IL-13 Associated Eosinophil Lung Responses

描述(由申请人提供)：临床和实验研究表明，Th2细胞、嗜酸性粒细胞与过敏性肺部疾病严重程度之间有很强的相关性，这表明这两种细胞在哮喘中起着不可或缺的作用。Th2细胞通过分泌细胞因子(IL-4和IL-13)来激活炎症和效应通路，从而诱发哮喘。IL-13的阻断能够消除实验性哮喘的关键方面，这导致了一种观点，即这是疾病发病机制中的关键细胞因子。广泛的研究还表明，趋化因子在协调哮喘反应的多个方面发挥着核心作用。特别是，CCR3及其配体在哮喘反应中已成为嗜酸性粒细胞的中央调节因子。我们已经证实，IL-13诱导CCR3激活的配体(例如嗜酸性粒细胞趋化因子)，这些趋化因子与IL-5一起诱导肺嗜酸性粒细胞增多，进而放大IL-13的产生和IL-13相关的肺病理，包括嗜酸性粒细胞介导的肺重塑(例如杯状细胞化生)。我们还证明了IL-13受体？1(IL-13R？1)，即2型IL-4R，在促进哮喘的基本特征(AHR和粘液产生)方面发挥了关键作用。然而，在OVA和IL-4诱导的实验性哮喘模型中，在没有IL-13R的情况下，气道嗜酸性粒细胞增多，这表明至少在这些实验条件下，嗜酸性粒细胞更依赖于IL-4而不是IL-13。这意味着1型IL-4R参与了嗜酸性粒细胞增多症的诱导，因为与IL-13不同，IL-4通过1型IL-4R和2型IL-4R发出信号。这些初步观察结果需要进一步阐明，因为它们暗示在哮喘患者中阻断IL-13可能导致持续的肺嗜酸性粒细胞增多。在这方面，我们正专注于确定与IL-13相关的肺嗜酸性粒细胞增多症的发展所涉及的替代途径和调节机制。值得注意的是，我们最近证明了细胞因子Relm-？在OVA模型中，IL-4和IL-13通过IL-13R？1非依赖的途径被诱导，并且Relm-？？显示嗜酸性粒细胞趋化活性。此外，我们已经开始鉴定IL-13诱导的microRNAs(MiR)，它可能调节包括嗜酸性粒细胞增多症在内的过敏性肺反应。这一应用的中心假设是，变应原诱导的肺嗜酸性粒细胞反应受1型和2型IL-4R和Relm-？和MIR-21。在目标1中，我们将研究嗜酸性粒细胞重新聚集到肺中的替代途径。这一目标的中心假设是，嗜酸性粒细胞向肺内的募集是由涉及1型和2型IL-4R途径的不同机制介导的。在目标2中，我们将研究REM-？在肺嗜酸性粒细胞增多症和其他IL-13驱动的反应中。我们将检验这样的假设：Relm-？有助于过敏原、IL-4和IL-13对过敏性肺部疾病的影响，并至少部分地通过调节嗜酸性粒细胞的聚集来实现这一点。在目标3中，我们将研究IL-13对嗜酸性粒细胞发育和激活的调节。我们将检验这一假设，即嗜酸性粒细胞的激活和/或发育是由(1)IL-13直接刺激，(2)由Relm-？(3)miR-21。公共卫生相关性：拟议的目标应该揭示趋化因子、嗜酸性粒细胞和IL-13在实验性哮喘的诱导中协同作用的机制。通过研究IL-13和趋化因子如何与嗜酸性粒细胞相互作用，重点研究miRNA对基因表达的调节和最近发现的Th2相关分子(Relm-？)，我们希望拓宽我们对哮喘相关肺病理的理解。这些结果将为理解目前正在开发的用于治疗哮喘的基于免疫的疗法(例如，抗细胞因子药物)的潜在效用提供基本基础，从而有助于阐明阻断IL-4、IL-13和/或它们的受体在哮喘中的独特和比较效果。

DESCRIPTION (provided by applicant): Clinical and experimental investigations have demonstrated a strong correlation between Th2 cells, eosinophils and allergic lung disease severity suggesting an integral role for both of these cells in asthma. Th2 cells induce asthma through the secretion of cytokines (IL-4 and IL-13) that activate inflammatory and effector pathways. The ability of IL-13 blockade to abrogate 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, CCR3 and its ligands have emerged as central regulators of eosinophils during asthmatic responses. We have established that IL-13 induces CCR3 activating ligands (e.g. the eotaxins), and in conjunction with IL-5, these chemokines induce lung eosinophilia, which in turn amplifies IL-13 production and IL-13-associated lung pathology including eosinophil-mediated lung remodeling (e.g. goblet cell metaplasia). We have also demonstrated a critical role for IL-13 receptor ?1 (IL-13R??1), the type 2 IL-4R, in promoting the cardinal features of asthma (AHR and mucus production). In OVA and IL-4-induced models of experimental asthma, airway eosinophilia, however, developed in the absence of IL-13R??1 suggesting that eosinophilia depends more on IL-4 than IL-13 at least under these experimental conditions. This implicates the type 1 IL-4R in the induction of eosinophilia because IL-4, unlike IL-13, signals through the type 1 as well as the type 2 IL-4R. These preliminary observations need to be further elucidated as they imply that IL-13 blockade in asthma patients could result in sustained lung eosinophilia. In this regard, we are focusing on identifying alternative pathways and regulatory mechanisms involved in the development of IL-13-associated lung eosinophilia. Notably, we have recently demonstrated that the cytokine Relm-? is induced by IL-4 and IL-13 by an IL-13R?1-independent pathway in the OVA model and that Relm-?? displays eosinophil chemoattractant activity. Furthermore, we have begun to characterize IL-13-induced microRNAs (miR) that may regulate allergic lung responses including eosinophilia. The central hypothesis of this application is that allergen-induced lung eosinophil responses are differentially regulated by the type 1 and type 2 IL-4R and by Relm-? and miR-21. In Aim 1, we will examine alternative pathways for eosinophil recruitment to the lung. The central hypothesis of this aim is that eosinophil recruitment to the lung is mediated by distinct mechanisms involving type 1 and type 2 IL-4R pathways. In Aim 2, we will examine the involvement of Relm-? in lung eosinophilia and other IL-13-driven responses. We will test the hypothesis that the Relm-? contributes to the effects of allergen, IL-4 and IL-13 on allergic lung disease and does this, at least in part, by regulating eosinophil accumulation. In Aim 3, we will examine the regulation of eosinophil development and activation by IL-13. We will test the hypothesis that eosinophil activation and/or development are stimulated by a combination of (1) IL-13 directly, (2) by Relm-? and (3) by miR-21. PUBLIC HEALTH RELEVANCE: The proposed aims should uncover mechanisms by which chemokines, eosinophils, and IL-13 cooperate in the induction of experimental asthma. By examining how IL-13 and chemokines interact with eosinophils and focusing on miRNA regulation of gene expression and a recently identified Th2-associated molecule (Relm-?), we hope to broaden our understanding of asthma-associated lung pathology. These results will provide a fundamental basis for understanding the potential utility of the immune-based therapeutics (e.g. anti-cytokines agents) that are currently being developed for the treatment of asthma; thus, helping to clarify the unique and comparative effects of interrupting IL-4, IL-13 and/or their receptors in asthma.