Chemokines and Th2 Cell Trafficking in Asthma

哮喘中的趋化因子和 Th2 细胞贩运

基本信息

批准号：
9176006
负责人：
ANDREW D LUSTER
金额：
$ 40.35万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-01-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9176006
关键词：
Allergens Allergic Allergic Disease Asthma Award Book Chapters CC chemokine receptor 4 CCL17 gene CCL22 gene CCR8 gene CXCR3 gene Cells Chemotactic Factors Child Critical Pathways Dendritic Cells Extrinsic asthma Funding Goals Grant Homing Human Image Immune Cell Activation Immunity Inflammation Mediators Laboratories Lead Ligands Lung Lung diseases Lymphatic Lymphocyte MHC Class II Genes Mus Myeloid Cells Pathogenesis Pathogenicity Pathway interactions Pattern Phenotype Play Prevalence Proteins Publications Published Comment Pulmonary Inflammation Recruitment Activity Regulatory T-Lymphocyte Reporter Role Severities Signal Transduction T-Lymphocyte Th2 Cells Therapeutic Intervention Virus Work asthmatic chemokine chemokine receptor design fMet-Leu-Phe receptor imprint intravital microscopy lymph nodes new therapeutic target pathogen response trafficking

项目摘要

This grant alms to understand the chemoattractant pathways that control the recruitment of Th2 effector lymphocytes into the airways in human asthma. Since allergen-specific Th2 cells play a key role in the pathogenesis of asthma, understanding the mechanisms that control their specific recruitment into the ain/vay has the potential to lead to new more specific therapies for allergic asthma while leaving overall T cellmediated lung immunity to viruses and other import human pathogens intact. In the 3.5 years of this R37 award, we have made significant progress towards this goal, and have also made some important related discoveries concerning chemokine control of Treg trafficking into the allergic lung and the ability of lung dendritic cells to imprint lung homing of T cells. In this project period, this grant has supported our work resulting in 9 original publications (7 from the Pis laboratory), 6 reviews, 1 commentary and 2 book chapters. In the prior funding period, we have identified CCR4 as an important chemokine receptor that participates in the control of Th2 cell recruitment into the airways in asthma. We also found that Tregs are recrOited into the lung in allergic pulmonary inflammation via a CCR4-dependent pathway where they have the ability to s.uppress allergic pulmonary inflammation. Since CCR4 only accounts for -50% of the Th2 cell trafficking signals, we clearly need to identify the other relevant chemoattractant pathways. In addition, since CCR4 is also important for Treg cell recruitment into the lung, the identification of additional chemokine pathways that participate in Th2 cells trafficking into the allergic lung could allow the specific targeting of Th2 cells, leaving Treg recruitment intact. In the MERIT extension period we will generate a CCL17 and CCL22 dual reporter mouse to determine the pattern of CCR4 ligand expression in the lung and lymph node in allergic pulmonary inflammation. We will also image the influence of chemokines on Th2, Treg and DC interactions in the lung using confocal and multiphtoton intravital microscopy. In addition, we will determine the chemokine receptors responsible for lung-specific homing and identify the lung DC subset that imprints lung-specific homing. In the prior funding period, our analysis of human T cells recruited into the airway following allergen challenge was restricted to bulk T cells, which include many bystander T cells. In our extension period, we will build upon our work using MHC class II allergen-specific tetramers to precisely define the chemokine receptor phenotype of allergen-specific T cells recruited into the lung. This is very important because in order to define the chemoattractant receptor pathways critical for pathogenic T cell recruitment into the airway in asthma, we need to define the relevant pathway for the critical cell, the allergen-specific T cell.

这项拨款施舍以了解控制Th2效应器募集的趋化途径淋巴细胞进入人类哮喘的气道。由于过敏原特异性TH2细胞在哮喘的发病机理，了解控制其特定募集到AIN/VAY的机制有可能导致新的更具体的过敏性哮喘疗法对病毒和其他进口人类病原体的肺免疫完整。在此R37的3。5年中奖励，我们已经朝着这个目标取得了重大进步，并且也使一些重要的相关关于Treg运输到过敏性肺的趋化因子控制的发现和肺的能力树突状细胞以烙印T细胞的肺归巢。在这个项目期间，该赠款支持我们的工作产生了9个原始出版物（来自PIS实验室的7个），6个评论，1个评论和2本书章节。在以前的资金期间，我们将CCR4确定为参与的重要趋化因子受体 Th2细胞募集到哮喘中的气道中。我们还发现Tregs被重新组合到通过CCR4依赖性途径在过敏性肺部炎症中肺有能力施加过敏性肺部炎症。由于CCR4仅占TH2细胞贩运的-50％信号，我们显然需要识别其他相关的化学吸引力途径。另外，由于CCR4是对于Treg细胞募集到肺部也很重要，鉴定了其他趋化因子途径参与运输到过敏性肺的Th2细胞可以允许TH2细胞的特定靶向 Treg招聘完整。在绩效延长期间，我们将生成CCL17和CCL22双重记者小鼠确定肺中CCR4配体表达的模式和过敏性肺中的淋巴结炎。我们还将图像趋化因子对肺中Th2，Treg和DC相互作用的影响使用共聚焦和多刺肠内显微镜。另外，我们将确定趋化因子负责肺特异性归巢的受体，并识别肺直流子群，该子群具有印记特异性肺部特异性归宿。在以前的资金期间，我们对人类T细胞的分析在过敏原后募集到气道中挑战仅限于大量T细胞，其中包括许多旁观者T细胞。在我们的延长期，我们将使用MHC II类过敏原特异性四聚体以我们的工作为基础，以精确定义趋化因子过敏原特异性T细胞的受体表型募集到肺中。这很重要，因为在为了定义对致病性T细胞募集至关重要的趋化受体途径气道在哮喘中，我们需要定义关键细胞（过敏原特异性T细胞）的相关途径。