Anti-IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL-5 and IL-5 receptor levels

Miguel L. Stein, Joyce M. Villanueva, Bridget K. Buckmeier, Yoshiyuki Yamada, Alexandra H. Filipovich, Amal H. Assa'ad, Marc E. Rothenberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Anti-IL-5 might be a useful therapeutic agent for eosinophilic disorders, yet its immunologic consequences have not been well characterized. Objective: We sought to characterize the hematologic and immunologic effects of anti-IL-5 in human subjects. Methods: The effects of 3-month infusions of mepolizumab were assessed in 25 patients with a variety of eosinophilic syndromes. Samples with increased IL-5 levels after therapy were analyzed by using size exclusion filtration. Immunoreactive IL-5 fraction and plasma samples were subsequently precipitated with saturating concentrations of protein A/G. Results: Twenty-three patients responded to anti-IL-5 therapy with a decrease in blood eosinophil counts and a reduced percentage of CCR3+ cells by 20- and 13-fold, respectively (P < .0001). Responsiveness was not related to the levels of baseline plasma IL-5 or the presence of FIP1L1-PDGFRA fusion gene. Persistently decreased blood eosinophilia remained for 3 months after final infusion in 76% of subjects. Therapy was associated with a large increase in blood IL-5 levels, likely because of a circulating IL-5/mepolizumab complex precipitated with protein A/G, a significant increase in eosinophil IL-5 receptor α expression, and increased percentage of CD4+ and CD8+ cells producing intracellular IL-5 (P < .05). Additionally, anti-IL-5 therapy decreased eotaxin-stimulated eosinophil shape change ex vivo. Conclusions: Anti-IL-5 therapy induces a dramatic and sustained decrease in blood eosinophilia (including CCR3+ cells), decreased eosinophil activation, and increased circulating levels of IL-5 in a variety of eosinophilic disorders. Increased levels of IL-5 receptor α and lymphocyte IL-5 production after anti-IL-5 therapy suggest an endogenous IL-5 autoregulatory pathway.

Original languageEnglish
Pages (from-to)1473-1483.e4
JournalJournal of Allergy and Clinical Immunology
Volume121
Issue number6
DOIs
StatePublished - Jun 2008
Externally publishedYes

Funding

FundersFunder number
CCHMC
USPHS GCRCM01 RR 08084
National Institutes of Health
U.S. Food and Drug Administration002313
National Center for Research ResourcesM01RR008084
Burroughs Wellcome Fund
American Physicians Fellowship for Medicine in Israel
Buckeye Career Center Foundation

    Keywords

    • Anti-IL-5
    • IL-5
    • cytokines
    • eosinophilia
    • esophagitis
    • hypereosinophilic
    • inflammation
    • mepolizumab

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