Peripheral expression of rod photoreceptor arrestin induces an epitope-specific, protective response against experimental autoimmune uveoretinitis.
OBJECTIVE
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) (Delta273-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 Delta273-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-gamma 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-gamma 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(H)2-like. Only IL-4 production was clearly associated with reduced susceptibility to EAU.
McPherson
Scott W
SW
Department of Ophthalmology, University of Minnesota, 2001 6th Street SE, Minneapolis, MN 55455-3007, USA. scott-m@lenti.med.umn.edu
Roberts
Josh P
JP
Gregerson
Dale S
DS
D000595:Amino Acid Sequence; D000818:Animals; D019393:Arrestin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D001483:Base Sequence; D004198:Disease Susceptibility; D005260:Female; D016056:Immunodominant Epitopes / Q000276:immunology*; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008214:Lymphocytes / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism*; D014018:Tissue Distribution; D014161:Transduction, Genetic; D014605:Uveitis / Q000276:immunology* / Q000473:pathology
D019393:Arrestin; D001323:Autoantibodies; D016056:Immunodominant Epitopes; D016753:Interleukin-10; D015847:Interleukin-4