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 (Δ273-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 Δ273-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. 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 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.
Bibliographical noteFunding Information:
This study was supported by NIH grant EY11542; Research to Prevent Blindness, Inc., the Anna Heil-maier Foundation, St. Paul, MN, and the Minnesota Lions and Lionesses Clubs. The authors thank Dr. John Torseth, Jing Xiao, Jing Yang, and Michelle Padua for their contributions to the study.
- Experimental autoimmune uveoretinitis (EAU)
- Immune privilege