Anti-IL-5 (mepolizumab) therapy induces bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics.
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.
Menzies-Gow
Andrew
A
Allergy and Clinical Immunology, National Heart and Lung Institute, Faculty of Medicine, Imperial College, London.
Flood-Page
Patrick
P
Sehmi
Roma
R
Burman
John
J
Hamid
Qutayba
Q
Robinson
Douglas S
DS
Kay
A Barry
AB
Denburg
Judah
J
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
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018952:Antigens, CD34; D015848:Interleukin-5; C434107:mepolizumab