INDUCTIVE EVENTS IN ORAL TOLERANCE IN THE TCR TRANSGENIC ADOPTIVE TRANSFER MODEL

Oral administration of antigen induces a systemic hyporesponsiveness t ermed oral tolerance. High doses of oral antigen lead to deletion or a nergy of T-cells whereas low doses induce regulatory T-cells that secr ete Th2 cytokines (IL-4/IL-10) and TGF-beta. The initiating events ass ociated with oral tolerance have not been well characterized. We inves tigated the induction phase of oral tolerance by adoptively transferri ng ovalbulumin (OVA) p (323-339) TcR specific transgenic (Tg(+)) T-cel ls 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 how cytometry using an anti-clonotypic monoclonal antibody. In high-dose-fed animals, Tg() cells increased six- to eightfold in Peyer's patches after one feedi ng and then progressively decreased to 44% of those in the control by Day 20. In contrast, a biphasic-type response was observed in lymph no de and spleen where Tg(+) cells decreased after the first feeding, ret urned to the control level, and then decreased to 36-63% of the contro l level by Day 20. In low-dose-fed animals, changes in Tg(+) T cells w ere only observed in Peyer's patches after five feedings, where cells increased approximately twofold. T cell activation as measured by prol iferation 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 la st feeding in low-dose-fed animals. Immunization with OVA/CFA demonstr ated peripheral tolerance as measured by decreased proliferation and I FN-gamma secretion and was associated with increased production of TGF -beta and IL-10. These results suggest that the inductive phase of ora l tolerance is characterized by an activation of antigen-specific T-ce lls that involves the initial secretion of IFN-gamma followed by prolo nged secretion of Th2 cytokines and TGF-beta. (C) 1997 Academic Press.