title: Anti-IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL-5 and IL-5 receptor levels.
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 alpha 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 alpha and lymphocyte IL-5 production after anti-IL-5 therapy suggest an endogenous IL-5 autoregulatory pathway.
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
authors.forename: Miguel L
authors.initials: ML
authors.lastname: Stein
authors.forename: Joyce M
authors.initials: JM
authors.lastname: Villanueva
authors.forename: Bridget K
authors.initials: BK
authors.lastname: Buckmeier
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yamada
authors.forename: Alexandra H
authors.initials: AH
authors.lastname: Filipovich
authors.forename: Amal H
authors.initials: AH
authors.lastname: Assa'ad
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D004802:Eosinophilia / Q000097:blood / Q000188:drug therapy*; D004804:Eosinophils / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000097:blood*; D008297:Male; D008875:Middle Aged; D053649:Receptors, Interleukin-5 / Q000097:blood / Q000187:drug effects*; D016176:T-Lymphocyte Subsets / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D015848:Interleukin-5; D053649:Receptors, Interleukin-5; C434107:mepolizumab