IL-13 Associated Eosinophil Lung Responses

描述（由申请人提供）：临床和实验研究已经证明了Th 2细胞、嗜酸性粒细胞和过敏性肺病严重程度之间的强相关性，表明这两种细胞在哮喘中的不可或缺的作用。Th 2细胞通过分泌激活炎症和效应途径的细胞因子（IL-4和IL-13）诱导哮喘。IL-13阻断消除实验性哮喘的关键方面的能力导致了这样的观点，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中发挥着重要作用。特别是，CCR 3及其配体已成为哮喘反应期间嗜酸性粒细胞的中枢调节因子。我们已经确定IL-13诱导CCR 3活化配体（例如嗜酸性粒细胞趋化因子），并且与IL-5结合，这些趋化因子诱导肺嗜酸性粒细胞增多，这又放大IL-13产生和IL-13相关的肺病理学，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受体的关键作用？1例（IL-13 R？1），2型IL-4 R，在促进哮喘的主要特征（AHR和粘液产生）。然而，在OVA和IL-4诱导的实验性哮喘模型中，气道嗜酸性粒细胞增多症在IL-13 R？1，表明至少在这些实验条件下，嗜酸性粒细胞增多症更依赖于IL-4而不是IL-13。这表明1型IL-4 R参与了嗜酸性粒细胞增多的诱导，因为IL-4与IL-13不同，通过1型和2型IL-4 R发出信号。这些初步观察结果需要进一步阐明，因为它们意味着哮喘患者中的IL-13阻断可能导致持续的肺嗜酸性粒细胞增多。在这方面，我们正集中于确定参与IL-13相关的肺嗜酸性粒细胞增多症的发展的替代途径和调节机制。值得注意的是，我们最近已经证明，细胞因子Relm-？是由IL-4和IL-13通过IL-13 R诱导的？1-独立途径的OVA模型和Relm-？？显示嗜酸性粒细胞趋化活性。此外，我们已经开始表征IL-13诱导的microRNA（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。本申请的中心假设是，过敏原诱导的肺嗜酸性粒细胞反应的差异调节1型和2型IL-4 R和Relm-？和miR-21。在目标1中，我们将研究嗜酸性粒细胞募集到肺的替代途径。这一目标的中心假设是，嗜酸性粒细胞募集到肺是由涉及1型和2型IL-4 R途径的不同机制介导的。在目标2中，我们将研究Relm-？在肺嗜酸性粒细胞增多症和其他IL-13驱动的反应中。我们将测试的假设，Relm-？有助于变应原、IL-4和IL-13对变应性肺病的作用，并且至少部分地通过调节嗜酸性粒细胞积累来实现这一点。在目标3中，我们将研究IL-13对嗜酸性粒细胞发育和活化的调节。我们将测试的假设，嗜酸性粒细胞的激活和/或发展刺激的组合（1）IL-13直接，（2）Relm-？（3）miR-21。公共卫生相关性：提出的目标应该揭示趋化因子，嗜酸性粒细胞和IL-13合作诱导实验性哮喘的机制。通过研究IL-13和趋化因子如何与嗜酸性粒细胞相互作用，并关注基因表达的miRNA调控和最近鉴定的Th 2相关分子（Relm-？），我们希望扩大我们对哮喘相关肺部病理学的理解。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治疗剂（例如抗细胞因子剂）的潜在效用提供基本基础;因此，有助于澄清中断IL-4、IL-13和/或其受体在哮喘中的独特和比较性作用。

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.