A humanized HLA-DR4 mouse model for autoimmune myocarditis.

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  • Additional Information
    • Source:
      Publisher: Academic Press Country of Publication: England NLM ID: 0262322 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-8584 (Electronic) Linking ISSN: 00222828 NLM ISO Abbreviation: J Mol Cell Cardiol Subsets: MEDLINE
    • Publication Information:
      Original Publication: London, New York, Academic Press.
    • Subject Terms:
      Autoimmune Diseases/*genetics ; Cardiac Myosins/*genetics ; HLA-DR4 Antigen/*genetics ; Myocarditis/*genetics; Animals ; Autoimmune Diseases/drug therapy ; Autoimmune Diseases/immunology ; Autoimmune Diseases/physiopathology ; Cell Proliferation/drug effects ; Disease Models, Animal ; HLA-DR4 Antigen/immunology ; Humans ; Immunoglobulin G/genetics ; Inflammation/genetics ; Inflammation/immunology ; Inflammation/physiopathology ; Mice ; Mice, Transgenic ; Myocarditis/drug therapy ; Myocarditis/immunology ; Myocarditis/physiopathology ; Peptides/administration & dosage ; Peptides/immunology ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
    • 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.
      (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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    • Grant Information:
      RG/09/006/27918 United Kingdom BHF_ British Heart Foundation
    • Contributed Indexing:
      Keywords: Autoimmunity; Cardiomyopathy; Heart failure; Myocarditis
    • Accession Number:
      0 (HLA-DR4 Antigen)
      0 (Immunoglobulin G)
      0 (Peptides)
      EC 3.6.1.- (Cardiac Myosins)
    • Publication Date:
      Date Created: 20170423 Date Completed: 20180309 Latest Revision: 20220129
    • Publication Date:
      20240829
    • Accession Number:
      PMC5466360
    • Accession Number:
      10.1016/j.yjmcc.2017.04.003
    • Accession Number:
      28431892