A mechanistic understanding of the selective clearance of encephalitogenic T cells (THER3P.882)

Abstract

Abstract Most therapeutic approaches to control multiple sclerosis (MS) target autoimmune effector cells via broad spectrum immunosuppression. In contrast to this approach we have recently described a therapeutic intervention for the MS model experimental autoimmune encephalomyelitis (EAE) that selectively eliminates encephalitogenic T cells, while sparing protective naive and memory T cell responses. Here we report the mechanistic pathway by which our selective therapy acts. The specificity of action that targets encephalitogenic T cell is through the action of the drug, etoposide, which acts by targeting the double stranded break repair mechanism associated with highly activated T cells. In combination with differential expression of Bcl-2 family member leads to the preferential deletion of effector T cells over memory and naive T cells clearance. Based on our understanding of etoposide-mediated clearance of encephalitogenic T cells we expanded our findings to include other genotoxic and non-genotoxic agents that synergize to afford more specific and less toxic means of controlling autoimmunity. This study further defines the mechanism for the selective clearance of self-reactive T cells by establishing a mechanistic understanding and rational approach to the use of agents that target autoreactive T cells in vivo and result in novel and enhanced therapy for autoimmune diseases.