ABSTRACT
BACKGROUND: Thymic expression of a photoreceptor cell antigen, interphotoreceptor retinoid-binding protein, is known to generate regulatory T cells (T(reg)) that prevent spontaneous autoimmune disease of the retina. However, the contribution of other endogenous, tissue-specific antigens (Ags) expressed in the retina to the generation of T(reg) is uncertain. METHODS: Transgenic mice that express beta-galactosidase (beta-gal) in photoreceptor cells, together with beta-gal-specific T cell receptor transgenic mice, were used to study the induction of T(reg) in vivo. RESULTS: Transgenic expression of beta-gal on the arrestin promoter led to a spontaneous immunoregulatory response that inhibited the development of immune responses to beta-gal. The regulation was transferred by CD3+4+25+ T(reg). Several strategies were then used to show that beta-gal expressed in the retina supported spontaneous, thymus-independent T(reg) development. The endogenous T(reg) also differed from the T(reg) induced by Ag inoculation into the anterior chamber of the eye. CONCLUSION: These results demonstrate that retinal expression of very small amounts of a tissue-specific Ag can generate T(reg) in the periphery.
Subject(s)
Autoantigens/immunology , Autoimmune Diseases/immunology , Photoreceptor Cells, Vertebrate/enzymology , Retina/immunology , T-Lymphocytes, Regulatory/immunology , Uveitis, Posterior/immunology , beta-Galactosidase/biosynthesis , Adoptive Transfer , Animals , Apoptosis/immunology , Autoimmune Diseases/enzymology , Autoimmune Diseases/pathology , Cells, Cultured , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Immune Tolerance , Lymphocyte Activation/immunology , Mice , Mice, Transgenic , Retina/enzymology , Retina/pathology , Retinitis/enzymology , Retinitis/immunology , Retinitis/pathology , T-Lymphocytes, Regulatory/metabolism , Thymus Gland/immunology , Thymus Gland/metabolism , Uveitis, Posterior/enzymology , Uveitis, Posterior/pathologyABSTRACT
PURPOSE: To compare the effects of allopurinol to those of prednisolone on the oxidative tissue damage and inflammatory response in experimental autoimmune uveitis (EAU). METHODS: Experiments were performed using 27 male Lewis rats. EAU was induced by means of crude retina extract, Freund's adjuvant and pertussis toxin. One group of animals served as controls and two groups were treated systemically, one with allopurinol and one with prednisolone. At the end of the experiments lipid peroxides (LPO), myeloperoxidase activity (MPO), and histological changes were determined in the retinal tissue. LPO were measured by two different methods [thiobarbituric acid reactive substances (TBARS) and malondialdehyde-like substances]. RESULTS: Allopurinol led to a significant reduction in LPO and MPO levels. The steroid treatment also resulted in a significant reduction in MPO activity but LPO were significantly reduced only when measured as TBARS. Histological changes were significantly reduced by allopurinol only. DISCUSSION: Allopurinol is more effective than prednisolone in treating EAU. Its efficacy can be explained by the antioxidative/antiinflammatory and probably immunological action. The antiinflammatory effects of prednisolone are not sufficient to reduce the tissue damage. Allopurinol promises to be a useful alternative to steroids in the treatment of uveitis.
Subject(s)
Allopurinol/administration & dosage , Anti-Inflammatory Agents/administration & dosage , Autoimmune Diseases/drug therapy , Free Radical Scavengers/administration & dosage , Prednisolone/administration & dosage , Uveitis, Posterior/drug therapy , Animals , Autoimmune Diseases/chemically induced , Autoimmune Diseases/enzymology , Autoimmune Diseases/pathology , Cattle , Injections, Intravenous , Lipid Peroxides/metabolism , Male , Peroxidase/metabolism , Rats , Rats, Inbred Lew , Retina/drug effects , Retina/enzymology , Retina/immunology , Retina/pathology , Uveitis, Posterior/enzymology , Uveitis, Posterior/immunology , Uveitis, Posterior/pathologyABSTRACT
We have previously demonstrated the effects of various inhibitors of arachidonic acid metabolism on experimental lens-induced granulomatous uveitis. In the present study, we investigated the effect of these same inhibitors on the expression of lysosomal enzymes at different stages of choroidal inflammation in experimental lens-induced granulomatous uveitis and compared this to the inflammation observed at each stage examined. Lysosomal enzymes such as acid phosphatase, beta-glucuronidase and succinate dehydrogenase are known to be liberated during the maturation of mononuclear phagocytes to epithelioid cell granulomas. Although animals treated with nordihydroguaiaretic acid showed less severe inflammation than did indomethacin-treated or control animals, none of these agents appeared to affect the expression of acid phosphatase and beta-glucuronidase, as determined histochemically. Succinate dehydrogenase could not be detected in any of the eyes examined, even though sections of liver and kidney from these same animals were positive for this enzyme.
