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

doi:10.1164/rccm.201611-2234OC

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 journal › Article › peer-review

89 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 language	English (US)
Pages (from-to)	1385-1395
Number of pages	11
Journal	American journal of respiratory and critical care medicine
Volume	196
Issue number	11
DOIs	https://doi.org/10.1164/rccm.201611-2234OC
State	Published - Dec 1 2017
Externally published	Yes

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.

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. The authors thank the participants in this study for their time and commitment to this research. The authors thank GlaxoSmithKline for kindly providing mepolizumab as a gift. The authors thank Larissa De Lain, B.S., and Lei Shi, Ph.D., for processing BAL samples; Elizabeth Schwantes, M.S., Paul Fichtinger, B.S., Ellen Cook, Ph.D., and Jim Stahl, Ph.D., for purification of blood and BAL eosinophils through the Laboratory Core (S.M., Principal Investigator [PI]); Larissa De Lain, B.S., for assistance with RT-qPCR work; Jami Hauer, B.S., for assistance with ELISAs; Drew Roenneburg, B.S., for EPX staining of biopsy tissue; Mary Jo Jackson, B.S.N., Michele Wolff, B.S.N., Holly Eversoll, B.S.N., and Evelyn Falibene, B.S., for participant recruitment and screening; Richard Cornwell, M.D., and Keith Meyer, M.D., for assistance with bronchoscopies through the Clinical Core (L.C.D., PI); Gina Crisafi, B.S., for assistance through the Administrative Core (N.N.J., PI), and Kathleen Schell, B.S., and Dagna Sheerar, B.S., for advice on flow cytometry.

Publisher Copyright:
Copyright © 2017 by the American Thoracic Society.

Keywords

Allergen challenge
IL-3 receptor
IL-5

Publisher link

10.1164/rccm.201611-2234OC

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736971

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@article{2e2da7a9cb35485a836310f58c9e9bb4,

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

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.",

keywords = "Allergen challenge, IL-3 receptor, IL-5",

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

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. 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. The authors thank the participants in this study for their time and commitment to this research. The authors thank GlaxoSmithKline for kindly providing mepolizumab as a gift. The authors thank Larissa De Lain, B.S., and Lei Shi, Ph.D., for processing BAL samples; Elizabeth Schwantes, M.S., Paul Fichtinger, B.S., Ellen Cook, Ph.D., and Jim Stahl, Ph.D., for purification of blood and BAL eosinophils through the Laboratory Core (S.M., Principal Investigator [PI]); Larissa De Lain, B.S., for assistance with RT-qPCR work; Jami Hauer, B.S., for assistance with ELISAs; Drew Roenneburg, B.S., for EPX staining of biopsy tissue; Mary Jo Jackson, B.S.N., Michele Wolff, B.S.N., Holly Eversoll, B.S.N., and Evelyn Falibene, B.S., for participant recruitment and screening; Richard Cornwell, M.D., and Keith Meyer, M.D., for assistance with bronchoscopies through the Clinical Core (L.C.D., PI); Gina Crisafi, B.S., for assistance through the Administrative Core (N.N.J., PI), and Kathleen Schell, B.S., and Dagna Sheerar, B.S., for advice on flow cytometry. Publisher Copyright: Copyright {\textcopyright} 2017 by the American Thoracic Society.",

year = "2017",

month = dec,

day = "1",

doi = "10.1164/rccm.201611-2234OC",

language = "English (US)",

volume = "196",

pages = "1385--1395",

journal = "American Review of Respiratory Disease",

issn = "1073-449X",

publisher = "American Thoracic Society",

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TY - JOUR

T1 - Mepolizumab attenuates airway eosinophil numbers, but not their functional phenotype, in asthma

AU - Kelly, Elizabeth A.

AU - Esnault, Stephane

AU - Liu, Lin Ying

AU - Evans, Michael D.

AU - Johansson, Mats W.

AU - Mathur, Sameer

AU - Mosher, Deane F.

AU - Denlinger, Loren C.

AU - Jarjour, Nizar N.

N1 - 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. 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. The authors thank the participants in this study for their time and commitment to this research. The authors thank GlaxoSmithKline for kindly providing mepolizumab as a gift. The authors thank Larissa De Lain, B.S., and Lei Shi, Ph.D., for processing BAL samples; Elizabeth Schwantes, M.S., Paul Fichtinger, B.S., Ellen Cook, Ph.D., and Jim Stahl, Ph.D., for purification of blood and BAL eosinophils through the Laboratory Core (S.M., Principal Investigator [PI]); Larissa De Lain, B.S., for assistance with RT-qPCR work; Jami Hauer, B.S., for assistance with ELISAs; Drew Roenneburg, B.S., for EPX staining of biopsy tissue; Mary Jo Jackson, B.S.N., Michele Wolff, B.S.N., Holly Eversoll, B.S.N., and Evelyn Falibene, B.S., for participant recruitment and screening; Richard Cornwell, M.D., and Keith Meyer, M.D., for assistance with bronchoscopies through the Clinical Core (L.C.D., PI); Gina Crisafi, B.S., for assistance through the Administrative Core (N.N.J., PI), and Kathleen Schell, B.S., and Dagna Sheerar, B.S., for advice on flow cytometry. Publisher Copyright: Copyright © 2017 by the American Thoracic Society.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

KW - Allergen challenge

KW - IL-3 receptor

KW - IL-5

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U2 - 10.1164/rccm.201611-2234OC

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C2 - 28862877

AN - SCOPUS:85038128366

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EP - 1395

JO - American Review of Respiratory Disease

JF - American Review of Respiratory Disease

IS - 11

ER -

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

Abstract

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