Immunization of Lewis rats with myelin basic protein (MBP) and its peptides induces autoimmune encephalomyelitis (EAE) as well as an anterior uveitis (AU) that closely mimics human anterior uveitis. This reflects the observation in humans that a significant percentage (20%) of multiple sclerosis patients suffer from AU. This proposal stems from the observation that MBP-induced eye disease was more persistent than the disease of the CNS and the uveitogenic activity of MBP-reactive T cells does not always parallel with the encephalitogenic activity of the cell, indicating that the mechanism involved in the pathogenesis and tolerance induction of the two diseases differ. These proposed studies will exploit a large volume of data and T cell lines obtained in my laboratory during the previous study of EAE and MBP to characterize uveitogenic T cells, and to elucidate the pathogenic mechanism by which MBP-induces different autoimmune diseases in the CNS and in the eye. We propose to determine whether uveitogenic and encephalitogenic T cells are distinct or overlapping subset(s) of MBP-specific T cells and to determine whether uveitogenic T cells have augmented activation in the eye leading to prolonged disease expression. Finally, we will determine whether the regulatory T cells elicited by MBP-specific encephalitogenic T subsets are less effective in neutralizing uveitogenic T cell activity and whether non-specific inhibitory cells like NKT cells will be more effective in down-regulating diverse uveitogenic T cells. Our proposal will be greatly promoted by the MBP-specific T cells lines already available in my laboratory and the experience of isolation and characterization of autoimmune regulatory T cells and autoreactive T cells elicited by whole MBP antigen and altered peptides. This project will enhance our ability to understand the mechanisms for the development of autoimmune diseases and also identify targets for the therapeutics in uveitis.
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