a1 Immunobiology Unit, Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust, London WC1N 1EH, UK
There is good clinical and experimental evidence that oral tolerance exists in man and that the timing of antigen (food) administration is an important factor in the development of food allergic sensitisation and disease. Induction of tolerance is often seen as a T-helper 2-skewed response, which on one side may prevent harmful mucosal immune reactions, but on the other side may contribute to adverse responses in the susceptible individual. The primary mechanisms by which tolerance may be mediated include T-cell deletion, anergy, suppression ‘ignorance’ and apoptosis. Cell-mediated delayed hypersensitivity reactions (T-helper 1), which are implicated as a pathogenetic principle in the development of autoimmune and gastrointestinal inflammation are particularly well suppressed. Regulatory events during the induction of tolerance (or sensitisation) are not well characterised and remain at times controversial. The balance between tolerance (suppression) and sensitisation (priming) is dependent on several factors, such as: (a) genetic background; (b) nature of antigen and dose of antigen; (c) frequency of administration; (d) age (maturity v. immaturity) at first antigen exposure; (e) immunological status of the host (e.g. virus infection); dietary exposure of the mother; (g) antigen transmission via breast milk, and others. Overall, there is evidence in rodents that multiple low-dose feeds are more likely to induce regulatory cytokines (e.g. transforming growth factor-β, interleukins 10 and 4) in part secreted by CD4+CD25+ T-regulatory cells. Despite the powerful suppressive effect of oral antigen exposure observed in experimental models, its application in clinical trials of autoimmune diseases has not yet yielded the expected beneficial results.