Food allergies affect 3-6% of the population and are difficult to diagnose and treat. Allergenic responses to food antigens are normally held in check by mucosal tolerance. A key player for maintaining this food tolerance is the regulatory T cells which in turn can be induced by a dendritic cell subset which expresses the adhesion molecule CD103. This dendritic cell type provides the link between food allergens and regulatory T cells and tolerance because they are located at the epithelial layer of the gastrointestinal tract and are equipped with tight junction proteins for their ready access to the intestinal lumen. However, CD103+ DC can also activate T helper 2 cells which participate in allergic responses and provide help for IgE synthesis and eosinophil development. Because this CD103+ dendritic cell type occupy such an important position in the decision of whether an immunological response to a food allergen is toleragenic or allergenic, more thorough understanding of the functions of this dendritic cell type in allergen responses in the intestines is warranted. Large amounts of preliminary data showing the phenotypic and functional differences between this and other dendritic cell subsets have been gathered and reagents and mutant mouse have been generated for the studies of CD103+ dendritic cells in food allergy. The long term goal of this project is to elucidate the function of CD103+ dendritic cells in mediating antigenic responses in the intestines and to develop therapeutic agents for food allergy treatment. An animal model for inducing intestinal allergic reactions to ovalbumin with eosinophilia, serum IgE levels, T helper 2 responses, intestinal inflammation, and diarrhea as indicators of allergy induction has been developed. A regulatory T cell deficient model as well as a mouse that provides large numbers of antigen-specific regulatory T cells have also been established. These mice will be used for studying the functions of integrin CD103 and CD103+ DC in food allergy and the efficacy of antigen-specific regulatory T cells in suppressing food allergies.
The specific aims are: (1) to study the role of CD103 and CD103+ dendritic cells in mediating allergenic responses to ovalbumin using CD103 deficient mice and anti-CD103 antibodies. The role of CD103+ DC in allergic reactions will be confirmed by immunizing CD103 deficient recipients that are adoptive transferred with CD103+ wild-type dendritic cells; (2) to study the suppression of the responses of regulatory T cell deficient ovalbumin-specific T cell receptor transgenic mice by graded doses of ovalbumin-specific regulatory T cells. The ability of the antigen-specific regulatory T cell to cross-inhibit the responses of an unrelated antigen and the regulatory T cell stimulation by the synthesis of the chemokine CCL22/MDC by CD103+ dendritic cells will be studied. The studies will establish the importance of CD103+ dendritic cells in food allergy and may help in the development of anti-CD103, regulatory T cells, or CCL22/MDC as immunotherapeutic agents. ? ? ? ?
