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Mepolizumab Attenuates Airway Eosinophil Numbers, but Not Their Functional Phenotype, in Asthma
Elizabeth A Kelly1, Stephane Esnault1, Lin Ying Liu1
11 Allergy, Pulmonary and Critical Care Medicine Division, Department of Medicine.
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. Clinical trial registered with www.clinicaltrials.gov (NCT00802438).
Insights
Mepolizumab (an IL-5-blocking antibody) reduces airway eosinophils in asthma but doesn't eliminate their activation. This suggests persistent eosinophil functionality may explain why exacerbations are reduced but not fully eradicated.
Area of Science:
- Immunology
- Respiratory Medicine
- Pharmacology
Background:
- Mepolizumab, an interleukin-5 (IL-5) blocking antibody, is effective in reducing exacerbations in severe eosinophilic asthma.
- While mepolizumab inhibits eosinophil maturation, the functional state of residual eosinophils in blood and airways post-treatment remains unclear.
Purpose of the Study:
- To investigate the impact of anti-IL-5 antibody therapy on the quantity and functional phenotype of allergen-induced eosinophils in circulation and airways.
Main Methods:
- Allergic asthma patients underwent segmental allergen challenge before and after mepolizumab treatment.
- Eosinophil analysis was performed on blood, bronchoalveolar lavage (BAL) fluid, and bronchial biopsies 48 hours post-challenge.
Main Results:
- Mepolizumab neutralized allergen-induced increases in circulating eosinophils and IL-3 receptor expression.
- Airway eosinophilia and eosinophil peroxidase deposition were reduced but not eliminated.
- Airway eosinophils exhibited an activated phenotype (higher IL-3, GM-CSF, CD69, CD44, CD23; lower IL-5, eotaxin receptors) that persisted post-mepolizumab.
Conclusions:
- Mepolizumab decreases airway eosinophil counts but has a limited impact on their activation markers, indicating retained functionality.
- Persistent eosinophil activation may contribute to the incomplete eradication of asthma exacerbations despite IL-5 neutralization.
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