This project is aimed at learning about the pathogenesis of inflammatory eye diseases which are grouped under the term """"""""uveitis"""""""". As a model for uveitis in man we have induced """"""""experimental autoimmune uveoretinitis"""""""" (EAU) in experimental animals by immunization with ocular-specific antigens. We have recently shown that a retinal component, the interphotoreceptor retinoid-binding protein (IRBP) is highly uveitogenic and produces EAU in various animals, including primates. Our main effort in FY- 1988 has focused on the identification of peptide determinants of IRBP that are responsible for inducing EAU and initiating immune responses. Of the fourteen peptides selected for synthesis from the IRBP sequence, four peptides were found to induce EAU in Lewis rats. One of the peptides, designated R14, was extremely potent, inducing disease at a dose as low as 0.06 mu g/rat; the other three peptides were approximately 1000 fold less active. A correlation was found between the capacity of the peptides to induce EAU and to initiate cellular immunity which cross reacts with the native IRBP molecule. Two peptides, R4 and R14, were also found to produce EAU in primates, thus suggesting that these peptides could be involved in human uveitic conditions as well. In other studies we have collected data to suggest the possible involvement of non-MHC-restricted killer lymphocytes (""""""""NK"""""""" and """"""""LAK"""""""") and of interferon-gamma (IFN-gamma) in the pathogenesis of EAU. A marked increase in the non-MHC-restricted cytotoxic activity was observed in monkeys immunized for induction of EAU. Treatment of mice with IFN-gamma significantly elevated the expression of Ia (class II) antigens on various ocular cells, with a pattern resembling that seen in animals which develop EAU.
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