Eosinophil, Chemokine and IL-13 Cooperativity in Asthma

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DESCRIPTION (provided by applicant): Clinical and experimental investigations have demonstrated a strong correlation between the presence of CD4+ T helper 2 lymphocytes (Th2 cells), eosinophils and disease severity suggesting an integral role for these cells in the pathophysiology of asthma. Th2 cells are thought to induce asthma through the secretion of an array of cytokines that activate inflammatory and residential effector pathways both directly and indirectly. The potency of the Th2 cytokine IL-13 in promoting AHR and mucus hypersecretion, and the ability of IL-13 blockade to abrogate several critical aspects of experimental asthma has led to the view that this is a critical cytokine in disease pathogenesis. Extensive studies have also demonstrated a central role for chemokines in orchestrating multiple aspects of the asthmatic response. In particular, CC chemokine receptor 3 (CCR3), and its ligands have emerged as central regulators of eosinophils during asthmatic responses. In our recent studies we have demonstrated that there is an intimate connection between eosinophils, chemokines, and IL-13 during the induction of experimental asthma. In particular, CCR3 activating ligands (e.g. the eotaxins) in conjunction with IL-5, induce lung eosinophilia, which in turn amplifies IL-13 production. At the same time, an eosinophil-inhibitory chemokine (monokine induced by gamma-interferon [Mig]) is produced in experimental asthma that inhibit IL-13 associated lung responses. The central hypothesis of this application is that IL-13 and chemokines critically cooperate in the pathogenesis of eosinophil-associated lung inflammation. In particular, Th2 cell derived IL-13 promotes eotaxin production, which subsequently provides a critical signal for eosinophils to amplify IL-13 production (from eosinophils themselves and from Th2 cells) and IL-13- associated lung pathology. Furthermore, allergen-induced Mig paradoxically curtails allergen-and IL-13- associated allergic airway inflammation. We propose a series of aims designed to test our central hypothesis and uncover the molecular mechanisms and consequences of chemokine, eosinophil, and IL-13 interactions in the pathogenesis of experimental asthma. In Aim I, we will examine the role of CCR3 and eotaxins in IL-13- induced experimental asthma. In Aim II, we will examine the role of eosinophils in amplifying IL-13- associated asthmatic responses. In Aim III, we will examine ability of Mig to inhibit IL-13-associated experimental asthma. Collectively, the proposed aims are designed to uncover the participation and mechanisms by which chemokines, eosinophils, and IL-13 cooperate in the induction of experimental asthma.