Enteroviral and immune mediated myocarditis in SCID mice

Severe combined immune deficiency (SCID) mice have been used as an animal m odel to study both the direct cytopathic effect of enteroviruses on the hea rt in the absence of an effective immune system and to investigate the role of immune mediated processes in the pathogenesis of human myocarditis. The infection of SCID mice with coxsackievirus B3 resulted in severe myocar ditis with very high titers of the virus in the myocardium and severe necro sis of myocytes. This direct cytopathic effect caused an impairment of the myocardial function and resulted in a high mortality rate of the infected a nimals. For the study of the immune mechanisms in human myocarditis, peripheral blo od leukocytes of patients with myocarditis, having an impaired left ventric ular function without viral persistence in the myocardium, were transferred into SCID mice. As controls peripheral blood leukocytes of normal donors w ere used. At 60 days after transfer, human immunoglobulines could be demons trated in the peripheral blood of the SCID mice, however, human autoantibod ies against the adenine nucleotide translocator, a myocardial autoantigen, were only present in the animals receiving peripheral blood leukocytes from patients with myocarditis. Cellular infiltrates of human leukocytes in the myocardium and an impaired left ventricular function were also only observ ed in animals reconstituted with peripheral blood leukocytes from patients. These effects were T cell dependent as shown by differential transfer. These results are of interest for the treatment of human myocarditis, sugge sting the avoidance of an immunosuppressive therapy in acute or chronic myo carditis with viral persistence to prevent a direct cytopathic effect in th e absence of an effective immune system. However, in the setting of a chron ic, (auto-)immunological myocarditis with the proven absence of entero- or adenoviral sequences an immunomodulatory therapy seems to be effective and safe.