Anti–IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL-5 and IL-5 receptor levels
Received 22 January 2008; received in revised form 21 February 2008; accepted 25 February 2008. published online 14 April 2008.
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.
aDivision of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
bDivision of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
Reprint requests: Marc E. Rothenberg, MD, PhD, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 7028, Cincinnati, OH 45229.
Supported by Food and Drug Administration grant no. FD-R 002313, the Burroughs Wellcome Fund, the CURED (Campaign Urging Research for Eosinophilic Diseases) Foundation, and the Buckeye Foundation. We are grateful to the Translational Research Office at CCHMC for their assistance and the General Clinical Research Center at CCHMC (supported by USPHS GCRC grant no. M01 RR 08084 from the National Center for Research Resources, National Institutes of Health). Miguel L. Stein is a recipient of a fellowship from the American Physicians Fellowship for Medicine in Israel.
Disclosure of potential conflict of interest: A. H. Assa'ad has consulting arrangements with and has received research support from GlaxoSmithKline and has served as an expert witness in food allergy and anaphylaxis litigation. M. E. Rothenberg has consulting arrangements with Merck, Ception Therapeutics, and Medacorp; is on the speakers' bureau for Merck; has received research support from the National Institutes of Health, the Food Allergy and Anaphylaxis Network, Ception Therapeutics, and Merck; and is on the advisory board for the National Institutes of Health and the American Partnership for Eosinophilic Disorders. The rest of the authors have declared that they have no conflict of interest.
ABSTRACT