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Gerhild Wildner, Andrea Huber, Maria Diedrichs-Möhring; Therapy of relapsing-remitting experimental uveitis in rats by oral tolerance induction. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2498.
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Antigen-specific tolerance induction would be a desired therapy for uveitis patients. Our relapsing-remitting EAU rat model, induced by immunization with IRBP peptide R14 offers the possibility to test the effect of oral tolerance induction on the prevention of relapses. We tested several peptides with sequences overlapping the amino acid sequence of R14 for preventing uveitis, and different doses of R14 for therapy. High dose of oral antigen should cause clonal deletion, low dose induce regulatory T cells, thus a combination of both, deleting autoreactive T cells and induce Tregs should be most effective.
Lewis rats were immunized with R14-CFA to induce EAU. Oral tolerance was induced prior to immunization (prophylaxis) with 200µg peptide 3x every other day before immunization, or from onset of EAU to termination to prevent relapses (therapy). For prophylaxis we also fed peptides overlapping the sequence of R14. Therapeutic feeding was performed with 200µg R14 during EAU, 3x2mg R14 followed by 200µg or 3x2mg R14 only after onset of EAU. Control groups received PBS only. Mesenteric LN cells were tested for surface markers, cytokines and Foxp3 expression.
Only preventive feeding of R14 and R16, but not of overlapping peptides suppressed EAU. R14 was more tolerogenic than R16 and also prevented relapses (EAU score PBS group: 2.4; R14-fed: 0.56; R16-fed: 1.25). Therapeutic feeding with R14 had no effect on the primary course of EAU, but reduced relapses to 19% of eyes and 23% of rats compared to 50% and 69% relapses in the control group). High-dose feeding (2mg) only had no effect, and 2mg+200µg feeding was less effective (23% relapses (eyes) vs. 31% of rats) than low-dose feeding only. After in vitro-stimulation with R14 TCRab+/CD4+ T cells increased in all R14-fed groups, while TCRab+/CD4+/CD8+ cells and IL-10-producing TCRab and TCRgd cells decreased. Less than 1% of the mLN T cells produced IL-17 or IFN-g, and less than 3% IL-10. Foxp3-expressing TCRab cells slightly increased to 1.4% in the 200µg fed group only.
Therapeutic feeding of R14 was highly effective in preventing relapses, making oral tolerance a useful therapy for relapsing-remitting uveitis. High- and low dose combination did not improve tolerance. There was no clear association with any of the analyzed mLN populations and successful oral tolerance induction.
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