T cell effector and regulatory mechanisms in asthma and food allergy

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DESCRIPTION (provided by applicant): The Massachusetts General Hospital/Harvard Medical School AADCRC entitled "T cell effector and regulatory mechanisms in asthma and food allergy" seeks to gain a better understanding of the role of allergen-specific effector and regulatory T cells in determining the physiological response to an allergen at mucosal surfaces. It is becoming increasingly clear that the net outcome of an inflammatory response is the balance of allergen-specific effector T cell activity and opposing regulatory T cell activity. Antigen-specific effector and regulatory T cell numbers and activity are in large measure determined by the outcome of allergen-loaded dendritic cell (DC) interactions with antigen-specific T cells. The MGH/Harvard AADCRC will explore the balance of effector and regulatory activity in asthma and food allergy and the ability of tolerogenic DCs to affect this balance. The Center will focus on two allergic conditions relevant to the mission of the NIAID, namely allergic asthma and food allergy, and utilize two clinical models [endobronchial segmental allergen challenge (SAC) and oral immunotherapy (OIT)] as a foundation for its studies. Project 1 focuses on the role of antigen-specific effector and regulatory T cells in determining airways inflammation and airways hyper-reactivity by correlating the numbers, phenotype and function of these cells in allergic asthmatics (AA) and allergic nonasthmatics (ANA) using innovative imaging techniques; Project 2 focuses on correlating the numbers, phenotype and function of these same T cell subsets with clinical outcomes of milk allergic patients undergoing milk OIT; and Project 3 focuses on the ability of tolerogenic DC therapy to manipulate the balance between these two opposing T cell populations in favor of regulatory T cells and tolerance in both asthma and food allergy. The three interrelated projects will be supported by Cores that will recruit, enroll and characterize allergic subjects for SAC and OIT, provide MHC class II tetramers to specifically identify and study allergen-specific T cells, and perform sophisticated transcriptome phenotypic analysis on T cell and DC subsets. The goal of this Center is to understand the balance of effector and regulatory allergen-specific T cell activity that determines clinical disease in asthma and food allergy and to establish the utility of using tolerogenic DCs to manipulate this balance to induce allergen-specific tolerance. This would pave the way for new therapeutic approaches to treat these and other allergic diseases.