Immunologic behavior of lymphocytes in experimental viral myocarditis: significance of T lymphocytes in the severity of myocarditis and silent myocarditis in BALB/c-nu/nu mice.

Abstract

To clarify the immune mechanism in myocarditis, we examined by immunofluorescence techniques the serial changes in percentages of T and B lymphocytes in the heart, spleen, and peripheral blood of DBA/2 mice inoculated with encephalomyocarditis (EMC) virus (experiment I To confirm the involvement of T cells in the development of myocarditis, we also carried out studies in which BALB/c-nu/nu mice (group 1, n = 58), BALBI c-nu/+ mice (group 2, n = 54), and BALB/c-nu/nu mice injected with 5 x 107 spleen cells from BALB/c-nu/ + mice (group 3, n = 50) were inoculated with EMC virus (experiment II). Four mice from each of the three groups were killed on day 6 for virologic studies. In experiment II, there were no significant differences in the incidence of myocarditis among the three groups. Virus titrations of the heart and serum neutralizing antibody titers did not show any significant differences between the three groups on days 6 and 16. Fifty-two percent of group 2 mice (26 of 50) and 43% of those in group 3 (20 of 46) died on days 9 to 15, when congestive heart failure developed. However, only 9% of group 1 (five of 54) died during this period. Pathologic examination confirmed the presence of congestive heart failure in groups 2 and 3 but not in group 1 during this period. Cellular infiltrations and myocardial necrosis were minimal in group 1. Thus, the severity of myocarditis seems to be mediated by T cells. The so-called silent myocarditis seen clinically may be similar to myocarditis in BALB/c-nu/nu mice. Circulation 71, No. 6, 1247-1254, 1985 MYOCARDITIS can develop rapidly and progress to congestive heart failure.' Congestive heart failure has been reported to result from many viral injections in man.2 Thus, a relationship between viral infection and cardiomyopathy has been suggested,3'4 but complete evidence for it is still lacking. Recently we found congestive heart failure after inducing encephalomyocarditis (EMC) virus infections in BALB/c-nu/ + mice5 and have also observed severe myocarditis in DBA/2

Enhanced Production of Macrophage Inflammatory Protein 2 (MIP-2) by In Vitro and In Vivo Infections with Encephalomyocarditis Virus and Modulation of Myocarditis with an Antibody against MIP-2

“…EMC, an enterovirus of the family Picornaviridae, can infect many mammals (8). We reported previously that EMC infection in the mouse may be followed by dilated cardiomyopathy and congestive heart failure, with pathological changes similar to those seen in humans (8,12).…”

“…The myocarditic strain of EMC virus was used. Virus stock was prepared as described previously (8,10,12) and stored at Ϫ80°C until it was diluted for use. Virus titers in the heart were determined by plaque formation on Vero (African green monkey kidney) cells.…”

“…Increasing evidence suggests that cytotoxic T cells (8,9), neurohumoral factors (17), and free radicals (4,5), possibly generated by infiltrating cells in the myocardium, play a significant role, separately or together, in the development of myocardial damage and dysfunction, in addition to the primary damage caused by viral infection. Inflammatory cytokines are also involved in the pathogenesis of myocardial injury in viral myocarditis (6,11).…”

“…Since monocyte migration is a crucial step in the development of myocarditis, we investigated the behavior of MIP-2 in encephalomyocarditis (EMC) virus infection both in vitro and in vivo and the effects of an anti-MIP-2 antibody on murine viral myocarditis (8,10,12).…”

Immunosuppression with high doses of cyclophosphamide reduces the severity of myocarditis but increases the mortality in murine Coxsackievirus B3 myocarditis.

“…CYP (100 mg/kg/day s.c.) was administered daily on days 0-8 (experiment 1; group 2), days 8-21 (experiment 2; group 4), and days [21][22][23][24][25][26][27][28][29][30][31][32][33][34] (experiment 3; group 6). Groups 1, 3, and 5 were infected control groups for each experiment.…”