Anti-IL5 in mild asthma alters rhinovirus-induced macrophage, B cell and neutrophil responses

Eosinophils are considered to drive the pathophysiology in asthma and therefore treatment is focused on reducing eosinophil numbers. Mepolizumab, a humanized monoclonal antibody that neutralizes interleukin 5 (IL-5), efficiently attenuates both systemic and local eosinophils but proved clinically effective only in severe eosinophilic asthma. To study the contribution of eosinophils to the pathophysiology in mild asthma we performed a placebo-controlled double-blind trial with mepolizumab after which patients were subjected to a rhinovirus (RV)16 challenge to induce loss of asthma control. Mepolizumab attenuated eosinophil numbers and reduced their activation status and enhanced NK cells. However, both FEV1, FVC and FeNO remained unaffected at baseline and after RV16. Furthermore, mepolizumab enhanced circulating NK cells at baseline. Upon RV16 challenge mepolizumab prevented reduction of B lymphocytes and macrophages as well as the increase of neutrophils and myeloperoxidase release. Furthermore, mepolizumab enhanced sIgA production and reduced tryptase in BALF. Finally, mepolizumab particularly affected RV16-induced MIP-3A, VEGF-A and IL-1RA production in BALF. Interestingly, patients receiving mepolizumab as compared to those receiving placebo had a significant enhanced viral load (p=0.0404). In mild asthma we found that IL-5, likely via eosinophils, drives both innate (neutrophils, macrophages, sIgA, tryptase, IL-1RA, VEGF-A and MIP-3a) and adaptive (B lymphocytes) immune responses to the RV16 challenge. These findings substantiate the pathophysiological role of IL-5 and eosinophils in mild asthma and lead to a new perspective on therapeutic benefits of reducing eosinophils in asthma.