Peripheral Expression of Rod Photoreceptor Arrestin Induces an Epitope-Specific, Protective Response Against Experimental Autoimmune Uveoretinitis

Abstract

Purpose: To examine the immunological basis for reduced susceptibility to experimental autoimmune uveoretinitis (EAU) in rats expressing retinal photoreceptor cell arrestin in the periphery. Methods: Peripheral expression of arrestin in Lewis rats was achieved by engraftment of syngeneic bone marrow (BM) transduced with retroviruses encoding wild-type arrestin or a mutant arrestin lacking the immunodominant epitope Arr273 − 289 (Δ 273-Arr). EAU was induced by immunization with arrestin peptides Arr273−289 or Arr343−362. Cultured splenocytes and/or lymphocytes from immunized rats were assayed for antigen-induced proliferation, antibody production, and cytokines. Results: Rats expressing Δ 273-Arr were not protected from Arr273 − 289-induced EAU, showing that protection was epitope specific. Proliferation assays found little difference in the ability of draining lymph node cells from arrestin-transduced rats to proliferate in response to the antigen, indicating that antigen-responsive T cells were not deleted in BM recipients. Only rats immunized with Arr343 − 362 elicited antibodies, but no difference in titer was found between transduced and control animals. Higher levels of IFN-γ mRNA were made by Arr273 − 289-immunized rats than Arr343 − 366-immunized rats, but in either case, the levels did not correlate with chimeric status or EAU susceptibility. Arr273 − 289-immunized rats had higher levels of IL-10 mRNA than Arr343 − 362-immunized rats, and those levels were decreased in arrestin chimeric rats. Overall, immunization with the more potently uveitogenic Arr343 − 362 induced lower levels of IL-10 and IFN-γ than the less uveitogenic Arr273 − 289. A strong correlation was found between the ability of lymphocytes to make IL-4 in the arrestin-chimeric animals and inhibition of EAU. Conclusions: Peripheral expression of arrestin in a regenerating immune system induces an epitope-specific protective response to EAU induced by arrestin peptides. Although IL-4 and IL-10 levels were altered in arrestin-chimeric mice, the outcome was not consistently TH2-like. Only IL-4 production was clearly associated with reduced susceptibility to EAU.