title: 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 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-5Ralpha(+) 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-5Ralpha 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-5Ralpha(+) cells, or eosinophil/basophil colony-forming units. There was a significant decrease in bronchial mucosal CD34(+)/IL-5Ralpha mRNA(+) cell numbers in the anti-IL-5 treated group (P =.04).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Allergy and Clinical Immunology, National Heart and Lung Institute, Faculty of Medicine, Imperial College, London.
authors.forename: Andrew
authors.initials: A
authors.lastname: Menzies-Gow
authors.forename: Patrick
authors.initials: P
authors.lastname: Flood-Page
authors.forename: Roma
authors.initials: R
authors.lastname: Sehmi
authors.forename: John
authors.initials: J
authors.lastname: Burman
authors.forename: Qutayba
authors.initials: Q
authors.lastname: Hamid
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Robinson
authors.forename: A Barry
authors.initials: AB
authors.lastname: Kay
authors.forename: Judah
authors.initials: J
authors.lastname: Denburg
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D018952:Antigens, CD34 / Q000032:analysis; D001249:Asthma / Q000097:blood / Q000188:drug therapy*; D001854:Bone Marrow Cells / Q000187:drug effects*; D001980:Bronchi / Q000187:drug effects*; D004311:Double-Blind Method; D004804:Eosinophils / Q000187:drug effects* / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D015848:Interleukin-5 / Q000032:analysis
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018952:Antigens, CD34; D015848:Interleukin-5; C434107:mepolizumab