Dendritic cells and IgE in asthma

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DESCRIPTION: Asthma is an airways disease characterized by a unique form of chronic inflammation associated with a profile of cytokines produced by the Th2-subset of helper T lymphocytes. Asthma is most often associated with atopy, allergen sensitization, and the IgE response, which are also regulated by Th2 cytokines. Using the human model of segmental allergen challenge (SAC), specific recruitment of eosinophils, basophils, and helper/memory T lymphocytes has been demonstrated, suggesting highly selective mechanisms of cellular recruitment. Our novel preliminary data indicates that dendritic cells (DCs) rapidly accumulate at sites of SAC in numbers sufficient to allow examination of their function. This proposal will examine the role of dendritic cells in the inflammatory and immunologic response to allergen. We will examine the hypothesis that early in the allergic response, DCs accumulate in the lung by direct recruitment or by differentiation from circulating monocyte precursors. By altering the balance of antigen presenting cell (APC) function, lung DCs play a critical role in localizing immune responses to the inflammatory site. Our approaches are as follows 1) We will examine the kinetics of myeloid and plasmacytoid DC recruitment to the lung, and identify the chemokines involved in lung DC recruitment. 2) Using purified DC subsets and CD4+ T cells, we will perform functional studies of lung DCs to define changes in ARC functions and DC cytokine production associated with recruitment to the lung. 3) We will evaluate the expression of high affinity IgE receptor (Fcc.RI) on lung DCs during inflammation, and explore the role of IgE-mediated mechanisms on DC function. In vitro studies will examine the effect on DC function of modulating IgE with a non-activating, anti-lgE (omalizumab) and other stimuli. Better understanding of DC recruitment, function, and the role of IgE may provide insight into strategies aimed at restoring balance to the dysregulated immune response in the airways associated with allergic asthma.