The effect of the oral administration of various antigens on the ocular immune response has been tested in the animal model for severe intraocular inflammatory disease, experimental autoimmune uveoretinitis, that is induced by both retinal S-antigen (S-Ag) and interphotoreceptor retinoid-binding protein (IRBP). Oral tolerance could be induced by repeatedly feeding S-Ag to rats. A randomized masked trial to evaluate the usefulness of S-Ag feeding in patients with intraocular inflammatory diseases finished recruitment in August 1995, with publication of the trial in early 1997. That study was aimed to evaluate the effect and safety of the oral administration of retinal antigens on various parameters of ocular inflammation. It was a phase I/II randomized, masked trial. In that study, patients with endogenous uveitis who were dependent on immunosuppressive agents were randomly assigned to receive either retinal S-antigen alone (n=10), retinal S-antigen and a mixture of soluble retinal antigens (n=10), retinal mixture of soluble antigens alone (n=10), or placebo (n-15). An attempt was then made to taper patients completely off their standard immunosuppressive therapy over an eight week period. Time to development of uveitis was the main study endpoint and was not statistically significantly different for any of the four treatment groups. However, the group receiving the purified S-Antigen alone appeared to be tapered off their immunosuppressive medication more successfully as compared to placebo (p=0.08), while all the other groups appeared to do worse than those receiving placebo. No toxic effects attributable to any treatment were observed. This study was used for further hypothesis development. Based on that and other studies. We have recently completed a study testing the use of Optiquel (provided under a CRADA by Enzo corporation) as a potential oral tolerance agent for uveitis. Optiquel is a B27PD peptide sequence found in several HLA-B-antigens, most remarkably in all those that are associated with uveitis, such as B27, B51 and B44 (genetically linked to HLA A29). The objective of the ongoing masked randomized study was to evaluate the safety and efficacy of Optiquel as a corticosteroid-sparing agent for chronic non-infectious uveitis in participants receiving oral corticosteroid therapy alone or combined with an immunosuppressive agent in a proof-of-concept clinical trial. Eligible patients with non-infectious uveitis requiring at least 20 mg of oral prednisone to maintain a quiescent eye were eligible. The protocol was performed under IRB approval and an IND. It is also an NIH Center for Human Immunology approved study While a second site was planned the decision was to not to go ahead with this approach and therefore was underpowered for the original goal. However a secondary analysis suggested that there was enough information for evaluation. The immunome is being extensively evaluated in collaboration with CHI and results are pending. In addition, based on recent immune data we have gathered, we are planning a multicenter study to evaluate the use of oral tolerance to prevent the advanced expression of age-related macular degeneration.