, UK; University of Bristol, School of Cellular and Molecular Medicine, University Walk, Bristol BS8 1TD, UK.
3
University of Bristol, School of Clinical Sciences, UK; Bristol Heart Institute, Bristol Royal Infirmary, Bristol BS2 8HW, UK. Electronic address: a.newby@bris.ac.uk.

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.

KEYWORDS:

Autoimmunity; Cardiomyopathy; Heart failure; Myocarditis

PMID:
28431892
PMCID:
PMC5466360
DOI:
10.1016/j.yjmcc.2017.04.003
[Indexed for MEDLINE]
Free PMC Article

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