Anti-IL5 mepolizumab minimally influences residual blood eosinophils in severe asthma

Abstract

Neutralising antibodies against the cytokine interleukin (IL)-5 have become widely used for the control of severe eosinophilic asthma. Remarkably, patients receiving neutralising anti-IL5 biological therapies retain a very stable population of residual blood eosinophils. Whether these residual eosinophils are endowed with particular biological activity has not yet been studied but is of importance in predicting potential long-term effects of IL5 neutralisation in patients. To tackle the effect of IL5 depletion on residual eosinophils, we used a comparative RNA-sequencing approach and compared the gene expression program of eosinophils arising in IL5-depleted or IL5-replete human or murine hosts, at steady-state in vivo and following in vitro stimulation with the eosinophil-activating alarmin IL33. We compared blood eosinophils from patients with severe allergic eosinophilic asthma treated with anti-IL5 mepolizumab therapy to those of healthy controls and matched asthma patients receiving anti-IgE omalizumab therapy. We made similar comparisons on bone marrow eosinophils from mice genetically deficient or not for IL5. We report that restriction of IL5 availability did not elicit any detectable transcriptional response in steady-state residual eosinophils in mepolizumab-treated patients or IL5-deficient mice, and influenced only a handful of genes in their response to IL33. Together, these results support the notion that treatment with IL5 neutralising antibodies spares a pool of circulating residual eosinophils largely resembling those of healthy individuals.

Subsets of Eosinophils in Asthma, a Challenge for Precise Treatment

“…They observed that there was virtually no difference in the gene expression program of residual eosinophils from mepolizumab-treated patients compared to the eosinophils of the healthy controls and omalizumab-treated patients at steady state. These results, therefore, support the idea that eosinophil endotyping does not occur in asthma and that anti-IL-5 biologicals do not act by modulating this process [ 150 ]. Forthcoming studies should, therefore, assess and compare the heterogeneity of blood (and possibly bone marrow) eosinophils in asthma (or other eosinophilic disorders) patients with different phenotypes [ 2 ].…”

The emerging roles of eosinophils: Implications for the targeted treatment of eosinophilic-associated inflammatory conditions

“…However, a recent study analyzing gene expression of human or murine eosinophils at steady-state conditions in vivo and after stimulation in vitro , showed that restriction of IL5 availability did not elicit any detectable transcriptional response in steady-state residual eosinophils, and influenced only a few genes in their response to in vitro stimulation. Ultimately, this seems to suggest that targeting the IL5 pathways spares a pool of circulating residual eosinophils largely resembling those of healthy individuals ( Von Hulst, 2021 ).…”

“…First, the existence of distinct eosinophils subtypes that are differently involved in these conditions could give important data for better disease management. Importantly, only rEos were described as IL-5 independent cells ( Von Hulst, 2021 ). The data suggest that basal levels of eosinophils left after absolute IL-5 depletion (mepolizumab or reslizumab) are a steady-state rEos population, and anti-IL-5 treatment affected eosinophils are in inflammatory processes involved iEos ( Januskevicius et al, 2020 ; Mesnil et al, 2016 ; Abdala-Valencia et al, 2016 , 2018 ).…”

Eosinophils as Drivers of Severe Eosinophilic Asthma: Endotypes or Plasticity?

“…In addition, eosinophilic exacerbations (sputum eosinophils >2%) still make up to 50% of residual asthma exacerbations in patients receiving mepolizumab, in spite of marked reductions in blood eosinophil counts [81]. It was also noted that mepolizumab does not alter the expression of activation markers on residual lung tissue eosinophils [82], nor does it elicit any detectable transcriptional alterations in blood eosinophils [83]. In addition, the risk for SEA exacerbations is better predicted with a combination of elevated blood eosinophil counts and elevated fractional exhaled nitrogen oxide (FeNO) than either parameter alone [73,84], and elevated FeNO levels are good predictors of eosinophilic exacerbations in mepolizumab-treated patients [81].…”

“…We argue that these views may be oversimplified given the current gaps in our knowledge for both murine and human eosinophil biology. To illustrate this notion and point toward important factors to consider in future studies of eosinophil endotypes, we will resort to a recent study from our laboratory [83].…”