Reviews and Feature Articles: Rapid Publications
Anti–IL-5 (mepolizumab) therapy induces bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics

https://doi.org/10.1067/mai.2003.1382Get rights and content

Abstract

Background: Eosinophils develop from CD34+ progenitors under the influence of IL-5. Atopic asthmatic individuals have increased numbers of mature eosinophils and eosinophil pro-genitors 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.

Section snippets

Study design

The clinical study of anti–IL-5 (mepolizumab) in asthma has previously been described.18 In brief, 24 volunteers with mild asthma were recruited to a 2-center, double blind, placebo-controlled, parallel-group study. At baseline, venous blood sampling, bone marrow aspiration, and fiberoptic bronchoscopy with endobronchial biopsy were performed. Two days later, the study medication (750 mg mepolizumab) or an equal volume of placebo was given as an intravenous infusion in a double-blind fashion.

Results

Eleven volunteers were randomized to receive mepolizumab, and 13 volunteers were randomized to receive placebo.

Discussion

We have demonstrated that IL-5 blockade with mepolizumab significantly reduced terminal differentiation of eosinophils (myelocytes, metamyelocytes, and mature eosinophils) within the bone marrow but had no significant overall effect on numbers of early eosinophil progenitors (CD34+/IL-5Rα+ cells or Eo/B-CFUs). Anti–IL-5 also significantly decreased numbers of CD34+/IL-5Rα mRNA+ cells in the bronchial mucosa. These findings are compatible with anti–IL-5–induced maturational arrest of bone marrow

References (27)

  • MJ Leckie et al.

    Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response

    Lancet

    (2000)
  • J Bosquet et al.

    Eosinophilic inflammation in asthma

    New Engl J Med

    (1990)
  • RT Palframan et al.

    Mechanisms of acute eosinophil mobilization from the bone marrow stimulated by interleukin-5: the role of specific adhesion molecules and phosphatidylinositol 3-kinase

    J Exp Med

    (1998)
  • Cited by (251)

    View all citing articles on Scopus

    Reprint requests: Judah Denburg, MD, Department of Medicine, McMaster University, HSC 3V46, 1200 Main Street West, Hamilton, Ontario, Canada, L8N 3Z5.

    View full text