Asthma is a complex syndrome broadly defined by inflammation of the airways. Affecting more than 10 million Americans, and with prevalence estimated at 5% of the population, asthma is one of the most common chronic diseases worldwide. Despite our increased understanding of the pathogenesis of asthma from murine models, the incidence of this disease and the frequency of its significant complications are increasing. Furthermore, rationale therapies developed based on animal model data have not proved effective. For example, anti-IL-5 therapy, which looked so promising in murine and primate models, was not effective at reducing or ameliorating human asthma, despite reducing pulmonary eosinophilia. This failure underscores the need to understand the pathogenic factors involved in human asthma, which can only be accomplished by studying humans with asthma.
Human asthma is driven by a distinct subset of T cells that are recruited into the lung following antigen challenge. But where these cells have been identified as Th2 cells in animal models, their phenotypic characteristics in humans have yet to be clearly identified. We hypothesize that there is a pathogenic population of T cells uniquely present in the lung of asthmatic patients following inhaled antigen challenge that can be defined based on their expression of cytokines, chemokines, and chemokine receptors. We further hypothesize that the factors recruiting these T cells into the lung will be found in the airways following antigen challenge and their identification will lead to novel therapies for asthma.
Aim 1: To identify chemokine receptors preferentially expressed on T cells recruited into the bronchoalveolar lavage (BAL) following aerosol antigen challenge of atopic asthmatic patients vs. T cells in their peripheral blood, and to compare the expression of these receptors on BAL T cells from atopic asthmatics vs. atopic persons without asthma.
Aim 2: To define the phenotype of T cells recruited into the BAL following antigen challenge of atopic asthmatics vs. atopic nonasthmatics, using flow cytometry, quantitative PCR and microarray analysis on sorted cells.
Aim 3: To determine the proteome profile of the factors released into the BAL following antigen challenge to identify chemoattractants responsible for recruiting T cells into the human allergic lung.