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.

这有助于了解控制 Th2 效应子募集的化学引诱途径淋巴细胞进入人类哮喘气道。由于过敏原特异性 Th2 细胞在哮喘的发病机制，了解控制其特定募集到 ain/vay 的机制有潜力为过敏性哮喘带来新的、更具体的疗法，同时保留整体 T 细胞介导的治疗方法肺部对病毒和其他输入人类病原体的免疫力完好无损。在这台R37的3.5年里获奖后，我们在实现这一目标方面取得了重大进展，并且还取得了一些重要的相关成果关于趋化因子控制 Treg 运输进入过敏性肺和肺功能的发现树突状细胞印记 T 细胞的肺归巢。在这个项目期间，这笔赠款支持了我们的工作产生了 9 篇原创出版物（7 篇来自 Pis 实验室）、6 篇评论、1 篇评论和 2 个书籍章节。在之前的资助期间，我们已经确定 CCR4 是一种重要的趋化因子受体，参与哮喘中 Th2 细胞招募至气道的控制。我们还发现 Tregs 被重新纳入肺通过 CCR4 依赖性途径参与过敏性肺部炎症，其中它们有能力 s.抑制过敏性肺部炎症。由于 CCR4 仅占 Th2 细胞运输的-50% 信号，我们显然需要确定其他相关的化学引诱途径。此外，由于 CCR4 是对于 Treg 细胞募集到肺部也很重要，识别其他趋化因子途径参与 Th2 细胞转运至过敏性肺的可能允许 Th2 细胞的特异性靶向，从而使 Treg 招募完好无损。在 MERIT 延长期内，我们将生成 CCL17 和 CCL22 双报告基因小鼠测定过敏性肺病患者肺和淋巴结中 CCR4 配体的表达模式炎。我们还将观察趋化因子对肺部 Th2、Treg 和 DC 相互作用的影响使用共焦和多光子活体显微镜。此外，我们将确定趋化因子负责肺特异性归巢的受体并识别印记肺特异性的肺 DC 子集归航。在之前的资助期间，我们对过敏原后招募到气道中的人类 T 细胞进行了分析挑战仅限于大量 T 细胞，其中包括许多旁观者 T 细胞。在我们的延长期内，我们将基于我们的工作，使用 MHC II 类过敏原特异性四聚体来精确定义趋化因子招募到肺部的过敏原特异性 T 细胞的受体表型。这非常重要，因为在为了确定对致病性 T 细胞募集到体内至关重要的趋化剂受体途径在哮喘气道中，我们需要定义关键细胞（过敏原特异性 T 细胞）的相关通路。