title: Inductive events in oral tolerance in the TCR transgenic adoptive transfer model.
abstract: Oral administration of antigen induces a systemic hyporesponsiveness termed oral tolerance. High doses of oral antigen lead to deletion or anergy of T-cells whereas low doses induce regulatory T-cells that secrete Th2 cytokines (IL-4/IL-10) and TGF-beta. The initiating events associated with oral tolerance have not been well characterized. We investigated the induction phase of oral tolerance by adoptively transferring ovalbulumin (OVA) p (323-339) TcR specific transgenic (Tg+) T-cells into BALB/c recipients that were then fed either a high (5 mg x 5) or a low (0.1 mg x 5) dose of OVA 323-329 peptide. The frequency of Tg+ T-cells in lymphoid tissues was determined by flow cytometry using an anti-clonotypic monoclonal antibody. In high-dose-fed animals, Tg+ cells increased six- to eightfold in Peyer's patches after one feeding and then progressively decreased to 44% of those in the control by Day 20. In contrast, a biphasic-type response was observed in lymph node and spleen where Tg+ cells decreased after the first feeding, returned to the control level, and then decreased to 36-63% of the control level by Day 20. In low-dose-fed animals, changes in Tg+ T cells were only observed in Peyer's patches after five feedings, where cells increased approximately twofold. T-cell activation as measured by proliferation and IFN-gamma secretion occurred in both low- and high-dose-fed animals after only one feeding and then declined whereas secretion of Th2 cytokines and TGF-beta remained high even 10 days after the last feeding in low-dose-fed animals. Immunization with OVA/CFA demonstrated peripheral tolerance as measured by decreased proliferation and IFN-gamma secretion and was associated with increased production of TGF-beta and IL-10. These results suggest that the inductive phase of oral tolerance is characterized by an activation of antigen-specific T-cells that involves the initial secretion of IFN-gamma followed by prolonged secretion of Th2 cytokines and TGF-beta.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Inobe
authors.forename: H L
authors.initials: HL
authors.lastname: Weiner
mesh_terms: D000284:Administration, Oral; D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens / Q000008:administration & dosage*; D005260:Female; D007108:Immune Tolerance / Q000502:physiology*; D008213:Lymphocyte Activation; D008221:Lymphoid Tissue / Q000276:immunology; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009928:Organ Specificity; D010047:Ovalbumin / Q000008:administration & dosage*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D010581:Peyer's Patches / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D018418:Th2 Cells / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000941:Antigens; D008222:Lymphokines; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; D010047:Ovalbumin