Oral tolerance: immune mechanisms and the generation of Th3-type TGF-beta-secreting regulatory cells

Oral tolerance is a tong recognized method to induce peripheral immune tole rance. Oral tolerance has been used successfully to treat animal models of autoimmune diseases and is being tested in human diseases. Low doses of ora l antigen induce active suppression, whereas high doses induce clonal anerg y and deletion. Oral antigen preferentially generates a Th2(IL-4/IL-10)- or a Th3(TGF-beta)-type response. Th3-type cells are a unique T-cell subset w hich primarily secrete TGF-beta, provide help for IgA and have suppressive properties for Th1 and other immune cells. Th3-type cells appear distinct f rom the Th2 cells as CD4(+) TGF-beta -secreting cells with suppressive prop erties in the gut have been generated from IL-4-deficient animals. In vitro differentiation of Th3-type cells from Th0 precursors from TCR transgenic mice is enhanced by culture with TGF-beta, IL-4, IL-10 and anti-IL-12. Beca use regulatory T cells generated by oral antigen are triggered in an antige n-specific fashion but suppress in an antigen-nonspecific fashion, they med iate 'bystander suppression' when they encounter the fed autoantigen at the target organ. Thus, mucosal tolerance can be used to treat inflammatory pr ocesses that are not autoimmune in nature. Mucosal antigen has also been us ed to treat animal models of stroke and of Alzheimer's disease. Induction o f low-dose oral tolerance is enhanced by oral administration of IL-4 and IL -10. Coupling antigen to CTB or administration of Flt-3 ligand enhances ora l tolerance. Anti-B7.2 but not anti-B7.1 blocks low-dose, but not high-dose oral tolerance. High-dose oral tolerance is blocked by anti-CTLA-4. CD25() CD4(+) regulatory T-cell function also appears to be related to TFG-beta. (C) 2001 Edition scientifiques et medicales Elsevier SAS.