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Roles of Unique Subsets of the Intestinal Intra Epithelial Lymphocytes (IEL) in the Development of Food-Borne Allergy

August, Avery; Huang, Fei
Cornell University
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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.

More information
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.

Specific Aim #1: We will first establish a mouse food allergy model by using OVA/gluten for induction of food allergy in young mice. Once it is established, we will determine the function of gut CD8aa ab-T cells in this food allergy model. The response of food allergy will be determined by measuring the increase in IgE production, increase in serum histamine concentration, body temperature loss, diarrhea, induction of Th2 cytokines, and the profiles of immune cells, such as Th2 cells, eosinophils and basophils that are associated with allergic responses, and the histological scores of intestinal inflammation. The number of mice used for the experiments will be determined by power analysis based on preliminary data to ensure sufficient mice are used to obtain statistically confident data, and significance determined by ANOVA and student T test. At the completion of the first aim, we expect to have developed 2 novel models of murine food borne allergy based on OVA/gluten exposure. This will provide a significant advancement for the study of food allergy in murine models. Through the novel food allergy models, as well as the model of Rag KO mice receiving naive T and B cells described in aim#1, we will be able to determine whether CD8aa ab-T cells in IEL play a role in protecting against the inappropriate development of allergic response to food borne allergen. These findings will add support to our hypothesis that specific T cell subsets within the IEL population regulate the development of food allergy.

Specific Aim #2: We will use gd-T cell KO and Cg1 KO mice as well as adoptive transfer techniques of gd-T cells and Vg1.1 bearing gd-T cells to determine the function of these specific cells in food allergy models developed in aim 1. At the completion of this aim, we expect to have determined the role of gd-T cells, and more specifically, Vg1.1 bearing gd-T cells, in the development of murine food borne allergy. The allergy responses will be measured and evaluated by the methods similarly to those in aim 1. These findings will add support to our hypothesis that specific T cell subsets within the IEL population regulate the development of food allergy. The work proposed in this application will allow us to develop experiments aimed at determining if humans have similar mechanisms of protection and promotion of development of allergic responses to food borne allergens. Upon completion of the experiments in this proposal, we expect to add a significant amount of information to the body of knowledge regarding not only the mechanism by which food allergies develop, but also the regulation of this response by specific T cell populations in the IEL. This work will have implications for the development of approaches to prevent food allergies from occurring in young children, but also to utilize specific cellular populations to manipulate the response. Therefore, we can use this information to eventually develop strategies to interfere with the process, providing novel options of therapies for food allergy.

Funding Source
Nat'l. Inst. of Food and Agriculture
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Sanitation and Quality Standards
Bacterial Pathogens