Abstract
Abstract: :
Purpose: Activation, recruitment and accumulation of lymphocytes in the target organ are important steps in the pathogenesis of autoimmune diseases. Trafficking of specific lymphocyte subpopulations is controlled by chemokines. We therefore investigated the role of chemokine receptor (CCR) blockades based on the biology of chemokine RANTES/CCL5 in a rat model of experimental autoimmune uveitis and oral tolerance induction, by using N–methionylated RANTES (Met–RANTES), a functional CCR1/CCR5 antagonist. Methods: Uveitis was induced in Lewis rats either by active immunization with S–Antigen peptide PDSAg or IRBP (interphotoreceptor retinoid binding protein) peptide R14, or by adoptive transfer of peptide–specific T cell lines. Met–RANTES was injected daily from immunization to onset of uveitis or at various time points after adoptive transfer of uveitogenic T cells until peak of clinical disease. To induce oral tolerance, rats were fed with PDSAg or R14 prior to immunization with the respective peptide. Met–RANTES was injected daily during peptide feeding until one day before immunization. Results: Application of Met–RANTES immediately after subcutaneous immunization with IRBP peptide R14 significantly decreased intraocular inflammation, whereas no significant effect was observed after immunization with PDSAg. Met–RANTES injection after adoptive transfer of uveitogenic T cells in order to impede the recruitment of inflammatory leucocytes into the eye had no effect on disease induced by R14–specific T cells, but completely blocked uveitis mediated by PDSAg–specific T cell lines. Daily i.p. injection or feeding of Met–RANTES during oral tolerance induction with PDSAg or R14 showed a trend towards a milder disease as compared to groups receiving oral peptide and saline alone. No differences in uveitis intensity were observed among the groups receiving oral control peptide, irrespective of Met–RANTES application. Conclusions: Met–RANTES or CCR antagonists with similar bioactivity may have a therapeutic potential in supporting oral tolerance induction rather than treating uveitis itself. The different effects of Met–RANTES on T cell responses specific for S–Ag– or IRBP–peptide indicate immunological differences with an impact on immune mediated therapies. Furthermore, these results point to differences in the immune responses to the peptides from S–Ag and IRBP used here.
Keywords: cytokines/chemokines • immunomodulation/immunoregulation • uveitis–clinical/animal model