Administration of exogenous interleukin‐18 and interleukin‐12 prevents the induction of oral tolerance

Interleukin-18 (IL-18), a pro-inflammatory member of the IL-1 family, has been associated with autoimmunity and allergic disease. This type of pathology is thought to be the result of a defect in immunological tolerance and is often observed in inflammatory disorders of the gut such as coeliac disease, Crohn's disease and ulcerative colitis. IL-18 has been implicated in a number of mucosal immune disorders, where it synergizes with IL-12 to induce the production of interferon-gamma (IFN-gamma). We have therefore investigated the effects of IL-18 and IL-12 administration on the induction of oral tolerance to ovalbumin. The suppression of specific Ig G2a production, delayed-type hypersensitivity responses and IFN-gamma production by antigen-specific T cells were all abrogated by the presence of exogenous IL-12 and IL-18, suggesting that oral tolerance was broken. The expression of the co-stimulatory molecule CD80 on dendritic cells was also shown to be increased by this combination of cytokines. As dendritic cells are thought to be of major importance in the induction of tolerance, this suggests a mechanism by which tolerance to mucosal antigens may be broken in vivo.