Protection against Experimental Autoimmune Myocarditis Is Mediated by Interleukin-10-Producing T Cells that Are Controlled by Dendritic Cells

Abstract

Experimental autoimmune myocarditis (EAM) can be induced in the LewisMyocarditis is an inflammatory heart disease that can be initiated by infectious pathogens. 1-3 Dilated cardiomyopathy, which may follow myocarditis and represent the chronic stage of disease, is a major cause of heart failure and heart transplantation. 4 -6 Evidence suggests that autoimmune responses to cardiac antigens exposed after heart damage may play an important role in prolonged damage of myocardium. 3,7-9 Nevertheless, little progress has been made in treating myocarditis by immunosuppression, because a complete understanding of key factors that regulate the pathogenic immune responses in autoimmune myocarditis are not well established.Experimental autoimmune myocarditis (EAM) generated in susceptible mouse and rat strains by immunization with purified cardiac myosin or a specific pathogenic cardiac myosin peptide in adjuvant has been used to investigate the pathogenesis of myocarditis induced by autoimmune mechanisms. 10 -20 Many studies have shown that cardiac antigen-induced myocarditis is a Tcell-mediated disease. 18,[21][22][23][24] However, the active induction of EAM relies on the use of bacterial adjuvants [complete Freund's adjuvant (CFA)] during immunization, suggesting that activation of the innate immune system is important in disease induction. [25][26][27] Inflammatory cytokines such as interleukin (IL)-1, tumor necrosis factor (TNF)-␣, and IL-12 promote myocarditis development in animals, 28 -31 whereas mice that lack TNF-Rp55 or are deficient in IL-12 signaling were protected from EAM. 32,33 In vivo inhibition of co-stimulatory molecule B7-1 and CD40 also markedly decreased myocardial inflammation. 34,35 A recent study directly demonstrated that cardiac antigen-loaded dendritic cells (DCs) induced autoimmune myocarditis when they were activated and transferred. 36 Taken together, these studies suggest that EAM induction is closely associated with not only the myocarditic epitopes of cardiac myosin and their reactive T cells, but also with the activation of antigen-presenting cells (APCs) such as DCs by inflammatory cytokines.

Susceptibility to Acute Rheumatic Fever Based on Differential Expression of Genes Involved in Cytotoxicity, Chemotaxis, and Apoptosis

“…The role of these cytokines in ARF/RHD has been explored in other studies. In the animal model of ARF (cardiac myosin-induced autoimmune myocarditis and valvulitis in the Lewis rat), protection is conferred by IL-10-producing lymphocytes (17). In our study, a decrease in expression or the number of such lymphocytes may account for the decrease in measurable IL-10 expression.…”

Treatment and Prevention of Experimental Autoimmune Myocarditis with CD28 Superagonists

“…A low-dose CD28 mAb was sufficient to up-regulate the expression of Foxp3 and to promote the expansion of T regs , thus suppressing the function of CD4+CD25– T regs . In addition, the protection induced against EAM in Lewis rats arose from T cells regulated by increased IL-10 production by dendritic cells [25]. Moreover, some studies showed that the protection against autoimmune myocarditis using hepatocyte growth factor and the Chinese medicinal herb radix astragali was closely associated with the up-regulation of IL-10 [26,27].…”

Future Therapeutic Strategies in Inflammatory Cardiomyopathy: Insights from the Experimental Autoimmune Myocarditis Model

“…In the context of inflammatory heart disease models, IL-10 or IL-10 producing T cells protected against viral and experimental autoimmune myocarditis in mice [71,77,78]. Furthermore, anti-IL-10 antibody treatments prevented the development of heart specific tolerance against α-myosin/CFA immunization in mice [79].…”