T cell activation requirement in autoimmune demyelinatio

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EXCEED THE SPACE PROVIDED. Multiple Sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) of unknown etiology. One possibility for the etiology of MS is that MS is an autoimmune disease, where T cells target myelin antigens. Whether MS is truly an autoimmune disease is still controversial. Many investigators continue to search for pathogens which may be the trigger for the development of this disease. Our prior work in patients with RRMS has suggested that myelin- reactive T cells in MS patients can be distinguished from those in healthy individuals by a lack of dependence upon costimulation for activation. Building on this prior work, we will test the hypothesis that the costimulatory requirements of these myelin-reactive T cells change over the course of disease. In particular, we are very interested in determining whether CD28-, costimulation-independent T cells arise as a result of the chronic inflammatory response that takes place during MS. We are very interested in determining whether myelin-reactive T cells develop a phenotype consistent with immunosenescence over time. In addition, building on our prior work examining programmed cell death in the experimental autoimmune encephalomyelitis (EAE) model, we will determine whether these costimulation-independent, CD28- T cells are more resistant to apoptosis. We will also examine whether polymorphisms in the CTLA-4 molecule can play a role in regulation of the T cell response in MS patients. Many of the proposed studies in MS patients will also be modeled in a murine EAE system. The results of these studies will enhance our understanding of how chronic antigenic stimulation, such as that which is suspected to occur in MS, modifies the immune response. Understanding how chronic inflammatory conditions modify myelin- reactive T cells in MS patients may have broad implications for a variety of immunologically based therapies and the timing of their use in treating patients with MS. PERFORMANCE SITE ========================================Section End===========================================