Pathogenesis of Autoimmune Myocarditis

Johns Hopkins University, Baltimore MD

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Myocarditis is a major cause of sudden death in people under 40 years of age. While some myocarditis patients recover, many of them progress to dilated cardiomyopathy, an often fatal condition and a frequent reason for cardiac transplantation. Many cases of myocarditis are associated with an autoimmune process in which cardiac myosin is a major autoantigen. The mechanisms leading to the immune-mediated damage to the heart, particularly the role of cytokines, are not fully elucidated. We propose to study these mechanisms using the murine model of cardiac myosin-induced experimental autoimmune myocarditis (EAM) previously established in our laboratory. The goal of the present proposal is to delineate the mechanisms by which IL-4 and IFN-gamma, prototypic Th2 and Th1 cytokines respectively, influence the disease process. Our interest in these two cytokines is based on our preliminary findings which indicate that IL-4 has a disease-promoting role in EAM, whereas IFN-gamma limits the disease. Specific aims 1 and 2 will address the role of IL-4 in EAM and the mechanisms by which IL-4 promotes disease. Specific aims 3 and 4 will examine the role of IFN-gamma and the mechanisms by which IFN-gamma limits disease. We are planning to achieve these specific aims by blocking cytokines with specific antibodies, using cytokine and cytokine receptor knock out mice, and transferring disease with antibodies and subsets of T cells. Disease outcomes will be assessed by gross and histologic examination of the hearts. In vivo assessment will include echocardiography and pressure-volume analysis. Our preliminary findings contrast with the prevailing opinion that organ-specific autoimmune diseases are driven by a Th1 response and are ameliorated by a Th2 response. The proposed study will help us understand how Th1 responses may limit and Th2 responses may promote organ-specific autoimmunity. It will also provide us with a basis for designing new therapeutic interventions in patients with myocarditis.