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）：这种竞争性更新将基于我们先前关于趋化因子及其受体在气道炎症中的作用的工作。对RSV感染有严重反应的儿童通常会发展为出现长期肺部问题。除了小儿种群外，最近的证据表明，成人人群（包括患有哮喘和COPD的人）与肺部疾病存在未知且相对尚未探索的关系。这种更新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对蟑螂过敏原诱导疾病加剧的影响。我们对该提案的假设是，RSV感染通过激活CD8+ T细胞反应取决于CCR1介导的机制引起气道疾病，而疾病的分辨率依赖于CXCR3介导的机制的激活。我们设计了实验，使用3个特定目标来检验我们的假设并确定疾病进展的机制。这些具体目的包括：I。确定CCR1+ T淋巴细胞在RSV诱导的疾病和加剧过敏性气道疾病中具有什么作用； ii。在免疫反应中建立CXCR3+及其配体的机理，导致RSV诱导的疾病和III的分辨率。为了鉴定趋化因子在DC子集中的差异作用，PDC与CDC，运输到肺部以及激活导致肺反应改变。我们的研究将检查主要的RSV诱导的反应以及RSV诱导的过敏性气道疾病的加重。确定推动对RSV的早期反应并减轻严重疾病的机制，将为针对早期表现而产生长期有害儿童的早期表现，并可能有助于将进展衰减到严重的肺部疾病中。现在，我们的模型已经得到很好的特征，并允许我们的研究解决所涉及的细胞群体以及驱动有害反应的相关机制。我们将扩展假设，包括CCR1+ CD8 T细胞是Th2细胞因子，尤其是IL-13的重要来源，尤其是IL-13，导致过敏性气道疾病加剧。 CCR1+ CD8 T细胞募集的机制将集中在RSV感染宿主的气道中引起的CCR1配体，尤其是CCL5的表达。现在，我们还提供了新的数据，这些数据已经确定CXCR3介导的机制通过募集和激活重要的先天细胞（尤其是浆细胞样树突状细胞）引起关键的抗病毒反应。使用缺乏靶向分子的特定动物的细胞转移实验将增强我们在复杂的免疫反应期间定义体内特定细胞机制的能力。这些机制可能与涉及婴儿的机制相似，在这些机制中，RSV感染的儿童通常会发展为长期肺部问题和哮喘患者的哮喘患者。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。鉴定趋化因子介质以及在过敏和病毒疾病期间的相关受体对于识别治疗慢性气道疾病的治疗靶标可能很重要。