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

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

Keywords

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

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