The Role of C-C Chemokines in Eosinophil Airway Inflammation

C-C 趋化因子在嗜酸性粒细胞气道炎症中的作用

• 批准号: 7846595
• 负责人: Nicholas W Lukacs
• 金额: $ 6.64万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846595
• 关键词: Address; Adult; Age; Allergens; Allergic; Animals; Antiviral Response; Asthma; Attenuated; CCR1 gene; CD8B1 gene; Cells; Child; Childhood; Chronic; Chronic Disease; Chronic Obstructive Airway Disease; Complex; Data; Dendritic Cells; Disease; Disease Progression; Functional disorder; Immune; Immune response; Infant; Infection; Inflammation; Interleukin-13; Laboratories; Lead; Leukocytes; Ligands; Lung; Lung diseases; Mediating; Mediator of activation protein; Modeling; Mus; Pathway interactions; Pediatric Intensive Care Units; Pneumonia; Population; Process; Production; Proteins; Published Comment; RANTES; Recruitment Activity; Resolution; Respiratory physiology; Role; Signal Transduction; Source; Stimulus; Syndrome; System; T-Lymphocyte; Testing; Time; Virus Diseases; Work; airway hyperresponsiveness; airway inflammation; allergic airway disease; attenuation; base; beta-Chemokines; chemokine; chemokine receptor; cockroach allergen; cytokine; design; eosinophil; experience; human disease; in vivo; lymph nodes; migration; novel; receptor; research study; response; therapeutic target; trafficking

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.

描述（由申请人提供）：这种竞争性更新将建立在我们之前关于趋化因子及其受体在气道炎症中的作用的工作的基础上。对 RSV 感染产生严重反应的儿童往往会出现长期肺部问题。除了儿科人群外，最近的证据表明，成人人群（包括哮喘和慢性阻塞性肺病患者）与肺部疾病之间存在未知且相对未经探索的关系。这项更新申请将重点关注特定趋化因子受体及其配体在 RSV 感染中的作用，以及 RSV 对蟑螂过敏原诱发疾病恶化的影响。我们对此提议的假设是，RSV 感染通过依赖于 CCR1 介导的机制激活 CD8+ T 细胞反应而导致气道疾病，而疾病的解决则依赖于 CxCR3 介导的机制的激活。我们使用 3 个具体目标设计了实验来检验我们的假设并确定疾病进展的机制。这些具体目标包括： I. 确定 CCR1+ T 淋巴细胞对 RSV 诱发的疾病和过敏性气道疾病恶化的作用；二.建立 CxCR3+ 及其配体在免疫反应中导致 RSV 诱导疾病消退的机制，以及 III。旨在确定趋化因子对 DC 亚群（pDC 与 cDC）、运输至肺部以及激活导致肺部反应改变的不同作用。我们的研究将检查 RSV 引起的原发反应以及 RSV 引起的过敏性气道疾病恶化。确定驱动 RSV 早期反应并介导或缓解严重疾病的机制，将为针对对儿童产生长期有害影响的早期表现提供绝佳的机会，并可能有助于减轻严重肺部疾病的进展。我们的模型现已得到很好的表征，使我们的研究能够解决所涉及的细胞群以及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，尤其是 IL-13，可导致过敏性气道疾病恶化。 CCR1+ CD8 T 细胞的招募机制将集中于 RSV 感染宿主气道内 CCR1 配体（尤其是 CCL5）的诱导表达。我们现在还提供了新的数据，表明 CxCR3 介导的机制通过招募和激活重要的先天细胞，特别是浆细胞样树突状细胞，诱导关键的抗病毒反应。对缺乏目标分子的特定动物进行细胞转移实验将增强我们在复杂的免疫反应过程中定义体内特定细胞机制的能力。这些机制可能与婴儿中所涉及的机制相似，在婴儿中，RSV 感染的儿童经常会出现长期肺部问题，并且哮喘病会恶化。项目叙述：肺部炎症期间趋化因子的协调产生导致各种白细胞募集到肺间质和气道中。识别过敏和病毒性疾病期间的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很重要。