P Abigail Alvarado-Vazquez, Erika Mendez-Enriquez, Maya Salomonsson, Peter Kopac, Ana Koren, Urska Bidovec-Stojkovic, Sabina Škrgat, Oscar E Simonson, Valentyna Yasinska, Sven-Erik Dahlén, Gunnar Pejler, Christer Janson, Peter Korosec, Andrei Malinovschi, Jenny Hallgren
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引用次数: 0
Abstract
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.
背景：目前，针对白细胞介素-5（IL-5）或其受体（IL-5Rα）的疗法被用于治疗严重嗜酸性粒细胞性哮喘患者：目的：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：方法：研究了小鼠肺部和骨髓中的肥大细胞及其祖细胞以及人类肺部和血液中的肥大细胞及其祖细胞表面IL-5Rα的表达。体外分析了在有或没有 IL-5 的情况下培养的分离人 MC 祖细胞。在抗IL-5（mepolizumab）或抗IL-5Rα（benralizumab）治疗前后，对重症哮喘患者循环中的MC祖细胞进行了定量分析。在抗IL-5Rα治疗前后对MC祖细胞进行了基因表达分析：结果：约50%的人类原发性肺MC和30%来自过敏性哮喘患者的人类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祖细胞的比例升高。此外，IL-5 还能促进分离的人类 MC 祖细胞的增殖和/或存活。此外，来自两个独立队列的重症哮喘患者在接受抗IL-5或抗IL-5Rα治疗后，血液中的MC祖细胞减少。这与哮喘控制的改善以及血液中嗜酸性粒细胞和Th2细胞的减少有关。最后，抗IL-5Rα（benralizumab）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：本研究提出了一种可能性，即在重症哮喘中靶向 IL-5/IL-5Rα 的临床效果也可能涉及 MC 群体的减少。
期刊介绍：
The Journal of Allergy and Clinical Immunology is a prestigious publication that features groundbreaking research in the fields of Allergy, Asthma, and Immunology. This influential journal publishes high-impact research papers that explore various topics, including asthma, food allergy, allergic rhinitis, atopic dermatitis, primary immune deficiencies, occupational and environmental allergy, and other allergic and immunologic diseases. The articles not only report on clinical trials and mechanistic studies but also provide insights into novel therapies, underlying mechanisms, and important discoveries that contribute to our understanding of these diseases. By sharing this valuable information, the journal aims to enhance the diagnosis and management of patients in the future.
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