Role of IL4R-Alpha Signaling in Food Allergen Sensitization and Anaphylaxis

Food allergy is an increasingly prevalent condition, affecting more than 2 million children in the U.S. The overall goal of this proposal is to examine the roles of domains which regulate signaling by the IL-4Ra chain of the Type I IL-4 receptor on 1) immune sensitization and 2) induction of allergic responses in the intestine. <P> In allergy-prone individuals, food ingestion can lead to the generation of Th2 polarized CD4+ T helper cells which orchestrate both the induction of allergic inflammation and the production of specific IgE antibodies. There is significant heterogeneity among individuals with respect to the tendency to generate Th2 responses but in all cases this is critically-dependent on IL-4.<P> We hypothesize that variations in structure which amplify IL-4Ra signaling will enhance immune sensitization to allergens. In the case of food allergy, there is a critical second level of heterogeneity regarding the severity of allergic responses exhibited by different subjects with similar IgE levels. IL-4 signaling has been shown to modulate sensitivity to anaphylaxis and we hypothesize that it may similarly regulate physiologic changes upon food allergen challenge.<P> Other atopic conditions have been linked to polymorphisms in components of the IL-4/13 cytokine/receptor axis including IL-4Ra1 and some recent preliminary findings suggest potential links to food allergy. We hypothesize that alterations in IL-4 receptor-a chain structure which enhance positive signals or dampen inhibitory signals will give rise to exaggerated food allergy responses in a murine model of food allergy by: 1) enhancing sensitization and 2) augmenting effector responses. <P> We will test this hypothesis by performing: <BR> 1. Detailed characterization of immune sensitization to the model food allergen, ovalbumin (OVA), in mice with targeted insertion of IL-4Rachain variants affecting signaling <BR>2. Analysis of IL-4Ra signaling effects on effector phase of response to food allergen.<P> Food allergy has become a major health issues in developed countries with an estimated prevalence of up to 6% in children and 3% in the adult population. It is difficult to elicit immune responses to ingested substances making studies of food allergy in animal models a challenge. In this proposal novel strain of mice, IL-4Ra Y709F, highly susceptible to developing immune responses to foods, will be used to study mechanisms of food allergy.