Targeting of the IL-5 pathway in severe asthma reduces mast cell progenitors

Background: Therapies targeting IL-5 or its receptor (IL-5Ra) are currently used to treat patients with severe eosinophilic asthma. Objective: We sought to investigate the impact of anti-IL-5 and anti-IL-5Ra biological therapies on mast cells (MCs) and their progenitors. Methods: Surface IL-5Ra 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-5Ra (benralizumab) therapy. Gene expression analysis of MC progenitors was performed before and after anti-IL-5Ra therapy. Results: Approximately 50% of the human primary lung MCs and 30% of the human MC progenitors from individuals with allergic asthma expressed IL-5Ra. In patients with mild to moderate allergic asthma and mice with acute allergic airway inflammation, the fraction of IL-5Ra1 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-5Ra 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-5Ra (benralizumab) treatment exhibited a downregulated expression of genes involved in growth and proliferation. Conclusions: This study introduces the possibility that the clinical effects of targeting IL-5/IL-5Ra in severe asthma may also involve reduction of MC populations. (J Allergy Clin Immunol 2025;155:1310-20.)