An immuno-protective treatment strategy for autoimmune diseases (P5201)

Abstract

Abstract The current clinical approach for treating autoimmune diseases is to blunt all immune responses as a means of preventing autoimmune pathology. A major side effect of this strategy is depressed beneficial immunity, and increased rates of infections and tumors. Here we report the novel application of etoposide, a topoisomerase inhibitor, to treat experimental autoimmune encephalomyelitis (EAE), a model for human multiple sclerosis. The moderate and temporally-limited use of etoposide results in significant reduction and severity of EAE while sparing beneficial naïve and memory immunity. Our approach of eliminating activated encephalogenic effector T cells reduces clinical scores, pathogenic cytokine production, and overall pathology, while dramatically limiting the off-target effects on naïve and memory adaptive immunity. Etoposide-treated mice exhibited ameliorated or no EAE pathology and reduced antigenic spread, yet had normal T cell and T-dependent B cell responses to de novo antigenic challenges, as well as unimpaired memory T cells responses to viral rechallenge. Thus, dosage limiting etoposide therapy can selectively ablate effector T cells and limit pathology in an animal model of autoimmunity, while sparing protective immune responses. This strategy could lead to a broad new paradigm for the treatment of autoimmune diseases with both enhanced efficacy and decreased treatment-associated morbidities.