Targeted at learning about the pathogenesis of inflammatory eye diseases grouped under the term """"""""uveitis,"""""""" this project continued to focus mainly on learning about ocular antigens that induce experimental autoimmune uveoretinitis (EAU), an animal model for uveitis in man, and on procedures that modulate this disease. Three major achievements of this study are as follows: (1) We found that the induction of EAU by bovine interphotoreceptor retinoid-binding protein (IRBP) in the Lewis rat involves a unique immunologic reaction in which lymphocytes sensitized against the immunodominant and uveitogenic determinants of this protein do not recognize the rat homologue of this determinant, but, rather, are stimulated by another peptide of the rat IRBP. This is the first description of a phenomenon in which a """"""""surrogate"""""""" peptide determinant of an organ-specific antigen is used to initiate an autoimmune pathogenic process. (2) To overcome the inaccessibility of large amounts of human S-antigen (S-Ag), we have used recombinant DNA technologies to produce this human antigen in Escherichia coli bacteria. The recombinant human S-Ag was found to cross-react with native bovine S-Ag and to be similarly capable of inducing EAU in Lewis rats. In addition, the recombinant human S-Ag was used to identify the immunodominant peptide determinants of this antigen, ie, the peptides recognized by lymphocytes sensitized against whole human S-Ag. Three regions of the molecules were found to harbor immunodominant determinants, with different peptides being selected as dominant in rats of different inbred strains. (3) A novel immunomodulator, linomide, was found to be effective in inhibiting EAU developing in rats and mice actively immunized with S-Ag or IRBP, respectively. This drug also inhibited the humoral and cellular immune responses in these animals. On the other hand, treatment with linomide had no effect on the development of EAU adoptively transferred by presensitized lymphocytes. The latter finding suggests that linomide cannot be useful for the treatment of uveitis in humans, in whom immunopathogenic processes are preactivated.
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