RATIONALE Eosinophils drive pathophysiology in stable and exacerbating eosinophilic asthma, and therefore treatment is focused on the reduction of eosinophil numbers. Mepolizumab, a humanized monoclonal antibody that neutralizes IL-5 and efficiently attenuates eosinophils, proved clinically effective in severe eosinophilic asthma but not in mild asthma. OBJECTIVES To study the effect of mepolizumab on virus-induced immune responses in mild asthma. METHODS Patients with mild asthma, steroid-naive and randomized for eosinophil numbers, received 750 mg mepolizumab intravenously in a placebo-controlled double-blind trial, 2 weeks after which patients were challenged with rhinovirus (RV) 16. FEV1, FVC, fractional exhaled nitric oxide, symptom scores (asthma control score), viral load (PCR), eosinophil numbers, humoral (luminex, ELISA), and cellular (flow cytometry) immune parameters in blood, BAL fluid, and sputum, before and after mepolizumab and RV16, were assessed. MEASUREMENTS AND MAIN RESULTS Mepolizumab attenuated baseline blood eosinophils and their activation, attenuated trendwise sputum eosinophils, and enhanced circulating natural killer cells. Mepolizumab did not affect FEV1, FVC, and fractional exhaled nitric oxide, neither at baseline nor after RV16. On RV16 challenge mepolizumab did not prevent eosinophil activation but did enhance local B lymphocytes and macrophages and reduce neutrophils and their activation. Mepolizumab also enhanced secretory IgA and reduced tryptase in BAL fluid. Finally, mepolizumab affected particularly RV16-induced macrophage inflammatory protein-3a, vascular endothelial growth factor-A, and IL-1RA production in BAL fluid. CONCLUSIONS Mepolizumab failed to prevent activation of remaining eosinophils and changed RV16-induced immune responses in mild asthma. Although these latter effects likely are caused by attenuated eosinophil numbers, we cannot exclude a role for basophils. Clinical trial registered with www.clinicaltrials.gov (NCT 01520051).

中文翻译：

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轻度哮喘中的抗IL-5改变鼻病毒诱导的巨噬细胞，B细胞和嗜中性粒细胞的反应（材料）。安慰剂对照的双盲研究。

理性的嗜酸性粒细胞在稳定且加剧嗜酸性粒细胞性哮喘中驱动病理生理，因此治疗的重点是减少嗜酸性粒细胞的数量。美泊珠单抗（Mepolizumab）是一种人源化的单克隆抗体，可中和IL-5并有效减弱嗜酸性粒细胞，已被证明在重度嗜酸性粒细胞性哮喘中有效，但在轻度哮喘中无效。目的研究美泊利单抗对轻度哮喘中病毒诱导的免疫反应的影响。方法在安慰剂对照双盲试验中，接受轻度哮喘，无激素治疗和随机嗜酸性粒细胞数量的患者静脉注射750 mg美泊利珠单抗，此后2周，患者接受鼻病毒（RV）16攻击。FEV1，FVC进行分数呼气一氧化氮，症状评分（哮喘控制评分），病毒载量（PCR），嗜酸性粒细胞数量，体液（luminex，ELISA），评估了美泊利单抗和RV16之前和之后的血液，BAL液和痰中的细胞（流式细胞仪）免疫参数。测量和主要结果Mepolizumab减弱基线血液嗜酸性粒细胞及其激活，减弱趋势性痰嗜酸性粒细胞，并增强循环自然杀伤细胞。美泊珠单抗在基线和RV16后均不影响FEV1，FVC和呼出的一氧化氮。在RV16激发中，美泊利单抗不能阻止嗜酸性粒细胞活化，但可以增强局部B淋巴细胞和巨噬细胞并减少中性粒细胞及其活化。美泊珠单抗还增强了BAL液中的分泌型IgA并降低了类胰蛋白酶。最后，美泊利单抗特别影响RV16诱导的巨噬细胞炎性蛋白3a，血管内皮生长因子A和BAL液中IL-1RA的产生。结论美泊利珠单抗未能预防轻度哮喘患者剩余嗜酸性粒细胞活化并改变RV16诱导的免疫反应。尽管后者可能是由嗜酸性粒细胞数量减少引起的，但我们不能排除嗜碱性粒细胞的作用。已在www.clinicaltrials.gov（NCT 01520051）注册的临床试验。