Blocking IL-25 prevents airway hyperresponsiveness in allergic asthma
Blocking IL-25 prevents airway hyperresponsiveness in allergic asthma
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DOI：
10.1016/j.jaci.2007.07.051
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发表时间：
2007-12-01
影响因子：
14.2
通讯作者：
McKenzie, Andrew N. J.
中科院分区：
文献类型：
--
作者：
Ballantyne, Sarah J.;Barlow, Jillian L.;McKenzie, Andrew N. J.
背景：白介素25(IL-25，IL-17E)是免疫调节性细胞因子IL-17家族中的一员，参与了2型免疫的调节。其在抗原驱动的气道炎症和高反应性(AHR)中的作用尚未完全确定。目的：我们试图确定抗IL-25的中和抗体是否代表了一种新的治疗呼吸道炎症和高反应的方法。方法：我们制备了一种抗IL-25的中和单抗，并用其在过敏性呼吸道疾病小鼠模型中抑制IL-25。结果：在过敏性哮喘的实验模型中，阻断IL-25可阻止AHR，这是临床哮喘的关键特征。在致敏阶段应用抗IL-25单抗可显著降低IL-5和IL-13的产生水平，减少嗜酸性粒细胞的浸润，减少杯状细胞的增生，减少血清IgE的分泌，从而抑制AHR。更引人注目的是，仅在应答的激发阶段给予抗IL-25单抗，即使在持续的2型炎症反应中也能特异性地预防A。结论：IL-25对AHR的发展至关重要。临床意义：我们定义了一条诱导AHR的新途径，并提示IL-25是治疗哮喘的重要治疗靶点。值得注意的是，我们的抗体还阻断了人IL-25与其受体的结合。
Background: IL-25 (IL-17E), a member of the IL-17 family of immunoregulatory cytokines, has been implicated in the regulation of type 2 immunity. Its roles in antigen-driven airway inflammation and airway hyperresponsiveness (AHR) remain to be fully established.Objective: We sought to determine whether a neutralizing antibody against IL-25 represents a novel therapeutic for airway inflammation and hyperresponsiveness.Methods: We generated a neutralizing mAb against IL-25 and used this to inhibit IL-25 in a mouse model of allergic airway disease.Results: Blocking IL-25 in an experimental model of allergic asthma prevented AHR, a critical feature of clinical asthma. Administration of anti-IL-25 mAb during the sensitization phase resulted in significantly reduced levels of IL-5 and IL-13 production, eosinophil infiltration, goblet cell hyperplasia, and serum IgE secretion, and prevented AHR. Even more striking was the ability of anti-IL-25 mAb, administered only during the challenge phase of the response, specifically to prevent A even during an ongoing type 2 inflammatory response in the lungs.Conclusion: IL-25 is critical for development of AHR.Clinical implications: We define a novel pathway for the induction of AHR and suggest that IL-25 represents an important therapeutic target for the treatment of asthma. Significantly, our antibody also blocks the binding of human IL-25 to its receptor.