CD8+ T-cells are required for the action of glatiramer acetate therapy for autoimmune demyelinating disease (164.19)

Abstract

Abstract Multiple sclerosis (MS) is a chronic disabling disease characterized by immune-mediated destruction of central nervous system (CNS) myelin. Murine experimental autoimmune encephalomyelitis (EAE) is a well characterized animal model of MS. The FDA-approved drug glatiramer acetate (GA, Copaxone®), discovered through EAE studies, ameliorates the symptoms of MS without immunosuppression, although its mechanism is still poorly understood. Our studies have suggested that CD8+ T-cells may be involved in exerting the therapeutic effects of the drug. We have shown that in response to drug treatment, the GA-specific subset of CD8+ T-cells greatly expands in MS patients and possesses the ability to suppress/kill CD4+ T-cells in vitro. We now demonstrate that GA also induces a robust CD8+ T-cell response in the mouse model. Importantly, GA treatment is ineffective in ameliorating EAE in mice deficient in CD8+ T-cells or MHC Class I, indicating that pathways involving only CD4+ T-cells and APCs bearing MHC Class II are insufficient to mediate protection. GA-induced CD8+ T-cells transferred into wild-type or CD8-deficient mice restore disease suppression. Induction of GA-induced regulatory CD8+ T-cells requires indoleamine 2,3-dioxygenase (IDO) and their function is dependent on IFNγ, perforin, and MHC Class I. These studies demonstrate an essential in vivo role for cytotoxic/suppressor CD8+ T-cells during GA therapy and identify their potential use as adoptive immunotherapeutic agents.