The central hypothesis for this SCOR proposal is that the initial event in allergic asthma is an inappropriately regulated (dysregulated) pulmonary immune response to an inhaled antigen, which is dependent on a combination of genetics, the developmental stage of the immune response, environmental effects, and the local cytokine milieu at the time of initial allergen challenge. This dysregulated immune response results in the local accumulation of allergen-specific IL-4 and IL-5 secreting T cells (a Th2 response). IL-4 and IL-5 enhance the development of specific IgE antibodies and eosinophilia, respectfully, followed by bronchial inflammation with increased local eosinophils, mast cells, and basophils; bronchial hyperresponsiveness; and the clinical expression of asthma. This proposal consists of five projects, which will examine different aspects of immune regulation and inflammation in asthma. Each project is a direct extension of ongoing research by principal investigators who are seasoned senior scientists. Project 1(Lipscomb) will examine what regulates T cell subset development and traffic to lungs in an OVA T cell receptor transgenic mouse model, the relative importance of IgE and eosoinphils on bronchial inflammation in a nontransgenic mouse model, and the effects of steroids and cromolyn on modifying pulmonary immunity and inflammation in both models. Project 2 (Oliver) will dissect intracellular signaling pathways in human mast cells and basophils and examine the hypothesis that intrapulmonary allergen exposure in asthmatics alters peripheral blood basophil signaling and adhesive properties. Project 3 (Schuyler), the clinical project, will determine whether the local lung environment in asthmatics influences the response to new aeroantigens. This project also proposes to determine whether suppressing local inflammation may alter an immune response to either locally instilled or systemically administered neoantigens. An Immunology Core laboratory (Lewis) will centralize most of the large numbers of immunologic assays required for the proposed studies. Collectively, these studies should provide important information about the cellular and molecular mechanisms of asthma and suggest possible new interventions in treating the disease.
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