Oral tolerance in experimental autoimmune uveoretinitis. Distinct mechanisms of resistance are induced by low dose vs high dose feeding protocols.

Studies of oral tolerance in LEW rat models of autoimmune diseases including S-antigen (S-Ag)-mediated experimental autoimmune uveoretinitis (EAU), and myelin basic protein-induced experimental autoimmune encephalomyelitis have produced conflicting evidence for the roles of clonal anergy and suppression. Using subpeptides from a region of S-Ag known to induce oral tolerance a protective site was localized to a nonamer of residues 347-355. This site was also uveitogenic, providing the basis for testable hypotheses for tolerance to be due to clonal anergy in pathogenic T cells specific for that site, or to suppression. Evidence for suppression was strongly supported by several observations. 1) Induction of oral tolerance with low dose feedings (250 micrograms/feeding) of peptide 343-362 conferred resistance to EAU induction by intact S-Ag, which should not be possible if only T cells specific for epitopes in 343-362 were rendered unresponsive, since there are several other pathogenic sites in S-Ag. 2) Low dose feeding induced resistance to EAU induction by a distinct, spatially separate peptide, residues 270-289, of S-Ag. 3) The requirement for linked recognition was shown by the inability of tolerance induced by feeding 343-362 to protect from EAU induction by a peptide, residues 521-540, derived from interphotoreceptor retinoid binding protein, a different uveitogenic retinal protein. 4) Resistance could be adoptively transferred. Conversely, induction of tolerance with high doses of peptide (5 mg/feeding) resulted in loss of resistance to EAU induced by S-Ag, although disease induction by the fed peptide was inhibited; observations that are consistent with clonal anergy. The apparent lack of suppression after high dose feeding could mean that suppressor T cells can also be rendered unresponsive or that induction of T suppressor cells is dependent on CD4+ Th cells, which were rendered anergic, leading to lack of T suppressor development. We suggest that oral tolerance operates by at least two distinct mechanisms that depend on the feeding dose; low doses induce suppression, whereas high doses induce unresponsiveness.