Coxsackieviruses are closely associated with myocarditis in humans and with a similar disease in Balb/c mice. The cardiac lesions are characterized by widespread mononuclear cell infiltration of the myocardium, and myocyte necrosis. Cardiac injury predominantly results from the induction of cytolytic T lymphocytes (CTL) in infected individuals. These CTL are highly cytolytic to cultured heart cells. As in humans the murine disease predominates in males and pregnant females while virgin females are protected. The sex-associated hormones, testosterone and progesterone simultaneous enhance myocarditis and virus concentrations in the heart as well as CTL generation in vivo. Estrogen treated animals lack CTL, have low virus concentrations and either minimal or no myocarditis. The present proposal will explore several hypotheses. First the hormones may influence myocarditis induction by altering virus binding, infection and replication in heart cells. Thus by affecting the antigen concentration in the animal, the cellular immune response is indirectly affected. Second, the hormones may directly alter precursor T lymphocyte stimulation, blastogenesis, differentiation and effector cell activity. Finally, the hormones may alter antigen specific suppressor cell generation which could prevent CTL induction and myocarditis. The studies into the mechanisms of hormonal action in myocarditis will generally focus on in vitro generation of CTL on cultured cardiac endothelial cells.
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