EXCEED THE SPACE PROVIDED. 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. Patients with MS may present clinically either with clearly defined relapses (relapsing-remitting MS; RRMS) or with gradual accumulating disability without clear periods of remission (progressive MS), which may be either primary (PPMS) or secondary (SPMS). In view of such a varied clinical spectrum, it has long been thought that MS may, in fact, represent a group of related disorders. 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. To understand the mechanism of such intervention and to design better therapeutic strategies, it is crucial to precisely delineate the nature of the underlying responses that exacerbate or regulate the disease process in different forms of MS. Glatiramer acetate (Copaxone ), a synthetic copolymer of four amino acids (alanine, glutamic acid, lysine and tyrosine), is one such immunomodulatory drug that has been shown to reduce the rate of exacerbation and inhibit the appearance of new lesions in patients with RRMS. It is currently also being tested for its efficacy in treating patients with PPMS in a multi-center, double-blind, placebo-controlled clinical trial. Copaxone is known to prime T-cell responses in treated patients. However, the exact nature of these responses, their role in immunomodulating the disease and the precise mechanisms by which Copaxone exerts its effects are presently unclear. Recent studies from our laboratory provide the first direct evidence that there is an induction of a potent CD8+ T cell response in MS patients following Copaxone therapy. Based on these observations, we hypothesize that Copaxone-induced CD8+ T cell responses play an important role in the immunomodulatory effect of the drug. Utilizing innovative flow cytometric and molecular approaches, we propose to build on our studies by further delineating the functional role of neuroantigen- and Copaxone-induced CD4+ and CD8+ T cell responses in the regulation of autoimmune demyelination in MS. PERFORMANCE SITE ========================================Section End===========================================
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