Eosinophil's Role Remains Uncertain as Anti–Interleukin-5 only Partially Depletes Numbers in Asthmatic Airway

Abstract

The role of eosinophils as effector cells in asthma pathogenesis has been questioned since an anti-interleukin (IL)-5 monoclonal antibody (mepolizumab), which depleted blood and sputum eosinophils, failed to inhibit allergen-induced bronchoconstriction and airway hyperresponsiveness. However, the effect of IL-5 blockade on tissue eosinophils was not examined. We sought to determine whether mepolizumab depletes airway tissue eosinophils and their products. Twenty-four patients with mild asthma received three intravenous doses of either 750 mg of mepolizumab or placebo in a randomized, double-blind, parallel-group fashion over 20 weeks. Mepolizumab produced a median decrease from baseline of 55% for airway eosinophils (interquartile range, 29-89%; p = 0.009 versus placebo), 52% for bone marrow eosinophils (45-76%, p = 0.003), and 100% for blood eosinophils (range, 67-100%, p = 0.02). Mepolizumab had no appreciable effect on bronchial mucosal staining of eosinophil major basic protein. There were no significant changes in clinical measures of asthma (airway hyperresponsiveness, FEV1, and peak flow recordings) between the mepolizumab and placebo-treated groups. Anti-IL-5 treatment reduces but does not deplete airway or bone marrow eosinophils. The role of the eosinophil remains uncertain. Further clinical studies in asthma with more effective antieosinophil strategies are required.

Granulocyte-Macrophage Colony-Stimulating Factor Is Required for Bronchial Eosinophilia in a Murine Model of Allergic Airway Inflammation

“…Our findings are relevant to the interpretation of clinical trials in asthma on the effect of neutralizing Abs to IL-5, which showed little benefit. In treated patients, substantial numbers of eosinophils were detected in bronchial biopsies, and it was suggested that GM-CSF may have contributed to eosinophil survival in the tissues (41). A second mechanism in GM-CSF Ϫ/Ϫ mice involves excessive IFN-␥ production in the airways, eliciting the generation of IFN-␥-inducible chemokines, which may antagonize CCR3 ligands and impair eosinophil migration to the airways.…”

Improving the diagnosis of eosinophilic asthma

“…The most important role for blood eosinophils is probably its role in identifying patients who are likely to respond to treatment with the new biological agents against Type 2 inflammation [25]. However, they seem to be less suitable to monitor treatment response, given the fact that biologicals such as anti-IL-5 strongly reduce blood eosinophils but affect tissue eosinophils to a much lesser extent [28]. This may also explain why anti-IL-5 treatment can effectively reduce exacerbations and systemic corticosteroid requirement but has only little effect on the forced expiratory volume in 1 s (FEV 1 ) [16].…”

Marked Airway Eosinophilia Prevents Development of Airway Hyper-responsiveness During an Allergic Response in IL-5 Transgenic Mice

“…For example, Leckie et al (7) used anti-IL-5 mAb to treat patients with mild asthma; it reduced the number of blood eosinophils and sputum eosinophils, but did not influence the allergen-induced late response or AHR. Recently, anti-IL-5 mAb only partially decreased airway tissue eosinophilia, making interpretation of the roles of IL-5 and eosinophils in human asthma even more difficult (8). In mice neutralization of IL-5 prevented allergen-induced AHR (9), and overproduction of IL-5 in the airways led to AHR (10).…”