Allergic asthma is a syndrome characterized by eosinophilic airway inflammation associated with airway hyperresponsiveness (AHR) and increased mucus production. CD4+ Th2 cells play a critical role in controlling the inflammation seen in asthma;however, the molecular mechanisms that control Th2 cell entry into the lung and the factors that determine whether these cells stay in the lung or leave are not completely known. In the last funding period, we have made considerable progress in answering these questions, which has led us to the central hypothesis of this renewal proposal: Th2 cell trafficking into the allergic lung is controlled sequentially by several discrete regulatory pathways. Here we propose that Th2 cell accumulation in the allergic lung is controlled by at least four discrete steps that include an Initiation Phase, a Propagation Phase, an Amplification Phase and a Resolution Phase. Based on our published and preliminary data, we hypothesize that Th2 cell recruitment into the asthmatic lung is initiated by the activation of mast cells and the release of leukotriene B4 and chemokines. This is followed by a Propagation Phase that is mediated by activation of Toll-like receptors (TLRs) on innate immune cells in the lung and the release of TLR- inducible chemokines. Once Th2 cells enter the lung, we propose an Amplification Phase that is mediated by IL-4 and IL-13 released from Th2 cells that induces the production of STAT6-inducible chemokines from resident pulmonary cells. We propose that the resolution of allergic inflammation is then mediated in part by the recruitment of Th2 cells out of the lung via the afferent lymphatics into the draining lymph node, mediated by CCR7 Th2 cell expression. We also propose that this egress pathway will contribute to Th2 immunologic memory. In this proposal, we will use a combination of transgenic and knockout mice in several adoptive transfer models of murine asthma as well as the study of human patients with allergic asthma to test these hypotheses. Specifically we propose: (1) To determine the role of mast cell-derived chemoattractants in the initial recruitment of antigen-specific Th2 cells into the allergic lung;(2) To determine if TLR-inducible chemokines contribute to the propagation of Th2 cell recruitment into the allergic lung;(3) To identify the key hematopoietic-derived cell that mediates STAT6-dependent amplification of Th2 cell recruitment into the allergic lung;(4) To determine the contribution of CCR7-mediated T cell egress from the asthmatic lung in the resolution of pulmonary inflammation and the establishment and maintenance of Th2 cell memory;and (5) To identify the mediators that control Th2 cell trafficking into the human lung early and late following Ag challenge. The identification of the relevant chemoattractant receptors that control Th2 cell entry into and exit from the allergic lung will not only provide key insight into the asthma pathogenesis but will also define excellent targets for therapeutic intervention. Project Narrative: Asthma is an allergic disease of the lung that is increasing in prevalence and severity, especially among children, despite current therapies. Asthma is caused by the inappropriate activation of T cells by normally innocuous aerosolized antigens. Once activated, these T cells accumulate in the lung, where they drive the asthmatic response through the release of potent inflammatory mediators. The goal of this grant is to identify the key proteins that control the accumulation of these pathogenic T cells in the lung, which will define excellent new targets for therapeutic intervention.
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