Eosinophil, Chemokine and IL-13 Cooperativity in Asthma

临床和实验研究表明，CD4+ T辅助2淋巴细胞（Th2细胞）、嗜酸性粒细胞和疾病严重程度之间存在很强的相关性，表明这些细胞在哮喘的病理生理中起着不可或缺的作用。Th2细胞被认为通过分泌一系列细胞因子来诱导哮喘，这些细胞因子直接或间接地激活炎症和驻留效应通路。Th2细胞因子IL-13在促进AHR和粘液高分泌方面的作用，以及IL-13阻断消除实验性哮喘几个关键方面的能力，使人们认为这是疾病发病机制中的关键细胞因子。广泛的研究也证明了趋化因子在协调哮喘反应的多个方面的核心作用。特别是，CC趋化因子受体3 （CCR3）及其配体已成为哮喘反应中嗜酸性粒细胞的中枢调节因子。在我们最近的研究中，我们已经证明在实验性哮喘的诱导过程中，嗜酸性粒细胞、趋化因子和IL-13之间存在密切的联系。特别是，CCR3激活配体（如eotaxins）与IL-5结合，诱导肺嗜酸性粒细胞增多，进而增加IL-13的产生。同时，实验性哮喘产生嗜酸性粒细胞抑制趋化因子（γ -干扰素诱导的单因子[Mig]），抑制IL-13相关的肺反应。本应用的中心假设是IL-13和趋化因子在嗜酸性粒细胞相关肺部炎症的发病机制中起关键作用。特别是，Th2细胞衍生的IL-13促进eotaxin的产生，这随后为嗜酸性粒细胞增加IL-13的产生（来自嗜酸性粒细胞本身和Th2细胞）和IL-13相关的肺部病理提供了一个关键信号。此外，过敏原诱导的Mig矛盾地减少了过敏原和IL-13相关的过敏性气道炎症。我们提出了一系列的目标，旨在验证我们的中心假设，并揭示趋化因子、嗜酸性粒细胞和IL-13相互作用在实验性哮喘发病机制中的分子机制和后果。在Aim I中，我们将研究CCR3和eotaxins在IL-13诱导的实验性哮喘中的作用。在Aim II中，我们将研究嗜酸性粒细胞在放大IL-13相关哮喘反应中的作用。在Aim III中，我们将检测Mig抑制il -13相关的实验性哮喘的能力。总的来说，提出的目标旨在揭示趋化因子，嗜酸性粒细胞和IL-13在实验性哮喘诱导中的参与和机制。

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.