Inhibition of Th1- and Th2-mediated airway inflammation by the sphingosine 1-phosphate receptor agonist FTY720
Inhibition of Th1- and Th2-mediated airway inflammation by the sphingosine 1-phosphate receptor agonist FTY720
复制标题
DOI：
10.4049/jimmunol.171.11.6206
复制
发表时间：
2003-12-01
影响因子：
4.4
通讯作者：
Walker, C
中科院分区：
文献类型：
--
作者：
Sawicka, E;Zuany-Amorim, C;Walker, C
鞘氨醇1-磷酸受体激动剂FTY720是一种新型的免疫调节剂，它将淋巴细胞隔离在次级淋巴器官中，从而防止它们迁移到炎症部位。然而，目前还没有关于该药物是否影响Th1或Th2细胞介导的肺炎症反应的信息。因此，FTY720在小鼠呼吸道炎症模型中进行了研究，该模型使用OVA特异的、体外分化的和过继转移的Th1和Th2细胞。Th1和Th2细胞都表达类似的FTY720靶向鞘氨醇1-磷酸受体。口服FTY720可明显抑制OVA诱导的Th1介导的以支气管肺泡灌洗液中淋巴细胞和中性粒细胞增多为特征的气道炎症。同样，FTY720可抑制Th2细胞诱导的支气管肺泡灌洗液嗜酸性粒细胞增多以及T淋巴细胞和嗜酸性粒细胞向支气管组织的渗透。此外，吸入偏甲胆碱后，Ag诱导的支气管高反应性几乎完全被阻断。FTY720对哮喘小鼠的气道炎症、高反应性诱导和杯状细胞增殖的抑制作用可在主动Ag致敏的小鼠哮喘模型中得到证实，这清楚地表明Th2细胞驱动的过敏性疾病，如哮喘，可以从这种治疗中受益。
The sphingosine 1-phosphate receptor agonist FTY720 is a novel immunomodulator that sequesters lymphocytes in secondary lymphoid organs and thereby prevents their migration to sites of inflammation. However, there is currently no information available on whether this drug affects Th1 or Th2 cell-mediated lung-inflammatory responses. The effect of FTY720 was therefore investigated in a murine airway inflammation model using OVA-specific, in vitro differentiated, and adoptively transferred Th1 and Th2 cells. Both Th1 and Th2 cells express a similar pattern of FTY720-targeted sphingosine 1-phosphate receptors. The OVA-induced Th1-mediated airway inflammation characterized by increased numbers of lymphocytes and neutrophils in bronchoalveolar lavage fluid was significantly inhibited by oral FTY720 treatment. Similarly, FTY720 suppressed the Th2 cell-induced bronchoalveolar lavage fluid eosinophilia and the infiltration of T lymphocytes and eosinophils into the bronchial tissue. Moreover, the Ag-induced bronchial hyperresponsiveness to inhaled metacholine was almost completely blocked. The inhibitory effect of FTY720 on airway inflammation, induction of bronchial hyperresponsiveness, and goblet cell hyperplasia could be confirmed in an actively Ag-sensitized murine asthma model, clearly indicating that Th2 cell-driven allergic diseases such as asthma could benefit from such treatment.