Division of Infection, Southampton National Institute of Health Research Respiratory Biomedical Research Unit, University of Southampton School of Medicine, Southampton, United Kingdom.
J Immunol. 2010 Apr 15;184(8):4568-74. doi: 10.4049/jimmunol.0901342. Epub 2010 Mar 17.
T lymphocytes of the Th2 type are central orchestrators of airway inflammation in asthma. The mechanisms that regulate their accumulation in the asthmatic airways remains poorly understood. We tested the hypothesis that CCR4, preferentially expressed on T lymphocytes of the Th2 type, plays a critical role in this process. We enumerated by flow cytometry the CCR4-expressing T cells from blood, induced sputum, and biopsy samples of patients with asthma and control subjects. We showed a positive correlation between the numbers of peripheral blood CCR4+ T cells and asthma severity, provided evidence of preferential accumulation of CCR4+ T cells in asthmatic airways, and demonstrated that CCR4+ but not CCR4- cells from patients with asthma produce Th2 cytokines. Explanted airway mucosal biopsy specimens, acquired by bronchoscopy from subjects with asthma, were challenged with allergen and the explant supernatants assayed for T cell chemotactic activity. Allergen-induced ex vivo production of the CCR4 ligand, CCL17 was raised in explants from patients with asthma when compared with healthy controls. Using chemotaxis assays, we showed that the T cell chemotactic activity generated by bronchial explants can be blocked with a selective CCR4 antagonist or by depleting CCR4+ cells from responder cells. These results provide evidence that CCR4 might play a role in allergen-driven Th2 cell accumulation in asthmatic airways. Targeting this chemokine receptor in patients with asthma might reduce Th2 cell-driven airway inflammation; therefore, CCR4 antagonists could be an effective new therapy for asthma. This study also provides wider proof of concept for using tissue explants to study immunomodulatory drugs for asthma.
Th2 型 T 淋巴细胞是哮喘气道炎症的核心调控者。调节其在哮喘气道中聚集的机制仍知之甚少。我们假设 CCR4（主要表达于 Th2 型 T 淋巴细胞）在这个过程中发挥关键作用，并对此进行了验证。我们通过流式细胞术对哮喘患者和对照者的外周血、诱导痰和活检样本中的 CCR4 表达 T 细胞进行了计数。我们发现外周血 CCR4+T 细胞数量与哮喘严重程度呈正相关，证明了 CCR4+T 细胞在哮喘气道中优先聚集，并证实了哮喘患者的 CCR4+细胞而非 CCR4-细胞可产生 Th2 细胞因子。通过支气管镜从哮喘患者获取气道黏膜活检标本，用变应原刺激后检测标本上清液中的 T 细胞趋化活性。与健康对照者相比，哮喘患者气道黏膜活检标本中 CCR4 配体 CCL17 的体外产生在变应原刺激下增加。通过趋化实验，我们发现支气管组织标本体外产生的 T 细胞趋化活性可以被选择性 CCR4 拮抗剂阻断，也可以通过从反应细胞中耗竭 CCR4+细胞来阻断。这些结果提示 CCR4 可能在变应原驱动的 Th2 细胞在哮喘气道中的聚集中发挥作用。在哮喘患者中靶向该趋化因子受体可能会减少 Th2 细胞驱动的气道炎症；因此，CCR4 拮抗剂可能成为哮喘的一种有效新疗法。该研究还为使用组织标本研究哮喘免疫调节药物提供了更广泛的概念验证。
