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

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-DQ8.Ab0 transgenic mice in the BALB/c background (HLA-DQ8BALB/c-Tg) developed early and progressive fatal heart failure from 4–5 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 anti-myosin 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-DQ8BALB/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.

Myocarditis in Humans and in Experimental Animal Models

“…This idea was functionally confirmed by introducing specific HLA complexes into a mouse. Replacement of mouse MHC class II with the specific HLA-DQ8 in NOD or BALB/c mice resulted in spontaneous development of myocarditis and iDCM phenotype (without evident fibrosis), and were associated with cardiac arrhythmias and high mortality of the transgenic mice (176–180). This model resembles a course of fatal fulminant myocarditis in humans.…”

Therapeutic Potential of Fingolimod in Diabetes Mellitus and Its Chronic Complications

“…In recent years, with the gradual deepening of research on the SphK/S1P/S1PRs signal axis and FTY720, a number of studies have shown that the S1PRs modulator FTY720 has significant protective effects in autoimmune myocarditis, uveal retinitis, systemic lupus erythematosus, atherosclerosis, and other models. 20–23 …”

“…In recent years, with the gradual deepening of research on the SphK/S1P/S1PRs signal axis and FTY720, a number of studies have shown that the S1PRs modulator FTY720 has significant protective effects in autoimmune myocarditis, uveal retinitis, systemic lupus erythematosus, atherosclerosis, and other models. [20][21][22][23] FTY720 and DM DM is one of the most common metabolic diseases in humans and is characterized by a reduction in the mass of functional islet β cells and insulin resistance. Previous studies have shown that the function and survival of islet β cells and insulin sensitivity play important roles in DM, both of which are regulated by the S1P signaling axis.…”