Description
Abstract: Background. Inbred mouse models of autoimmune myocarditis are routinely used to investigate the immune mechanisms underlying dilated cardiomyopathy. However, their translational relevance is limited because observations made in a single inbred strain may not reflect those of outbred human populations. This limitation can be overcome by using diversity outbred (DO) mice, whose genetic variability is comparable to that of humans. Methods. To investigate the utility of DO mice, we characterized their immune cell distributions and induced myocarditis by immunization with porcine cardiac myosin (PCM) emulsified in complete Freund's adjuvant. Antigen-specific T cell and antibody responses were evaluated using lymphocytes and serum samples, respectively, and hearts were examined histologically for inflammatory changes. Results. First, we noted no significant variations in the majority of immune cell populations, which include T cells and B cells. Second, upon immunization, we demonstrated that the PCM was immunogenic, and the PCM-reactive T cell responses were generated in both males and females, as measured by a proliferation assay. Third, cytokine analysis revealed increased production of Th1 (IFN [interferon]-γ) and Th17 (interleukin [IL-17]) cytokines marginally, whereas anti-inflammatory Th2 cytokines, including IL-10, remained low. Fourth, determination of PCM-reactive antibody responses revealed significant amounts of IgG1 and IgG2b isotypes. Finally, histological analysis indicated varied degrees of myocarditis severity in both sexes. Conclusions. Our data suggest that mild autoimmune myocarditis can be induced in DO mice. However, to capture the heterogeneity in disease susceptibility, large sample cohorts are required.