Treatment with Anti-IL5 (Mepolizumab) Restores Eosinophil  Kinetics in Blood and Sputum in Patients with Eosinophilic Asthma

Abstract

Background: Mepolizumab (anti-IL-5) is a successful biological for treatment of moderate-to-severe T2 eosinophil asthma. However, nothing is known regarding the effect of this treatment on the kinetics of eosinophils and basophils and their progenitors in situ. Therefore, these kinetics were determined by stable isotope labelling in blood and sputum of patients with moderate to severe eosinophilic asthma. Methods: Cellular kinetics were determined by pulse-chase labelling with 6,6- 2 H 2 -glucose of patients with moderate to severe eosinophilic asthma who were treated short term (4 days) and long term (84 days) with mepolizumab (n=10) or placebo (n=10). 2 H-enrichment in DNA of eosinophils and basophils was determined by GC-MS. Results: Treatment with mepolizumab induced a fast eosinopenia in peripheral blood associated with no effect on CD34+ eosinophil progenitors. In contrast, the loss of DNA enrichment in blood eosinophils was significantly delayed (p<0.001) in the short-term treated group compared to placebo, whereas no such effect on kinetics was measured in the long-term treated group. Loss of label in sputum eosinophils was faster in both mepolizumab treated groups. In contrast, kinetics of blood basophils was not affected by treatment with mepolizumab. Conclusions: Our data fit with the hypothesis that IL-5 increases the number of IL-5 responsive progenitors leading to reactive eosinophilia in blood and tissues without affecting differentiation of eosinophils in the bone marrow per se . The quick eosinopenia and delayed kinetics induced by short-treatment with mepolizumab imply that IL-5 controls the exchange of eosinophils to and from the tissues. Long-term treatment with mepolizumab restores the kinetics as normally found in homeostasis.