ABSTRACT
Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a model for multiple sclerosis, is a chronic T cell-mediated disease. Development of clinical symptoms in susceptible mouse strains generally correlates with TMEV-specific delayed-type hypersensitivity (DTH) responses. These responses, minimal or absent in resistant mouse strains, have been proposed as the pathogenic basis for the central nervous system inflammation and demyelination characterizing the disease. We demonstrate here that normally resistant (C57BL/6 x DBA/2)F1 hybrid mice develop clinical symptoms and DTH responses against TMEV after low doses of gamma-irradiation. Parental C57BL/6 animals remain resistant after similar pretreatment. Thus low-dose irradiation elicits a "latent" susceptibility to TMEV-IDD in some, but not all, resistant mice. Adoptively transferred spleen cells from syngeneic, unirradiated donors reconfer resistance on irradiated, infected B6D2F1 hybrids and reduce DTH responsiveness against TMEV, suggesting a protective role for a radiation-sensitive splenic population(s). The closely related C57BL/6 and C57BL/10 strains differ with respect to intrinsic and latent susceptibility.
Subject(s)
Demyelinating Diseases/immunology , Poliomyelitis/immunology , Theilovirus , Animals , Demyelinating Diseases/genetics , Demyelinating Diseases/microbiology , Hypersensitivity, Delayed/immunology , Immunity, Innate/genetics , Immunity, Innate/radiation effects , Immunotherapy, Adoptive , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred DBA , Poliomyelitis/genetics , Poliomyelitis/microbiology , Species Specificity , Whole-Body IrradiationABSTRACT
Theiler's murine encephalomyelitis virus-induced demyelinating disease, a murine model for multiple sclerosis, is the result of persistent infection which leads to a T cell-mediated immunopathology. Susceptible strains develop virus-specific DTH responses while resistant strains do not, and this response has been proposed as the basis for inflammation and demyelination. (C57BL/6 x DBA/2)F1 hybrid animals, normally resistant to TMEV-induced demyelinating disease, become susceptible when treated in vivo prior to infection with low dose cyclophosphamide. Comparable pretreatment of other resistant animals, C57BL/6 and CB6 (BALB/c x C57BL/6) F1 hybrids, does not render them susceptible (despite the H-2 identity of CB6F1 and B6D2F1 hybrids). Thus the "latent" susceptibility in B6D2F1 hybrids must be attributed to non-H-2 genes from the susceptible D2 parent. Resistance can be restored to CY-treated B6D2F1 animals by the adoptive transfer of splenic cells (including T cell enriched populations) from non-CY-treated donors. Resistance to TMEV-IDD in these animals, therefore, may involve active inhibition of a "latent" disease susceptibility.
