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

Cassandra M. Lawson

Philip D. Hodgkin^>

Department of Microbiology, University of Western Australia, Nedlands, 6009, Western Australia

The 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 MHC-restricted 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/10 and B10.BR 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.

Keywords: cytomegalovirus, murine, cyclosporin, MHC

Present address: Department of Medicine, University of Western Australia, Nedlands, 6009, Western Australia.

^> Present address: DNAX Research Institute of Molecular and Cellular Biology, 901 California Avenue, Palo Alto, California, 94304-1104, U.S.A.

Received 8 August 1988; accepted 16 January 1989.