The prevalence and severity of allergic diseases is rising and poses an increasing clinical problem. Food allergies are a major course of life-threatening hypersensitivity reactions, but the immunological mechanisms underlying the induction of sensitisation or tolerance to food proteins are poorly understood. This study examined the immunological outcome of exposure to peanut protein and chicken egg ovalbumin (OVA) at the intestinal mucosae and skin surfaces. The aim was to determine whether skin exposure to allergens may interfere with oral tolerance and promote food allergies. A murine BALB/c model of oral tolerance or sensitisation to peanut protein was developed and compared to a model of oral tolerance to OVA. Tolerance to peanut required a significantly higher oral dose than tolerance to OVA and low doses of peanut protein were more likely to induce sensitisation. Oral tolerance mediated suppression of both Th1 and Th2 responses. A high dose feed of peanut protein induced a population of CD4 CD25 CTI

\-4 T cells with regulatory properties, suggesting that apopulation of cells similar to the naturally occurring thymic derived CD4

CD25″T

can be induced in the periphery. Epicutaneous exposure to peanut proteinand OVA on abraded skin (epicutaneous immunisation) induced potent Th2-type immunity with high levels of antigen-specific IL-4, IgE and IgG1 with no IgG2a. Abrasion of the skin increased expression of activation markers on Langerhans cells (LCs), but rapid migration from epidermis to draining lymph nodes was observed only after both skin abrasion and exposure to antigen, suggesting that maturation and migration of LCs are independently regulated events. Primary skin exposure prevented the induction of oral tolerance. Upon oral challenge mice were further sensitised and developed strong specific IL-4 and IgE responses as well as clinical signs of anaphylaxis. This suggests that epicutaneous exposure to protein allergens specifically drives Th2 responses and may promote food allergy. Primary epicutaneous immunisation changed responses elicited by subcutaneous antigen in complete Freund’s adjuvant from Thl to Th2. Additionally, epicutaneous immunisation converted an existing antigen-specific Thl response to a Th2 response, indicating dominance of the skin-induced immunity. Together these results suggest that epicutaneous immunisation may be a useful non-invasive, non-adjuvant-dependent method of vaccination and therapy.