title: Oral tolerance in experimental autoimmune uveoretinitis. Distinct mechanisms of resistance are induced by low dose vs high dose feeding protocols.
abstract: 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.
authors.affiliation: Department of Ophthalmology, University of Minnesota, Minneapolis 55455.
authors.forename: D S
authors.initials: DS
authors.lastname: Gregerson
authors.forename: W F
authors.initials: WF
authors.lastname: Obritsch
authors.forename: L A
authors.initials: LA
authors.lastname: Donoso
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000097:blood; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology*; D019393:Arrestin; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D002417:Cattle; D000939:Epitopes; D005136:Eye Proteins / Q000008:administration & dosage / Q000276:immunology*; D005260:Female; D007108:Immune Tolerance; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D012173:Retinitis / Q000276:immunology*; D014605:Uveitis / Q000276:immunology*
chemical_list: D000906:Antibodies; D000941:Antigens; D019393:Arrestin; D001324:Autoantigens; D000939:Epitopes; D005136:Eye Proteins; D010446:Peptide Fragments