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首页> 外文期刊>Allergy >Blockade of CCR4 in a humanized model of asthma reveals a critical role for DC-derived CCL17 and CCL22 in attracting Th2 cells and inducing airway inflammation.
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Blockade of CCR4 in a humanized model of asthma reveals a critical role for DC-derived CCL17 and CCL22 in attracting Th2 cells and inducing airway inflammation.

机译：在人源化哮喘模型中对CCR4的阻断揭示了DC衍生的CCL17和CCL22在吸引Th2细胞和诱导气道炎症中的关键作用。

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BACKGROUND: As Th2 type lymphocytes orchestrate the cardinal features of allergic asthma, inhibiting their recruitment to the lungs could be of therapeutic benefit. Although human Th2 cells express the CCR4 chemokine receptor and increased production of CCR4 ligands has been found in asthmatic airways, studies in animals have reached contradictory conclusions on whether blocking this pathway would be beneficial. OBJECTIVE: As a lack of efficacy might be due to differences between mouse and man, we readdressed this question using a humanized severe combined immunodeficiency model of asthma. METHODS: Mice received peripheral blood mononuclear cells from house dust mite (HDM) allergic asthmatic patients and then underwent bronchial challenge with HDM. RESULTS: This resulted in marked allergic inflammation and bronchial hyper-reactivity. Administration of CCR4 blocking antibody abolished the airway eosinophilia, goblet cell hyperplasia, IgE synthesis and bronchial hyper-reactivity. In this chimeric system, human CD11c+ dendritic cells (DCs) were the predominant source of CCR4 ligands, suggesting that DC-derived chemokines attract Th2 cells. In separate experiments using human DCs, in vitro exposure to HDM of DCs from HDM allergic patients but not healthy controls caused CCL17 and CCL22 release that resulted in chemoattraction of polarized human Th2 cells in a CCR4-dependent way. CONCLUSIONS: Taken together, our data provide proof of concept that CCR4 blockade inhibits the salient features of asthma and justify further clinical development of CCR4 antagonists for this disease.
机译：背景：由于Th2型淋巴细胞编排过敏性哮喘的主要特征，抑制其向肺的募集可能具有治疗作用。尽管人类Th2细胞表达CCR4趋化因子受体，并且在哮喘气道中发现了CCR4配体的产生增加，但动物实验已得出有关阻断该途径是否有益的矛盾结论。目的：由于缺乏功效可能是由于小鼠和人类之间的差异所致，因此我们使用人源化的严重哮喘联合免疫缺陷模型重新解决了这个问题。方法：小鼠从屋尘螨（HDM）过敏性哮喘患者的外周血单个核细胞中提取，然后接受HDM支气管激发。结果：这导致明显的过敏性炎症和支气管高反应性。施用CCR4阻断抗体消除了气道嗜酸性粒细胞增多，杯状细胞增生，IgE合成和支气管高反应性。在这种嵌合系统中，人CD11c +树突状细胞（DC）是CCR4配体的主要来源，表明DC衍生的趋化因子吸引Th2细胞。在使用人DC的单独实验中，来自HDM过敏患者而不是健康对照组的DC的体外暴露于HDM导致CCL17和CCL22释放，从而导致CTL4依赖性极化人Th2细胞的化学吸引。结论：综上所述，我们的数据提供了概念证明，CCR4阻断剂可抑制哮喘的显着特征，并为该疾病的CCR4拮抗剂的进一步临床开发提供依据。

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