Spontaneous induction of immunoregulation by an endogenous retinal antigen.

PURPOSE Ocular immune deviation studies have relied on intraocular injections of antigen to induce altered immune responses. Contributions of the injection process itself have complicated study of the mechanisms and interpretations of biological significance. In the current study, transgenic mice were used to determine the presence of immune deviation or other evidence of immunoregulation, elicited by endogenous Escherichia coli beta-galactosidase (beta-gal) expressed through a retinal arrestin promoter. METHODS Mice that express beta-gal in the retina and various control mice were immunized with beta-gal and tested for immune responsiveness by the ear-swelling test for delayed-type hypersensitivity (DTH), in vitro proliferation assays, and cytokine assays. Spleen cells from transgenic mice were also transferred to normal recipients to test for transfer of immune deviation. RESULTS Endogenous retinal beta-gal expression depressed the DTH response and proliferation assays after beta-gal immunization. The ability to depress DTH was transferred by naïve spleen cells from transgenic mice to nontransgenic mice. Use of an immunization protocol that included high-dose Mycobacterium tuberculosis (M tb) H37Ra adjuvant and concurrent administration of pertussis toxin reversed the inhibition of DTH. CONCLUSIONS An endogenous neo self-retinal antigen alters subsequent immune responses without intraocular injection, suggesting that normal retinal proteins in quiet eyes induce immunoregulatory responses. Based on cytokine assays, there were similarities to the immune deviation induced by intraocular inoculation in the IL-4 response, but the IL-10, IFN-gamma, and TGF-beta1 results were not similar, indicating that the mechanisms differ. The ability of supplemented adjuvant to overcome endogenous tolerance may be related to the requirement for supplemented adjuvants in the induction of experimental autoimmune uveoretinitis.