Oral Administration of Retinoic Acid Receptor-α/β-Specific Ligand Am80 Suppresses Experimental Autoimmune Uveoretinitis

PURPOSE. To determine whether synthetic retinoic acid receptor (RAR)-alpha/beta-specific agonist Am80 reduces inflammation in experimental autoimmune uveoretinins (EAU). METHODS. Naive CD4(+) T cells were activated with anti-CD3, anti-CD28, and transforming growth factor (TGF)-beta, in the presence or absence of Am80. Intracellular expression of forkhead box p3 (Foxp3) and interleukin (IL)-17 in the activated CD4(+) T cells was assessed by flow cytometry. For induction of EAU, C57BL/6 mice were immunized with human interphotoreceptor retinoid binding protein (IRBP) peptide 1 to 20 Am80 was administered orally every other day (3 mg/kg/time point) from day 0 to day 21. In vivo primed draining lymph node cells front vehicle-treated or Am80-treated mice were stimulated with IRBP(1-20), and culture supernatant was harvested for assay of interferon (IFN)-gamma, IL-6, IL-10, and IL-17. The expression of Faxp3 and IL-6 receptor a in CD(4+) T cells of draining lymph node cells was assessed by a flow cytometer. RESULTS. Am80 synergized with TGF-beta to induce Foxp3(+) T regulatory cells (Treg) and reciprocally inhibited development of IL-17-producing T helper cells (Th17) induced by TGF-beta and IL-6. Am80 treatment reduced the severity of EAU clinically, and IFN-gamma and IL-17 production was significantly reduced in Am80-treated mice. In addition, the expression of IL-6 receptor a on CD4+ T cells was downregulated in Am80-treated mice. CONCLUSIONS. These findings demonstrate that Am80 treatment ameliorates severity of EAU and reduces the Th1/Th17 responses. The synthetic retinoid Am80 appears to be a promising agent for preventing autoimmune uveoretinal inflammation. (Invest Ophthalmol Vis Sci 2011;52:1548-1556) DOI:10.1167/iovs.10-5963