Anti-IL-5 in Mild Asthma Alters Rhinovirus-induced Macrophage, B-Cell, and Neutrophil Responses (MATERIAL) A Placebo-controlled, Double-Blind Study
Anti-IL-5 in Mild Asthma Alters Rhinovirus-induced Macrophage, B-Cell, and Neutrophil Responses (MATERIAL) A Placebo-controlled, Double-Blind Study
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DOI：
10.1164/rccm.201803-0461oc
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发表时间：
2019-02-15
影响因子：
24.7
通讯作者：
Lutter, Rene
中科院分区：
文献类型：
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作者：
Pineros, Yanaika S. Sabogal;Bal, Suzanne M.;Lutter, Rene
原理：嗜酸性粒细胞驱动稳定型和加重型嗜酸性粒细胞哮喘的病理生理，因此治疗的重点是减少嗜酸性粒细胞的数量。Mepolizumab是一种人源化单克隆抗体，可中和IL-5并有效减毒嗜酸性粒细胞，临床证明对重度嗜酸性粒细胞哮喘有效，但对轻度哮喘无效。目的：研究美泊珠单抗对轻度哮喘患者病毒诱导免疫反应的影响。方法：在一项安慰剂对照双盲试验中，轻度哮喘、未使用类固醇、嗜酸性粒细胞随机分组的患者静脉注射750 mg mepolizumab， 2周后接受鼻病毒（RV）攻击16。评估mepolizumab和RV16前后血液、BAL液和痰中的FEV1、FVC、呼气一氧化氮分数、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）和细胞（流式细胞术）免疫参数。测量结果和主要结果：Mepolizumab降低了基线血嗜酸性粒细胞及其激活，减弱了趋势性痰嗜酸性粒细胞，并增强了循环自然杀伤细胞。Mepolizumab在基线和RV16后均不影响FEV1、FVC和分数呼出一氧化氮。在RV16攻击时，mepolizumab不能阻止嗜酸性粒细胞的激活，但可以增强局部B淋巴细胞和巨噬细胞，并降低中性粒细胞及其激活。Mepolizumab还增强了BAL液中IgA的分泌并降低了胰蛋白酶。最后，mepolizumab特别影响rv16诱导的巨噬细胞炎症蛋白-3a、血管内皮生长因子- a和BAL液中IL-1RA的产生。结论：Mepolizumab未能阻止轻度哮喘患者剩余嗜酸性粒细胞的激活和改变rv16诱导的免疫反应。虽然后一种影响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。
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.