The Role of C-C Chemokines in Eosinophil Airway Inflammation

描述（由申请人提供）：这一竞争性更新将建立在我们以前对趋化因子及其受体在气道炎症中的作用的研究基础上。对RSV感染有严重反应的儿童往往会发展成长期的肺部问题。除儿科人群外，最近的证据表明，成人人群（包括哮喘和COPD患者）与肺部疾病之间存在未知且相对未探索的关系。此次更新申请将重点关注特异性趋化因子受体及其配体在RSV感染中的作用，以及RSV对蟑螂过敏原诱导疾病恶化的影响。我们对此建议的假设是，RSV感染通过依赖于CCR1介导机制的CD8 + T细胞应答的激活引起气道疾病，而疾病的消退依赖于CxCR3介导机制的激活。我们设计了3个特定目的的实验来验证我们的假设，并确定疾病进展的机制。这些具体目标包括：确定CCR1 + T淋巴细胞在RSV诱导的疾病和过敏性气道疾病加重中的作用; II.建立CxCR3+及其配体在导致RSV诱导的疾病消退的免疫应答中的机制，以及III.确定趋化因子对DC亚群pDC与cDC的不同作用，运输至肺和激活导致肺反应改变。我们的研究将检查原发性RSV诱导的反应以及RSV诱导的过敏性气道疾病恶化。确定驱动对RSV的早期反应并介导或减轻严重疾病的机制将提供一个很好的机会来靶向对儿童具有长期有害影响的早期表现，并可能有助于减缓进展为严重肺部疾病。我们的模型现在已经得到了很好的表征，使我们的研究能够解决所涉及的细胞群和驱动有害反应的相关机制。我们将扩展我们的假设，包括CCR1 + CD8 T细胞是Th2细胞因子的重要来源，特别是IL-13，导致过敏性气道疾病加重。CCR1 + CD8 T细胞的募集机制将集中在RSV感染宿主的气道内诱导CCR1配体，特别是CCL5的表达上。我们现在还提供了新的数据，已经确定CxCR3介导的机制通过募集和激活重要的先天性细胞，特别是浆细胞样树突状细胞，诱导关键的抗病毒反应。利用缺乏靶分子的特定动物进行细胞转移实验，将增强我们在复杂免疫应答期间体内确定特定细胞机制的能力。这些机制可能与婴儿中涉及的机制相似，其中RSV感染的儿童通常进展为具有长期的肺部问题，并且在哮喘患者中进展为加重的疾病。项目叙述：在肺部炎症过程中趋化因子的协调产生导致各种白细胞募集到肺组织和气道中。在过敏性和病毒性疾病中识别趋化因子介质以及相关受体对于识别治疗慢性气道疾病的治疗靶点可能是重要的。

DESCRIPTION (provided by applicant): This competitive renewal will build upon our previous work on the role of chemokines and their receptors in airway inflammation. Children that had experienced severe responses to RSV infections often progress into developing long-term pulmonary problems. In addition to pediatric populations, recent evidence has indicated that there is an unknown and relatively unexplored relationship to pulmonary disease in adult populations, including those with asthma and COPD. This renewal application will focus on the role of specific chemokine receptors and their ligands in RSV infection as well as the effects of RSV on exacerbation of cockroach allergen induced disease. Our hypothesis for this proposal is that RSV infection causes airways disease via the activation of CD8+ T cell responses dependent upon CCR1-mediated mechanisms, whereas resolution of disease relies upon the activation of CxCR3-mediated mechanisms. We have designed experiments using 3 specific aims to test our hypothesis and to identify the mechanisms of disease progression. These specific aims include: I. To determine what role CCR1+ T lymphocytes have on RSV-induced disease and in exacerbation of allergic airway disease; II. To establish the mechanism of CxCR3+ and its ligands in the immune response leading to the resolution of RSV-induced disease, and III. To identify the differential role of chemokines for DC subset, pDC vs. cDC, trafficking to the lungs and activation leading to altered pulmonary responses. Our studies will examine both a primary RSV-induced response as well as RSV-induced exacerbation of allergic airway disease. Determining the mechanisms that drive the early responses to RSV and mediate or alleviate severe disease will offer an excellent opportunity to target the early manifestations that have long-term detrimental effects in children, and possibly aid in attenuating progression into severe pulmonary disease. Our models have now been well characterized and allow our studies to address the cell populations involved and the relevant mechanisms that drive the detrimental responses. We will extend our hypothesis to include that CCR1+ CD8 T cells are a significant source of Th2 cytokines, especially IL-13, that lead to exacerbated allergic airway disease. The mechanism of the recruitment of CCR1+ CD8 T cells will center on the induced expression of CCR1 ligands, especially CCL5, within the airways of RSV-infected hosts. We have now also provided novel data that has identified that CxCR3-mediated mechanisms induce a critical anti-viral response via recruitment and activation of important innate cells especially plasmacytoid dendritic cells. The use of cellular transfer experiments with specific animals deficient in targeted molecules will enhance our ability to define the particular cellular mechanisms in vivo during a complex immune response. These mechanisms may be similar to those that are involved in infants, where RSV-infected children often progress into having long-term pulmonary problems and in asthmatics for exacerbated disease. Project Narrative: The coordinated production of chemokines during pulmonary inflammation leads to the recruitment of various leukocytes into the lung interstitium and airway. Identifying chemokine mediators as well as the relevant receptor during allergic and viral disease may be important for identifying therapeutics targets for treating chronic airway disease.