The Role of C-C Chemokines in Eosinophil Airway Inflammation

描述(由申请人提供)：这次竞争性更新将建立在我们之前关于趋化因子及其受体在呼吸道炎症中的作用的工作的基础上。对RSV感染有严重反应的儿童通常会发展成长期的肺部问题。除了儿科人群，最近的证据表明，成人人群中存在未知和相对未被探索的与肺部疾病的关系，包括那些患有哮喘和COPD的人。这一新的应用将集中在特定的趋化因子受体及其配体在RSV感染中的作用以及RSV在蟑螂变应原诱导的疾病恶化中的作用。我们的假设是，RSV感染通过激活CD8+T细胞反应引起呼吸道疾病，这依赖于CCR1介导的机制，而疾病的解决依赖于CXCR3介导的机制的激活。我们设计了3个特定目标的实验，以验证我们的假设并确定疾病进展的机制。这些特异性目标包括：1.确定CCR1+T淋巴细胞在呼吸道合胞病毒(RSV)诱导的疾病和过敏性呼吸道疾病加重中的作用；2.建立CXCR3+及其配体在导致RSV诱导的疾病缓解的免疫反应中的机制；3.确定趋化因子在DC亚群、PDC和CDC中的不同作用，向肺转运和激活导致肺反应改变。我们的研究将检验RSV诱导的原发反应以及RSV诱导的过敏性呼吸道疾病的加重。确定驱动RSV早期反应和调节或减轻严重疾病的机制将提供一个极好的机会，以针对对儿童具有长期有害影响的早期表现，并可能有助于减缓向严重肺部疾病的进展。我们的模型现在已经被很好地描述，并使我们的研究能够解决所涉及的细胞群体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，导致过敏性呼吸道疾病加重。CCR1+CD8T细胞募集的机制将集中在诱导呼吸道合胞病毒感染宿主呼吸道内CCR1配体，尤其是CCL5的表达。我们现在还提供了新的数据，证实了CXCR3介导的机制通过招募和激活重要的固有细胞，特别是浆细胞样树突状细胞来诱导关键的抗病毒反应。对缺乏靶向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反应期间确定体内特定细胞机制的能力。这些机制可能类似于婴儿的机制，在婴儿中，RSV感染的儿童通常进展为长期的肺部问题，而哮喘患者的病情加重。项目简介：在肺部炎症期间，趋化因子的协调产生导致各种白细胞重新聚集到肺间质和呼吸道。在过敏性和病毒性疾病中识别趋化因子介体和相关受体对于确定慢性呼吸道疾病的治疗靶点可能很重要。

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.