CD4 T CELLS: LESSONS LEARNED FROM ASTHMA

CD4 T 细胞：从哮喘中吸取的教训

• 批准号: 7720877
• 负责人: Laurie A Whittaker
• 金额: $ 28.31万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720877
• 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

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 囊性纤维化（CF）是一种常见的致命遗传疾病，是由CF跨膜电导调节剂（CFTR）缺陷引起的。 大多数CF患者死于进行性呼吸衰竭，尽管对CF肺部疾病进行了半个多世纪的研究，但我们对其发病机理的了解仍然不完整。 大量研究集中在气道上皮和中性粒细胞上，但在组织水平CF上是一种淋巴细胞疾病。 哮喘和过敏性支气管肺曲霉病（ABPA）通常在CF患者中发现并代表了旺盛的CD4 TH2细胞炎症反应，这表明CD4 TH2细胞在CF气道疾病中也可能很重要。 尽管许多研究检查了CFTR在气道上皮的作用，但对于骨髓衍生细胞中的CFTR功能知之甚少。 由于T淋巴细胞表达CFTR，因此很可能会受到CFTR缺陷的影响。 我们已经使用了两种不同的CF鼠模型（Delta F508和CFTR敲除）研究了CF气道中对曲霉菌丝抗原的炎症反应。 在这两种动物中，我们都发现，与野生型相比，CF小鼠（Delta F508和CFTR淘汰）会因烟曲霉暴露而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和上皮粘液过度分泌。 此外，来自烟曲霉的CD4 T细胞暴露于CF小鼠（Delta F508和CFTR敲打）产生的白介素-4（IL-4）比对照组产生的更多，而来自非暴露的Delta F508和CFTR敲除小鼠的CD4 T细胞具有自发性CD4 TH2偏置的自发性CD4 TH2偏置。 总之，我们的研究清楚地表明，缺乏功能性CFTR会导致响应烟曲霉暴露而夸张的气道炎症，这似乎与Th2偏见有关。 此外，他们表明，即使在没有烟曲霉的情况下，来自两个不同CF鼠菌株的CD4 T细胞也具有固有的CD4 TH2偏置。 我们未来的重点是确定Th2偏置是否来自CFTR对CD4 T细胞的缺陷，还是由免疫系统另一组成部分或肺气道环境中的CFTR不足引起的。 我们还将研究CD4 T细胞对CFTR表达的校正是否会响应烟曲霉暴露和固有的Th2偏置，使气道炎症过多。 此外，我们将开始研究，以了解CFTR缺陷CD4 T细胞中如何导致IL-4产生增加的机制。 我们的日志术语目标是定义炎症细胞缺陷如何促进CF中的气道破坏。