Peripheral deletion of antigen-reactive T cells in oral tolerance

Abstract

Oral administration of antigen is used to induce antigen-specific peripheral immune tolerance. As well as preventing systemic immune responses to ingested proteins, oral tolerance to autoantigens has also been used to suppress autoimmune diseases in animals and humans. Both active suppression and clonal anergy are suggested to be mechanisms of oral tolerance, depending on the dose of antigen fed. Here we report that oral antigen can delete antigen-reactive T cells in Peyer's patches, in mice transgenic for the ovalbumin-specific T-cell receptor genes. The deletion was mediated by apoptosis, and was dependent on dosage and frequency of feeding. At lower doses deletion was not observed; instead there was induction of antigen-specific cells that produced transforming growth factor (TGF)-beta and interleukin (IL)-4 and IL-10 cytokines. At higher doses, both Th1 and Th2 cells were deleted following their initial activation, whereas cells which secrete TGF-beta were resistant to deletion. These findings demonstrate that orally administered antigen can induce tolerance not only by active suppression and clonal anergy but by extrathymic deletion of antigen-reactive Th1 and Th2 cells.

Mucosal tolerance to E-selectin provides cell-mediated protection against ischemic brain injury

“…Repetitive mucosal tolerization with low-dose antigen generates regulatory T cells (5,6), in contrast to intranasal administration of high-dose antigen that leads to clonal anergy or clonal deletion of T cells (4,7). Dendritic cells and macrophages are subjacent to the mucosa of the nasal passages and act as antigen-presenting cells in the nasal-associated lymphoid tissue.…”

“…The schedule and amount of antigen administration determine the nature of the tolerance. Clonal deletion or anergy of antigenreactive T cells can occur after a single feeding of very high-dose antigen (4); active tolerance with production of regulatory T cells occurs after repetitive administrations of low-dose antigen (5,6). T cells tolerized with a low-dose regimen secrete cytokines such as IL-10 and transforming growth factor (TGF) ␤1 on antigen restimulation, which suppress cell-mediated, or T H 1, immune responses (5).…”

Peptide-induced nasal tolerance for a mycobacterial heat shock protein 60 T cell epitope in rats suppresses both adjuvant arthritis and nonmicrobially induced experimental arthritis

“…Three distinct mechanisms are possibly operational in oral tolerance: clonal deletion, anergy, and active suppression (11,16,17,30,31). The dosage of the administered antigen appears to determine which mechanism prevails (10,(32)(33)(34). High antigen doses lead to clonal deletion or anergy whereas low doses may lead to (bystander) suppression, possibly mediated by CD8 ϩ or CD4 ϩ T cells capable of producing the inhibitory cytokines such as transforming growth factor ␤ and IL-4.…”

Oral tolerance with Copolymer 1 for the treatment of multiple sclerosis

“…Low doses of antigen induce regulatory T cells that act by secreting anti-inflammatory cytokines such as transforming growth factor (TGF) type ␤, IL-10, and IL-4 (8, 9). Higher doses induce anergy or deletion of cells specific for the fed antigen (10,11). These multiple mechanisms most probably evolved to maintain tolerance to the large variety of proteins that are ingested over a wide dose range.…”