Airway inflammation is currently regarded as the major pathogenetic mechanism leading to airway hyperresponsiveness. Although many different cell types and their products contribute to the inflammatory reaction in the airways of sensitized patients or animals, the T lymphocyte appears to play a pivotal role. T lymphocytes regulate IgE production and secrete a number of proinflammatory cytokines, one of which, IL-5, controls eosinophil production, activation and survival. The objectives of this proposal are to delineate the roles of humoral and cell-mediated immunity in the development of airway hyperresponsiveness. Using a murine model of allergen-sensitization via the airways, we have identified the convergence of three essential components in the development of altered airway responsiveness, antigen challenge via the airways, the production of (concordant) antigen-specific IgE, and the antigen-dependent activation of T cells (both CD4+ and CD8+) resulting in IL-5 production and eosinophil accumulation in the lung. Using immunologic and genetic manipulations, we will now define the role antigen-specific IgE plays in the amplification of T-cell recruitment, expansion and differentiation, perhaps through binding to CD23 on B cells. We will characterize the role individual T-cell subsets play in the development of the altered airway response using adoptive transfer of T cells in nude mice, analyzing cytokine profiles of these cells and homing responses following airway challenge. Utilizing IL-5 and IL-4 deficient mice, we will identify the role of these cytokines in the development of eosinophilic inflammation. Based on prior studies of the efficacy of nebulized interferon-gamma to modulate these antigen-specific responses, we will define how this important regulatory cytokine alters B and T-cell function to normalize airway responsiveness following primary or secondary allergen challenge. These studies will identify the important immunologic contributions to the acquisition altered airway responsiveness, paving the way to a better understanding of the pathogenesis of asthma and the development of novel therapeutic options.
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