Multiple Sclerosis (MS) is an autoimmune disease that affects ~400,000 people in the US. It is a life-long chronic disease diagnosed primarily in young adults. There is, as yet no cure for MS. The current treatment includes use of immunosuppressive drugs that often exhibit toxic side effects.Thus, there is a pressing need for alternate and more effective treatment strategies that target the components of inflammatory cells. CAM therapies constitute an important strategy to treat and control the disease. Experimental autoimmune encephalomyelitis is an animal model of MS induced by injection of self antigens, myelin basic protein, proteolipid protein or myelin oligodendrocyte glycoprotein and adjuvants. Resveratrol (RES;3,5,4'- trihydroxystilbene), a nonflovaonoid polyphenol found in various plants including mulberries, peanuts and grapes has been shown to have beneficial effects particularly on cardiovascular diseases through its antiinflammatory properties. Our Preliminary Studies have demonstrated that RES induces apoptosis primarily in activated T cells through Fas-FasL interactions, involving aryl hydrocarbon receptor (AhR) and estrogen receptor (ER). Moreover, in vivo, RES down regulates CD44 and upregulates FoxpS. We are also excited by our findings that RES treatment decreases the inflammation and clinical symptoms of EAE. In the current study, we will test the central hypothesis that RES treatment is effective against EAE through multiple pathways incuding induction of apoptosis in myelin-specific T cells, suppression of DC functions, decreased T cell infiltration in the CMS due to CD44 down-regulation on T cells, and upregulation of T regs. We will pursue the specific aims: # 1. Study the role of Fas-FasL interactions in resveratrol (RES)-induced apoptosis in T cells and dendritic cells (DCs) involving autocrine or paracrine path ways.#2. Investigate the role of AhR in Fas-FasL upregulation and consequent apoptosis induced by RES in T cells.tf 3. Test the role of ER in the induction of apoptosis in T cells and peripheral T dysfunction following RES treatment.^ 4. Study the effect of RES on initiation and progression of EAE. These studies are aimed at providing insights into the efficacy of RES mainly in acute, remitting-relapsing and chronic forms of the disease which represent diverse pathological and immunological characteristics. Together, our studies should provide novel mechanistic clues on how RES helps in the treatment of MS and develop better CAM therapies to control the disease.
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