BACKGROUND Therapies targeting interleukin-5 (IL-5) or its receptor (IL-5Rα) are currently used to treat patients with severe eosinophilic asthma. OBJECTIVE To investigate the impact of anti-IL-5 and anti-IL-5Rα biological therapies on mast cells (MCs) and their progenitors. METHODS Surface IL-5Rα expression was investigated on MCs and their progenitors in mouse lungs and bone marrow, and in human lungs and blood. Isolated human MC progenitors cultured in the presence or absence of IL-5 were analyzed in vitro. Circulating MC progenitors were quantified in patients with severe asthma, before and after anti-IL-5 (mepolizumab) or anti-IL-5Rα (benralizumab) therapy. Gene expression analysis of MC progenitors was performed before and after anti-IL-5Rα therapy. RESULTS Approximately 50% of the human primary lung MCs, and 30% of the human MC progenitors from individuals with allergic asthma expressed IL-5Rα. In patients with mild-to-moderate allergic asthma and mice with acute allergic airway inflammation, the fraction of IL-5Rα + MC progenitors was elevated. Additionally, IL-5 promoted the proliferation and/or survival of isolated human MC progenitors. Further, patients with severe asthma from two independent cohorts demonstrated a reduction of blood MC progenitors after anti-IL-5 or anti-IL-5Rα treatment. This was associated with improved asthma control, as well as a decline in both blood eosinophils and Th2 cells. Finally, the blood MC progenitors remaining after anti-IL-5Rα (benralizumab) treatment exhibited a downregulated expression of genes involved in growth and proliferation. CONCLUSION This study introduces the possibility that the clinical effects of targeting IL-5/IL-5Rα in severe asthma also may involve reduction of MC populations.

中文翻译：

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在严重哮喘中靶向 IL-5 通路可减少肥大细胞祖细胞。


背景 靶向白细胞介素 5 （IL-5） 或其受体 （IL-5Rα） 的疗法目前用于治疗严重嗜酸性粒细胞性哮喘患者。目的 探讨抗 IL-5 和抗 IL-5Rα 生物疗法对肥大细胞 （MCs） 及其祖细胞的影响。方法 研究小鼠肺和骨髓、人肺和血液中 MCs 及其祖细胞表面 IL-5Rα 的表达。在体外分析在存在或不存在 IL-5 的情况下培养的分离人 MC 祖细胞。在抗 IL-5 （美泊利单抗） 或抗 IL-5Rα （贝那利珠单抗） 治疗前后，对严重哮喘患者的循环 MC 祖细胞进行量化。在抗 IL-5Rα 治疗前后进行 MC 祖细胞的基因表达分析。结果 大约 50% 的人类原代肺 MC 和 30% 的过敏性哮喘个体的人类 MC 祖细胞表达 IL-5Rα。在轻中度过敏性哮喘患者和急性过敏性气道炎症小鼠中，IL-5Rα + MC 祖细胞的分数升高。此外，IL-5 促进分离的人类 MC 祖细胞的增殖和/或存活。此外，来自两个独立队列的严重哮喘患者在抗 IL-5 或抗 IL-5Rα 治疗后表现出血液 MC 祖细胞减少。这与哮喘控制的改善以及血嗜酸性粒细胞和 Th2 细胞的下降有关。最后，抗 IL-5Rα （贝那利珠单抗） 治疗后残留的血液 MC 祖细胞表现出参与生长和增殖的基因表达下调。结论 本研究引入了靶向 IL-5/IL-5Rα 在严重哮喘中的临床效果也可能涉及 MC 群体减少的可能性。