CD4 T CELLS: LESSONS LEARNED FROM ASTHMA

CD4 T 细胞：从哮喘中吸取的教训

基本信息

批准号：
7609701
负责人：
Laurie A Whittaker
金额：
$ 27.69万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7609701
关键词：
Affect Allergic Bronchopulmonary Aspergillosis Animals Antigens Aspergillus fumigatus Asthma Bone Marrow CD4 Positive T Lymphocytes Cells Computer Retrieval of Information on Scientific Projects Database Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Defect Disease Environment Eosinophilia Epithelial Extrinsic asthma Funding Future Goals Grant Hereditary Disease Immune system In Vitro Inflammatory Inflammatory Response Institution Interleukin-4 Knock-out Knockout Mice Knowledge Learning Lung Lymphocyte Modeling Mucous body substance Mus Numbers Pathogenesis Personal Satisfaction Production Pulmonary Cystic Fibrosis Research Research Personnel Resources Respiratory Failure Role Source T-Lymphocyte Th2 Cells Tissues United States National Institutes of Health airway epithelium airway inflammation cystic fibrosis airway cystic fibrosis mouse cystic fibrosis patients neutrophil response

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cystic Fibrosis (CF) is a common, lethal genetic disease that arises from defects in CF transmembrane conductance regulator (CFTR). The majority of patients with CF die of progressive respiratory failure and despite over a half a century of research on CF lung disease, our knowledge of its pathogenesis remains incomplete. Numerous studies have focused on the airway epithelium and the neutrophil, yet on the tissue level CF is a lymphocytic disease. Both asthma and allergic bronchopulmonary aspergillosis (ABPA) are commonly found in patients with CF and represent an exuberant CD4 Th2 cell inflammatory response, suggesting that CD4 Th2 cells may be important in CF airway disease as well. Although a number of studies have examined the role of CFTR in airway epithelium, little is known about CFTR function in bone marrow derived cells. Since T lymphocytes express CFTR, they may well be affected by CFTR defects. We have studied the inflammatory response to Aspergillus fumigatus hyphal antigens in the CF airway using two different murine models of CF (delta F508 and CFTR knock out). In both animals we have found that compared to wild type, CF mice (delta F508 and CFTR knock out) generate excessive airway inflammation in response to A. fumigatus exposure. This inflammatory response is characterized by airway eosinophilia and epithelial mucus hypersecretion. In addition, CD4 T cells from A. fumigatus exposed CF mice (delta F508 and CFTR knock out) produce more interleukin-4 (IL-4) than controls, while CD4 T cells from non-exposed delta F508 and CFTR knock out mice have a spontaneous CD4 Th2 bias following in vitro activation. Together, our studies clearly demonstrate that the absence of functional CFTR results in exaggerated airway inflammation in response to A. fumigatus exposure and this appears to be associated with a Th2 bias. Moreover, they show that CD4 T cells from two different CF murine strains have an inherent CD4 Th2 bias even in the absence of A. fumigatus exposure. Our future focus will be to determine if the Th2 bias arises from a deficit of CFTR on CD4 T cells or if it results from a CFTR deficit in another constituent of the immune system or the from the lung airway environment. We will also investigate if correction of CFTR expression by CD4 T cells resolves excessive airway inflammation in response to A. fumigatus exposure and inherent Th2 bias. In addition we will begin studies to understand the mechanism of how a deficit in CFTR on the CD4 T cell results in increased IL-4 production. Our log term goal is to define how inflammatory cell defects contribute to airway destruction in CF.

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目和研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是中心，不一定是研究者的机构。囊性纤维化 (CF) 是一种常见的致命遗传性疾病，由 CF 跨膜电导调节因子 (CFTR) 缺陷引起。大多数 CF 患者死于进行性呼吸衰竭，尽管对 CF 肺病的研究已有半个多世纪，但我们对其发病机制的了解仍然不完整。许多研究都集中在气道上皮和中性粒细胞上，但在组织水平上CF是一种淋巴细胞疾病。哮喘和过敏性支气管肺曲霉病 (ABPA) 均常见于 CF 患者，代表着旺盛的 CD4 Th2 细胞炎症反应，表明 CD4 Th2 细胞在 CF 气道疾病中也可能很重要。尽管许多研究已经检验了 CFTR 在气道上皮中的作用，但对骨髓来源细胞中 CFTR 的功能知之甚少。由于 T 淋巴细胞表达 CFTR，它们很可能会受到 CFTR 缺陷的影响。我们使用两种不同的 CF 小鼠模型（delta F508 和 CFTR 敲除）研究了 CF 气道中烟曲霉菌丝抗原的炎症反应。在这两种动物中，我们发现与野生型相比，CF 小鼠（delta F508 和 CFTR 敲除）在暴露于烟曲霉后会产生过度的气道炎症。这种炎症反应的特征是气道嗜酸性粒细胞增多和上皮粘液分泌过多。此外，烟曲霉暴露的 CF 小鼠（delta F508 和 CFTR 敲除）的 CD4 T 细胞比对照产生更多的白细胞介素 4 (IL-4)，而来自未暴露的 delta F508 和 CFTR 敲除小鼠的 CD4 T 细胞产生更多的白细胞介素 4 (IL-4)。体外激活后自发的 CD4 Th2 偏向。总之，我们的研究清楚地表明，功能性 CFTR 的缺失会导致烟曲霉暴露后气道炎症加剧，这似乎与 Th2 偏向相关。此外，他们表明，即使在没有暴露于烟曲霉的情况下，来自两种不同 CF 鼠科动物品系的 CD4 T 细胞也具有固有的 CD4 Th2 偏好。我们未来的重点将是确定 Th2 偏向是否由 CD4 T 细胞上的 CFTR 缺陷引起，或者是否由免疫系统的另一个组成部分或肺气道环境中的 CFTR 缺陷引起。我们还将研究 CD4 T 细胞对 CFTR 表达的校正是否可以解决烟曲霉暴露和固有 Th2 偏好引起的过度气道炎症。此外，我们将开始研究了解 CD4 T 细胞上 CFTR 缺陷如何导致 IL-4 产量增加的机制。我们的对数目标是定义炎症细胞缺陷如何导致 CF 气道破坏。