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Cardiovasc Pathol. 2016 Sep-Oct;25(5):353-61. doi: 10.1016/j.carpath.2016.05.003. Epub 2016 May 17.

FTY720 (Gilenya) treatment prevents spontaneous autoimmune myocarditis and dilated cardiomyopathy in transgenic HLA-DQ8-BALB/c mice.

Author information

1
Section of Molecular Medicine, Rush University Medical Center, Chicago, IL, USA; Department of Immunology and Biotechnology, University of Pécs, Hungary. Electronic address: boldizsar.ferenc@pte.hu.
2
Section of Molecular Medicine, Rush University Medical Center, Chicago, IL, USA.
3
Section of Molecular Medicine, Rush University Medical Center, Chicago, IL, USA; Department of Immunology and Biotechnology, University of Pécs, Hungary.
4
Section of Molecular Medicine, Rush University Medical Center, Chicago, IL, USA. Electronic address: Tibor_Rauch@rush.edu.

Abstract

Although dilated cardiomyopathy (DCM) is often caused by viral infections, it frequently involves autoimmune mechanisms associated with particular HLA-DR and DQ alleles. Our homozygous HLA-DQ8Ab(0) transgenic mice in the BALB/c background (HLA-DQ8(BALB/c)-Tg) developed early and progressive fatal heart failure from 4 to 5 weeks of age. Clinical signs of the disease included cyanotic eyes, tachycardia with dyspnea (from pale to cyanotic limbs), and terminal whole body edema. Sick mice had extremely dilated hearts, enlarged liver and spleen, and pleural/peritoneal effusion. Histology of the heart showed extensive heart muscle destruction with signs of fibrosis. The autoimmune nature of the disease was shown by high titers of antimyosin antibodies in the sera and IgG deposits in sick heart muscles, as well as focal neutrophil, T cell, and macrophage infiltration of the heart muscle. The sera of the sick mice showed a granular staining pattern on sections of healthy heart muscle. Quantitative analyses of DCM-specific gene expression studies revealed that sets of genes are involved in inflammation, hypoxia, and fibrosis. Treatment with FTY720 (Fingolimod/Gilenya) protected animals from the development of cardiomyopathy. HLA-DQ8(BALB/c)-Tg mice represent a spontaneous autoimmune myocarditis model that may provide a useful tool for studying the autoimmune mechanism of DCM and testing immunosuppressive drugs.

KEYWORDS:

Autoimmune cardiomyopathy; FTY720; Mouse model

PMID:
27288745
PMCID:
PMC5372700
DOI:
10.1016/j.carpath.2016.05.003
[Indexed for MEDLINE]
Free PMC Article

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