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INVESTIGATOR: Huang, F.; August, A.

PERFORMING INSTITUTION:
CORNELL UNIVERSITY
ITHACA, NEW YORK 14853

ROLES OF UNIQUE SUBSETS OF THE INTESTINAL INTRA EPITHELIAL LYMPHOCYTES (IEL) IN THE DEVELOPMENT OF FOOD-BORNE ALLERGY

NON-TECHNICAL SUMMARY: Food allergy has been rising as a serious health problem in US. The prevalence of egg allergy is estimated to be 1.6 - 3.2% of the pediatric population. The interactions of the food borne allergen and gut mucosal immune system may play a critical role in food allergy. We recently found two specialized immune cells residing within the intestine that may regulate the sensitivity to food allergens. These are {alpha beta}-T cells bearing CD8{alpha alpha} and a specific population of {gamma delta}-T cells. In order to understand how the mucosal immunity in gut determines whether food allergy develops or not, we propose to build novel animal models of food allergy, and examine the role of specific immune cell populations in the development of food allergic responses. We will first develop a novel model of food allergy based on exposure to egg albumin and gluten, a wheat protein, which may enhance access of food allergens to the immune system. Through this novel model, we will further test the hypothesis that specific immune cell populations mentioned above regulate the development of food allergy. The rationale for this proposal is that once we know the mechanism by which food allergens develop, we can use this information to eventually develop strategies to interfere with the process. If successful, our work will provide an innovative and realistic model of food allergy development, which will allow us to develop effective strategies to treat and prevent the food allergy responses.

OBJECTIVES: Our long-range goal is to provide a detailed understanding of the mechanism by which the mucosal immune system, particularly in the gut, determines the immune response between tolerance and allergy. In pursuit of that goal, the objective of this application is to determine the role of wheat gluten in allowing specific IEL populations access to food borne allergens, leading to the development of an allergic response to a food borne allergen. We hypothesize that specific T cell subsets within the IEL population along with exposure to wheat gluten in foods, regulate the development of food allergy. Using murine exposure to gluten and chicken egg albumin (OVA) as a model, we will test this hypothesis by performing experiments in the following 2 specific aims: Specific Aim #1: Determine the function of CD8{alpha alpha} (CD8aa) bearing {alpha beta}-T cells (ab-T cells) in suppressing the development of IgE mediated allergy to OVA. The objectives of aim #1 are to develop a novel murine model of food allergies, and determine whether the CD8aa bearing ab-T cells act to prevent the development of inappropriate immune response to food borne allergens in young mice. Our approach will be to utilize young mice and the egg allergen ovalbumin, along with exposure to gluten, to develop a model of egg allergy. We expect to find that young mice are highly susceptible to developing an IgE response to food borne allergens, and that this is controlled by immunosuppressive cells in the IEL population, the CD8aa ab-T cells. Specific Aim #2: Determine the role of gut {gamma delta} (gd)-T cells in controlling B cell class switch leading to the development of IgE mediated allergy to chicken egg albumin. In the first aim, we will address the role of IEL ab-T cell populations carrying the CD8aa as protective populations. This will help to understand why children who have food allergies most likely are sensitized at an early age to allergens, delivered via food products that contact the immune system through the gut mucosal immune system or in their mother's milk. In aim #2 of the proposal, we will further address another potential gd-T cell population that may be allergy promoting T cells in gut. Published work, along with our preliminary data, provide strong support for the idea that gd-T cells bearing specific T cell receptors are involved in the development of IgE responses. Therefore, the objective of aim 2 is to determine the role of these Vgamma1.1 (Vg1.1) gd-T cells in the development of inappropriate immune responses to food borne allergens in our mouse models. Our approach will be to utilize the models developed in aim 1, as well as mice lacking gd-T cells, or the Cgamma1-/- (Cg1-/-) mice carrying elevated Vg1.1+ T cell populations to address the objective. Based on the published data and our preliminary experiments, we expect to find that Vg1.1+ T cells promote the development of allergic response to food borne allergens.