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 Arr_{273 − 289} (Δ 273-Arr). EAU was induced by immunization with arrestin peptides Arr_273−289 or Arr_343−362. 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 Arr_{273 − 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 Arr_{343 − 362} elicited antibodies, but no difference in titer was found between transduced and control animals. Higher levels of IFN-γ mRNA were made by Arr_{273 − 289}-immunized rats than Arr_{343 − 366}-immunized rats, but in either case, the levels did not correlate with chimeric status or EAU susceptibility. Arr_{273 − 289}-immunized rats had higher levels of IL-10 mRNA than Arr_{343 − 362}-immunized rats, and those levels were decreased in arrestin chimeric rats. Overall, immunization with the more potently uveitogenic Arr_{343 − 362} induced lower levels of IL-10 and IFN-γ than the less uveitogenic Arr_{273 − 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 T_H2-like. Only IL-4 production was clearly associated with reduced susceptibility to EAU.

KEYWORDS:

• experimental autoimmune uveoretinitis (EAU)
• immune privilege
• retina
• tolerance