INHIBITION OF THEILERS-VIRUS MEDIATED DEMYELINATION BY PERIPHERAL IMMUNE TOLERANCE INDUCTION

Theiler's murine encephalomyelitis virus (TMEV), a member of the cardi ovirus subfamily of the Picornaviridae, is a natural pathogen of mice. Thirty to 60 days following intracerebral infection with TMEV, suscep tible inbred mouse strains develop a chronic, progressive, T cell-medi ated inflammatory demyelinating disease of the central nervous system (CNS) characterized by spastic hind limb paralysis and a lifelong pers istent CNS virus infection. We have examined the effect of peripheral virus-specific tolerance on the development of demyelinating disease. Treatment of SJL/J mice with TMEV-coupled, ethyl carbodiimide-treated splenocytes either before or after infection with live TMEV prevented the development of clinical disease, including inflammation and demyel ination in the CNS. Prevention of clinical disease was paralleled by s ignificant reductions in virus-specific immune responses, including de layed type hypersensitivity and T cell proliferative responses. Tolera nce induction resulted in a significant reduction in the absolute numb ers of mononuclear cells infiltrating the CNS, particularly the CD4(+) IL-2R(+) T cell subset, 3, 5, and 8 wk postinfection. in contrast, tol erance induction had no effect on the numbers of CD8(+)IL-2R(+) T cell s infiltrating the CNS. Treatment with TMEV-coupled splenocytes failed to prevent the development of relapsing experimental autoimmune encep halomyelitis, demonstrating the specificity of in vivo tolerance induc tion. Prevention of demyelinating disease did not correlate with the i ncreased TMEV-specific Ab responses observed in tolerized mice. These results indicate that induction of immune tolerance to TMEV can down-r egulate a chronic immunopathogenic disease directed against virus Ag p ersisting in the CNS that normally results in a progressive demyelinat ing disease similar to multiple sclerosis.