The Effect of Cyclosporin on Major Histocompatibility Complex-linked Resistance to Murine Cytomegalovirus

Abstract

SUMMARYThe ability of mice to survive infection with murine cytomegalovirus (MCMV) is known to be influenced by genes of the major histocompatibility complex (MHC). One hypothesis to account for this association is that MHC-linked resistance to MCMV is an 'immune response' gene effect, caused by differences in the strength of the MHCrestricted T cell response of mouse strains with different MHC haplotypes. Therefore, removal of T cell responses in mouse strains differing only at the MHC should render them equally susceptible to the virus infection. To test this hypothesis, the immunosuppressive drug cyclosporin (CsA) was used to reduce T cell responses in inbred congenic mouse strains carrying either a resistant or susceptible MHC haplotype. CsA reduced the delayed-type hypersensitivity (DTH) response to MCMV in both resistant and susceptible mouse strains to background levels, equivalent to control uninfected mice. CsA treatment had little effect on the susceptibility of C57BL/I 0 and B 10. B R mice to the virus and the differences in susceptibility between these strains remained. In contrast, CsA increased the susceptibility of the genetically susceptible BALB/c mice (H-2 d) by 100-fold and increased the susceptibility of resistant BALB.K mice (H-2 k) by 15-fold. Thus the H-2-determined difference in susceptibility between these strains was increased after CsA treatment. The results obtained with congenic strains show that MHC-linked resistance patterns to MCMV are not eliminated by CsA and suggest therefore that T cells are not responsible for this phenomenon. Interestingly, the mean time to death was delayed for CsA-treated BALB/c mice compared with untreated mice given equivalent virus doses. In addition, although CsA prevented DTH responses in both genetically susceptible A/J (H-2 a) and resistant CBA (H-2 k) mice, CsA treatment markedly increased the susceptibility of A/J mice (32-fold) but had little effect on the susceptibility of CBA mice to the virus.

Effect of host genotype in determining the relative roles of natural killer cells and T cells in mediating protection against murine cytomegalovirus infection

“…A comparative study of the susceptibility of athymic mice to MCMV suggested that host genotype influences the importance of T cell-mediated immunity . Furthermore, cyclosporin A treatment, which inhibits T cell function, has been shown to markedly increase the susceptibility to infection of BALB/c and A/J mice, but not that of more resistant mouse strains (Lawson et al, 1989). Thus, our first aim was to examine the importance of immunity mediated by T cell subsets in the control of MCMV infection in a panel of inbred strains of mice, including a second susceptible mouse strain (A/J), and two relatively resistant mouse strains (CBA/CaH and C5 7BL/10).…”

Evidence for mimicry by viral antigens in animal models of autoimmune disease including myocarditis

“…Athymic nude mice do not develop myocarditis following MCMV infection even though they disseminate the viral infection and produce higher titres of virus in many tissues [40]. Mice immunosuppressed with cyclosporin A showed a delayed onset of myocarditis by about 4 days and also produced higher titres of virus with an increased organ distribution of viral infection compared with untreated MCMV-infected mice [41]. In addition to antibodies reactive to MCMV antigens, autoantibodies to heart antigens, including reactivity to the heart contractile proteins, troponin, tropomyosin, myosin, and actin are found during acute MCMV infection of mice [6,42].…”