BALANCE BETWEEN PERSISTENT VIRUS-INFECTION AND IMMUNE CELLS DETERMINES DEMYELINATION

We addressed the contributions of persistent virus infection and immun e cells to the pathogenesis of Theiler's virus-induced demyelination, a model for human multiple sclerosis, We developed a model involving t he transfer of spleen cells into immunodeficient C.B-17-scid (SCID) mi ce, which normally die of overwhelming virus encephalitis without demy elination when infected with Theiler's virus, Adoptive transfer of non immune spleen cells from BALB/c mice into SCID mice resulted in the su rvival of all mice. However, these mice developed extensive demyelinat ion and virus Ag/RNA persistence in the spinal cord white matter, The most demyelination was observed when mice received an intermediate num ber of spleen cells (1.8-7.5 x 10(6)), whereas too few cells (0.5 x 10 (6)) did not ameliorate the SCID phenotype, and too many cells (30 x 1 0(6)) resulted in almost complete viral clearance with minimal demyeli nation. 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 vir us. These experiments support the hypothesis that demyelination is the result of a balance between persistent virus infection and immune inj ury mediated by either CD4(+) or CD8(+) T cells.