Alvarado-Vazquez P Abigail, Mendez-Enriquez Erika, Salomonsson Maya, Kopac Peter, Koren Ana, Bidovec-Stojkovic Urska, Škrgat Sabina, Simonson Oscar E, Yasinska Valentyna, Dahlén Sven-Erik, Pejler Gunnar, Janson Christer, Korosec Peter, Malinovschi Andrei, Hallgren Jenny
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia; Medical Faculty, University of Ljubljana, Ljubljana, Slovenia.
J Allergy Clin Immunol. 2025 Apr;155(4):1310-1320. doi: 10.1016/j.jaci.2024.10.025. Epub 2024 Nov 7.
Therapies targeting IL-5 or its receptor (IL-5Rα) are currently used to treat patients with severe eosinophilic asthma.
We sought to investigate the impact of anti-IL-5 and anti-IL-5Rα biological therapies on mast cells (MCs) and their progenitors.
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.
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. In addition, IL-5 promoted the proliferation and/or survival of isolated human MC progenitors. Furthermore, patients with severe asthma from 2 independent cohorts demonstrated a reduction in 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 T2 cells. Finally, the blood MC progenitors remaining after anti-IL-5Rα (benralizumab) treatment exhibited a downregulated expression of genes involved in growth and proliferation.
This study introduces the possibility that the clinical effects of targeting IL-5/IL-5Rα in severe asthma may also involve reduction of MC populations.
目前，针对白细胞介素-5（IL-5）或其受体（IL-5Rα）的疗法被用于治疗重度嗜酸性粒细胞性哮喘患者。
我们试图研究抗IL-5和抗IL-5Rα生物疗法对肥大细胞（MCs）及其祖细胞的影响。
研究了小鼠肺和骨髓以及人肺和血液中MCs及其祖细胞表面IL-5Rα的表达。对在有或无IL-5存在的情况下培养的分离的人MC祖细胞进行体外分析。对重度哮喘患者在接受抗IL-5（美泊利单抗）或抗IL-5Rα（贝那利珠单抗）治疗前后的循环MC祖细胞进行定量。在抗IL-5Rα治疗前后对MC祖细胞进行基因表达分析。
约50%的人原发性肺MCs和30%来自过敏性哮喘个体的人MC祖细胞表达IL-5Rα。在轻度至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祖细胞的比例升高。此外，IL-5促进了分离的人MC祖细胞的增殖和/或存活。此外，来自2个独立队列的重度哮喘患者在接受抗IL-5或抗IL-5Rα治疗后，血液中的MC祖细胞减少。这与哮喘控制改善以及血液嗜酸性粒细胞和2型细胞减少有关。最后，抗IL-5Rα（贝那利珠单抗）治疗后剩余的血液MC祖细胞表现出参与生长和增殖的基因表达下调。
本研究提出了一种可能性，即针对重度哮喘中IL-5/IL-5Rα的临床效果可能还涉及MC群体的减少。
