Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS) and is responsible for long-term morbidity in 250,000-350,000 people in the United States. Although the precise etiology of MS is unknown, it is thought to be a T-cell-mediated process due to characteristic histologic features and the presence of neuroantigen-specific immune responses in the blood and cerebrospinal fluid. Thus, several immunomodulatory therapies are being investigated to combat this disease. The vast majority of studies assessing the immune system in MS have focused on evaluating and targeting CD4+ T cell responses. However, several reports from others and us present strong evidence for a role of CD8+ T cells in the pathogenesis. Glatiramer acetate (GA, Copaxone) is an immune modulatory agent that is FDAapproved for the treatment of RRMS. However, the mechanism of its action still remains poorly understood. We have provided the first direct evidence that Copaxone induces not only CD4+, but also CD8+ T cell responses. Copaxone-specific CD8+ T cell responses are deficient in untreated MS patients and are restored during Copaxone therapy. We have thus uncovered a novel mechanism through which this FDAapproved drug may mediate its immunologic effects. We hypothesize that Copaxone-induced CD8+ T cells are important regulatory populations of cells that mediate the clinical effects of the drug through multiple mechanisms. In this project, we will continue to delineate the functional role and diversity of these suppressor CD8+ T cells and dissect the requirements of appropriate presentation of Copaxone to induce their response. We believe these studies will provide important insights into an overlooked area of MS immunology and will help generate better immunotherapeutic strategies.
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