Anti-IL-5 (mepolizumab) therapy induces bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics

Abstract

Background: Eosinophils develop from CD34+ progenitors under the influence of IL-5. Atopic asthmatic individuals have increased numbers of mature eosinophils and eosinophil progenitors within their bone marrow and bronchial mucosa. We have previously reported that anti-IL-5 monoclonal antibody treatment decreases total bone marrow and bronchial mucosal eosinophil numbers in asthma. Objective: Using an anti-IL-5 monoclonal antibody, we examined the role of IL-5 in eosinophil development within the bone marrow and bronchial mucosa in asthma. Methods: Blood, bone marrow, and airway mucosal biopsy specimens were examined before and after anti-IL-5 (mepolizumab) treatment of asthmatic individuals in a double-blind, placebo-controlled trial. Numbers of mature and immature eosinophils were measured by histologic stain (bone marrow myelocytes, metamyelocytes, and mature eosinophils), flow cytometry (bone marrow and blood CD34+/IL-5Rα+ cells), enumeration of bone marrow-derived eosinophil/basophil colony-forming units in methylcellulose culture, and sequential immunohistochemistry and in situ hybridization (bronchial mucosal CD34+/IL-5Rα mRNA+ cells). Results: Mepolizumab decreased mature eosinophil numbers in the bone marrow by 70% (P = .017) in comparison with placebo and decreased numbers of eosinophil myelocytes and metamyelocytes by 37% (P = .006) and 44% (P = .003), respectively. However, mepolizumab had no effect on numbers of blood or bone marrow CD34+, CD34+/IL-5Rα+ cells, or eosinophil/basophil colony-forming units. There was a significant decrease in bronchial mucosal CD34+/IL-5Rα mRNA+ cell numbers in the anti-IL-5 treated group (P = .04). Conclusion: These data suggest that anti-IL-5 therapy might induce partial maturational arrest of the eosinophil lineage in the bone marrow. The reduction in airway CD34+/IL-5 mRNA+ cell numbers suggests that IL-5 might also be required for local tissue eosinophilopoiesis.