Anti-IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL-5 and IL-5 receptor levels
Anti-IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL-5 and IL-5 receptor levels
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DOI：
10.1016/j.jaci.2008.02.033
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发表时间：
2008-06-01
影响因子：
14.2
通讯作者：
Rothenberg, Marc E.
中科院分区：
文献类型：
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作者：
Stein, Miguel L.;Villanueva, Joyce M.;Rothenberg, Marc E.
背景资料：抗IL-5可能是一个有用的治疗剂嗜酸性粒细胞性疾病，但其免疫学后果还没有得到很好的characteristic.Objective：我们试图描述抗IL-5在人类subjects.Methods的血液学和免疫学的影响：3个月的美泊利单抗输注的影响进行了评估，在25例患者的各种嗜酸性粒细胞综合征。通过使用尺寸排阻过滤分析治疗后IL-5水平升高的样品。随后用饱和浓度的蛋白A/G沉淀免疫反应性IL-5组分和血浆样品。结果：23例患者对抗IL-5治疗有反应，血液嗜酸性粒细胞计数减少，CCR 3（+）细胞百分比分别减少20倍和13倍（P < .0001）。治疗反应性与基线血浆IL-5水平或FIP 1 L1-PDGFPA融合基因的存在无关。76%的受试者在末次输注后3个月内持续降低血嗜酸性粒细胞增多症。治疗与血液IL-5水平的大幅增加相关，可能是因为循环中的IL-5/mepolizumab复合物与蛋白A/G沉淀，嗜酸性粒细胞IL-5受体et表达的显著增加，以及产生细胞内IL-5的CD 4（+）和CD 8（+）细胞百分比的增加（P <0.05）。此外，抗IL-5治疗减少了嗜酸性粒细胞活化趋化因子刺激的嗜酸性粒细胞的形状变化exvivo.Conclusions：抗IL-5治疗诱导血液嗜酸性粒细胞（包括CCR 3（+）细胞），减少嗜酸性粒细胞活化，并在各种嗜酸性粒细胞疾病中增加IL-5的循环水平显着和持续的减少。抗IL-5治疗后IL-5受体α和淋巴细胞IL-5产生水平的增加提示内源性IL-5自身调节途径。
Background: Anti-IL-5 might be a useful therapeutic agent for eosinophilic disorders, yet its immunologic consequences have not been well characterized.Objective: We sought to characterize the hematologic and immunologic effects of anti-IL-5 in human subjects.Methods: The effects of 3-month infusions of mepolizumab were assessed in 25 patients with a variety of eosinophilic syndromes. Samples with increased IL-5 levels after therapy were analyzed by using size exclusion filtration. Immunoreactive IL-5 fraction and plasma samples were subsequently precipitated with saturating concentrations of protein A/G.Results: Twenty-three patients responded to anti-IL-5 therapy with a decrease in blood eosinophil counts and a reduced percentage of CCR3(+) cells by 20- and 13-fold, respectively (P < .0001). Responsiveness was not related to the levels of baseline plasma IL-5 or the presence of FIP1L1-PDGFPA fusion gene. Persistently decreased blood eosinophilia remained for 3 months after final infusion in 76% of subjects. Therapy was associated with a large increase in blood IL-5 levels, likely because of a circulating IL-5/mepolizumab complex precipitated with protein A/G, a significant increase in eosinophil IL-5 receptor et expression, and increased percentage of CD4(+) and CD8(+) cells producing intracellular IL-5 (P < .05). Additionally, anti-IL-5 therapy decreased eotaxin-stimulated eosinophil shape change ex vivo.Conclusions: Anti-IL-5 therapy induces a dramatic and sustained decrease in blood eosinophilia (including CCR3(+) cells), decreased eosinophil activation, and increased circulating levels of IL-5 in a variety of eosinophilic disorders. Increased levels of IL-5 receptor alpha and lymphocyte IL-5 production after anti-IL-5 therapy suggest an endogenous IL-5 autoregulatory pathway.