The Role of Therapy-Induced CD8+ T Cells in a Mouse Model of Multiple Sclerosis
Mendoza, Jason Paul
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Murine experimental autoimmune encephalomyelitis (EAE) is an induced, autoimmune, demyelinating disease model for human multiple sclerosis (MS). Glatiramer acetate (GA) is an approved immunomodulatory therapy for MS that was discovered through studies in EAE. It is thought that the main mode of action of GA is the induction of a Th1 to Th2 shift in CD4+ T cells. We have shown that, in human MS, GA therapy induces an upregulation of cytotoxic, suppressor CD8+ T cell responses, suggesting that these cells are integrally involved in mediating the immune effects of this drug. In this study, we show that GA induces robust CD8+ T cell responses even in mice. Whereas GA immunization ameliorates the clinical and histologic severity of EAE in wild type C57BL/6 mice, such protection is not observed in CD8(-/-) mice, indicating that CD8+ T cells are required in mediating the effects of GA. Moreover, adoptive transfer of CD8+ T cells from GA-immunized (but not OVA-immunized) mice results in amelioration of EAE in CD8(-/-) and wildtype mice, suggesting therapeutic potential for GA-specific CD8+ T cells. These cells appear to mediate their effects through a cytotoxic/suppressor mechanism, similar to our findings in human MS. In addition, GA treatment results in decreased myelin oligodendrocyte glycoprotein (MOG)-specific CD4+ T cell responses. In conclusion, our studies provide strong evidence that the in vivo induction of immune modulatory CD8+ T cells is an essential step in mediating therapeutic protection during autoimmune demyelination.