Selective down-regulation of Th2 cell-mediated airway inflammation in mice by pharmacological intervention of CCR4
Selective down-regulation of Th2 cell-mediated airway inflammation in mice by pharmacological intervention of CCR4
复制标题
DOI：
10.1111/j.1365-2222.2011.03847.x
复制
发表时间：
2012-02-01
影响因子：
6.1
通讯作者：
Hiroi, T.
中科院分区：
文献类型：
--
作者：
Kaminuma, O.;Ohtomo, T.;Hiroi, T.
趋化因子受体CCR4参与Th2细胞介导的免疫应答。然而，已知其他T细胞亚群也参与过敏性炎症。目的探讨CCR4在Th1、Th2和Th17细胞介导的变应性气道炎症中的作用。方法通过体外极化卵清蛋白（OVA）特异性Th1、Th2和Th17细胞过继转移建立过敏性气道炎症模型。研究了低分子量CCR4拮抗剂化合物22对该模型的影响。结果DO11.10幼稚T细胞体外极化后，Th1-和th2极化细胞分别主要表达CXCR3和CCR4，而th17极化细胞主要表达CCR6和CCR4。每个T细胞亚群转移的小鼠鼻内ova攻击诱导肺中T细胞的积累。嗜酸性粒细胞也在th2转移小鼠中大量积累，而中性粒细胞在th1和th17转移小鼠中优先募集。化合物22以及抗ccl17或抗ccl22抗体选择性地抑制Th2转移和ova小鼠肺中Th2细胞和嗜酸性粒细胞的积累。化合物22还能抑制th2转移小鼠和ova小鼠的支气管高反应性，但对杯状细胞增生的影响不大。结论及临床意义不同T细胞亚群介导的变应性肺部炎症有显著差异。阻断CCR4可通过阻断Th2细胞浸润选择性抑制Th2介导的变应性炎症。
Background The chemokine receptor CCR4 has been implicated in Th2 cell-mediated immune responses. However, other T cell subsets are also known to participate in allergic inflammation.Objective The role of CCR4 in Th1, Th2, and Th17 cell-mediated allergic airway inflammation was investigated.Method We generated an allergic airway inflammation model by adoptive transfer of in vitro-polarized ovalbumin (OVA)-specific Th1, Th2, and Th17 cells. The effect of a low-molecular weight CCR4 antagonist, Compound 22, on this model was examined.Results Upon in vitro polarization of DO11.10 naive T cells, Th1- and Th2-polarized cells dominantly expressed CXCR3 and CCR4, respectively, while Th17-polarized cells expressed CCR6 and CCR4. Intranasal OVA-challenge of mice transferred with each T cell subset induced accumulation of T cells in the lungs. Eosinophils were also massively accumulated in Th2-transferred mice, whereas neutrophils were preferentially recruited in Th1-and Th17-transferred mice. Compound 22, as well as anti-CCL17 or anti-CCL22 antibody selectively suppressed accumulation of Th2 cells and eosinophils in the lungs of Th2-transferred and OVA-challenged mice. Compound 22 also inhibited bronchial hyper-responsiveness but had little effect on goblet cell hyperplasia in Th2-transferred and OVA-challenged mice.Conclusions and Clinical Relevance There were notable differences in allergic lung inflammation mediated by different T cell subsets. CCR4 blockage was selectively effective for suppression of Th2-mediated allergic inflammation by blocking infiltration of Th2 cells.