TY - JOUR
T1 - Oral tolerance in experimental autoimmune uveoretinitis
T2 - Distinct mechanisms of resistance are induced by low dose vs high dose feeding protocols
AU - Gregerson, Dale S.
AU - Obritsch, Wesley F.
AU - Donoso, Larry A.
PY - 1993/11/15
Y1 - 1993/11/15
N2 - 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 μg/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.
AB - 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 μg/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.
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M3 - Article
C2 - 7693817
AN - SCOPUS:0027384272
SN - 0022-1767
VL - 151
SP - 5751
EP - 5761
JO - Journal of Immunology
JF - Journal of Immunology
IS - 10
ER -