Mepolizumab attenuates airway eosinophil numbers, but not their functional phenotype, in asthma

Elizabeth A. Kelly, Stephane Esnault, Lin Ying Liu, Michael D. Evans, Mats W. Johansson, Sameer Mathur, Deane F. Mosher, Loren C. Denlinger, Nizar N. Jarjour

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Rationale: Mepolizumab, an IL-5–blocking antibody, reduces exacerbations in patients with severe eosinophilic asthma. Mepolizumab arrests eosinophil maturation; however, the functional phenotype of eosinophils that persist in the blood and airway after administration of IL-5 neutralizing antibodies has not been reported. Objectives: To determine the effect of anti–IL-5 antibody on the numbers and phenotypes of allergen-induced circulating and airway eosinophils. Methods: Airway inflammation was elicited in participants with mild allergic asthma by segmental allergen challenge before and 1 month after a single intravenous 750-mg dose of mepolizumab. Eosinophils were examined in blood, bronchoalveolar lavage, and endobronchial biopsies 48 hours after challenge. Measurements and Main Results: Segmental challenge without mepolizumab induced a rise in circulating eosinophils, bronchoalveolar lavage eosinophilia, and eosinophil peroxidase deposition in bronchial mucosa. IL-5 neutralization before allergen challenge abolished the allergen-induced rise in circulating eosinophils and expression of IL-3 receptors, whereas airway eosinophilia and eosinophil peroxidase deposition were blunted but not eliminated. Before mepolizumab treatment, bronchoalveolar lavage eosinophils had more surface IL-3 and granulocyte–monocyte colony–stimulating factor receptors, CD69, CD44, and CD23 and decreased IL-5 and eotaxin receptors than blood eosinophils. This activation phenotype indicated by bronchoalveolar lavage eosinophil surface markers, as well as the release of eosinophil peroxidase by eosinophils in the bronchial mucosa, was maintained after mepolizumab. Conclusions: Mepolizumab reduced airway eosinophil numbers but had a limited effect on airway eosinophil activation markers, suggesting that these cells retain functionality. This observation may explain why IL-5 neutralization reduces but does not completely eradicate asthma exacerbations.

Original languageEnglish (US)
Pages (from-to)1385-1395
Number of pages11
JournalAmerican journal of respiratory and critical care medicine
Volume196
Issue number11
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

Bibliographical note

Funding Information:
Supported by National Institutes of Health Program Project grant P01 HL88594, General Clinical Research Center grant M01 RR03186, and Clinical and Translational Science Award grant UL1 RR25011. Mepolizumab was a gift from GlaxoSmithKline. GSK had no role in the conduct of the study, data analysis or interpretation, preparation of the manuscript, or the decision to submit the manuscript for publication.

Keywords

  • Allergen challenge
  • IL-3 receptor
  • IL-5

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