The Balance between Persistent Virus Infection and Immune Cells Determines Demyelination

We addressed the contributions of persistent virus infection and immune cells to the pathogenesis of Theiler's virus-induced demyelination, a model for human multiple sclerosis. We developed a model involving the transfer of spleen cells into immunodeficient C.B-17-scid (SCID) mice, which normally die of overwhelming virus encephalitis without demyelination when infected with Theiler's virus. Adoptive transfer of nonimmune spleen cells from BALB/c mice into SCID mice resulted in the survival of all mice. However, these mice developed extensive demyelination and virus Ag/RNA persistence in the spinal cord white matter. The most demyelination was observed when mice received an intermediate number of spleen cells (1.8-7.5 × 10⁶), whereas too few cells (0.5 × 10⁶) did not ameliorate the SCID phenotype, and too many cells (30 × 10⁶) resulted in almost complete viral clearance with minimal demyelination. Adoptive transfer of spleen cells depleted of either CD4⁺ or CD8⁺ T cells produced vacuolar demyelination associated with virus persistence. In contrast, reconstitution with both CD4⁺ and CD8⁺ T cells produced less severe demyelination and partial clearance of virus. These experiments support the hypothesis that demyelination is the result of a balance between persistent virus infection and immune injury mediated by either CD4⁺ or CD8⁺ T cells.