Rationale: Mepolizumab, an interleukin-5 blocking antibody, reduces exacerbations in severe eosinophilic asthma patients. Mepolizumab arrests eosinophil maturation; however, the functional phenotype of eosinophils that persist in the blood and airway after administration of interleukin-5 neutralizing antibodies has not been reported. Objective: To determine the effect of anti-IL-5 antibody on the numbers and phenotypes of allergen-induced circulating and airway eosinophils. Methods: Airway inflammation was elicited in mild allergic asthma participants by segmental allergen challenge before and one month after a single intravenous 750 milligram dose of mepolizumab. Eosinophils were examined in blood, bronchoalveolar lavage, and endobronchial biopsies forty-eight hours after challenge. Measurements and Main Results: Segmental challenge without mepolizumab induced a rise in circulating eosinophils, bronchoalveolar lavage eosinophilia, and eosinophil peroxidase deposition in bronchial mucosa. Interleukin-5 neutralization before allergen challenge abolished the allergen-induced rise in circulating eosinophils and expression of interleukin-3 receptor; whereas, airway eosinophilia and eosinophil peroxidase deposition were blunted but not eliminated. Before mepolizumab treatment, bronchoalveolar lavage eosinophils had more surface interleukin-3 and granulocyte-monocyte colony-stimulating factor receptors, CD69, CD44, and CD23 and decreased interleukin-5 and eotaxin receptors than blood eosinophils. This activation phenotype indicated by bronchoalveolar lavage eosinophil surface markers, as well as the release of eosinophil peroxidase by eosinophils in the bronchial mucosa was maintained after mepolizumab. Conclusions: Mepolizumab reduced airway eosinophil numbers, but had limited effect on airway eosinophil activation markers suggesting these cells retain functionality. This observation may explain why interleukin-5 neutralization reduces but does not completely eradicate asthma exacerbations. Clinical trial registration available at www.clinicaltrials.gov, ID NCT00802438.

中文翻译：

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美泊利珠单抗减轻气道嗜酸性粒细胞数量，但不减弱其在哮喘中的功能表型

原理：美泊利单抗，一种白介素5阻断抗体，可减轻严重嗜酸性粒细胞性哮喘患者的病情加重。美泊利单抗阻止嗜酸性粒细胞的成熟；然而，尚未报道施用白介素-5中和抗体后在血液和气道中持续存在的嗜酸性粒细胞的功能表型。目的：确定抗IL-5抗体对变应原诱导的循环和气道嗜酸性粒细胞数量和表型的影响。方法：在轻度过敏性哮喘参与者中，单次静脉注射750毫克美泊珠单抗之前和之后1个月，通过分段过敏原激发引起气道炎症。攻击后四十八小时，在血液，支气管肺泡灌洗液和支气管内活检中检查嗜酸性粒细胞。测量和主要结果：没有美泊利单抗的节段性刺激引起循环性嗜酸性粒细胞，支气管肺泡灌洗液嗜酸性粒细胞增多和支气管黏膜中嗜酸性粒细胞过氧化物酶沉积的增加。变应原攻击前的白细胞介素5中和作用消除了变应原诱导的循环性嗜酸性粒细胞增多和白细胞介素3受体的表达。然而，气道嗜酸性粒细胞增多和嗜酸性粒细胞过氧化物酶沉积减弱，但并未消除。在美泊利单抗治疗之前，与血液嗜酸性粒细胞相比，支气管肺泡灌洗嗜酸性粒细胞具有更多的表面白细胞介素3和粒细胞-单核细胞集落刺激因子受体CD69，CD44和CD23，白细胞介素5和嗜酸性粒细胞趋化因子受体减少。这种激活表型由支气管肺泡灌洗嗜酸性粒细胞表面标志物指示，美泊珠单抗后，维持嗜酸性粒细胞在支气管粘膜中的释放以及嗜酸性粒细胞过氧化物酶的释放。结论：Mepolizumab减少了气道嗜酸性粒细胞数量，但对气道嗜酸性粒细胞激活标记的作用有限，表明这些细胞保留了功能。该观察结果可以解释为什么白介素5的中和作用降低但不能完全根除哮喘发作的原因。可在www.clinicaltrials.gov上找到临床试验注册，ID NCT00802438。