Induction of anergy or active suppression following oral tolerance is determined by antigen dosage.

TLDR

Oral tolerance was induced in mice and rats by feeding hen egg white lysozyme or guinea pig myelin basic protein at low (1 mg) or high (5–20 mg) doses. High antigen doses produced anergy with elevated IL‑4 and little active suppression, whereas low doses elicited active suppression with increased TGF‑β and IL‑4, demonstrating distinct cytokine profiles and tolerance mechanisms that may inform oral therapies for autoimmune disease.

Abstract

Oral tolerance was generated to hen egg white lysozyme in the mouse or to guinea pig myelin basic protein in the rat by a low-dose (1 mg) or a high-dose (5-20 mg) feeding regimen. High doses of antigen induced tolerance characterized by anergy with little or no active suppression and increased secretion of interleukin 4 (IL-4). Anergy was shown by an increase in frequency of IL-2-secreting cells following culture in recombinant IL-2. Low doses of antigen induced tolerance characterized by antigen-driven active suppression with increased secretion of transforming growth factor beta (TGF-beta) and IL-4 and minimal anergy. Without further immunization, spleen cells from animals orally tolerized by both regimens secreted increased levels of IL-4 and TGF-beta in an antigen-specific manner. Animals fed high doses secreted more IL-4 and less TGF-beta, whereas those fed low doses secreted more TGF-beta and less IL-4. These results demonstrate that the two feeding regimens induced cell populations that differed in their cytokine secretion profile and their capacity to actively suppress in vitro and to induce anergy. Our results provide a basis for distinguishing different forms of antigen-driven peripheral tolerance and have important implications for orally induced antigen-specific modulation of human autoimmune diseases.