Allergic asthma is a chronic, often debilitating disease which currently affects 10-15 million people in the U.S. alone. Alarming increasing in the incidence, morbidity and mortality of this disease have been noted over the last decade. It has recently become appreciated that allergic asthma is an inflammatory disease associated with aberrant immune responses to inhaled allergens. Specifically, a subset of CD4+ T lymphocytes termed Th2 cells has been shown to play a critical role in the pathogenesis of allergic asthma. The molecular mechanisms underlying the pathogenic effects of T cell derived cytokines is currently unknown. Previous studies have suggested that IL-4 and IL-5 were the essential factors for induction of the allergic phenotype, however recent studies have shown that neither pf these cytokines is sufficient to induce disease. Our preliminary studies in a murine model of allergen-induced airway hyperresponsiveness provide compelling evidence that, IL-13, a Th2 cytokine, which shares many but not all functions with IL-4 through a shared receptor chain, is both necessary and sufficient to induce the allergic phenotype. Thus, we plan to critically examine the hypothesis that the pathophysiological features of the allergic response are due to the production of IL-13 in susceptible individuals. Two general aims are outlined in this proposal: 1) to elucidate the unique role of IL-13 in the induction of airway inflammation and airway hyperreactivity; and 2) to determine the cellular and molecular mechanism(s) of IL-13 induced airway hyperresponsiveness. First: to establish the unique effector role of IL-13 in the development of airway inflammation and airway hyperresponsiveness, we will determine: ) if IL-13 plays a role in T cell differentiation in response to inhaled antigen exposure; b) if the kinetics of IL-4 and IL-13 production differ during the immune response to inhaled antigens: and 3) if receptor complex expression (IL-4Ralpha1, IL-13Ralpha2 and combinations thereof, in the lung favor IL-13 binding. Secondly, a series of experiments will be aimed at determining the mechanisms by which IL-13 induces the immunopathology of allergic asthma in a murine model. Specifically, we will: a) determine whether IL-13 induced AHR is mediated via direct or indirect effects on cholinergic regulation of airway smooth muscle tone; b) determine the involvement of 15-lipoxygenase products in IL-13 induced AHR; c) determine the role of IL-13-stimulated IgE production in the development of airway hyperresponsiveness;; D) Determine the role of mast cells in airway responses to IL-13 administration: e) determine whether IL-13-induces AHR through its ability to recruit and activate eosinophils in the lung: and f) determine whether IgE-, mast cell and eosinophil dependent processes work in concert to induce AHR. The results of these studies will provide valuable insight into the immunopathogenic mechanisms involved in the development of allergen-induced AHR and may lead to the development of novel immunotherapeutic interventions for the treatment of this increasingly important disease.
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