Therapeutic efficacy of IL-17A neutralization with corticosteroid treatment in a model of antigen-driven mixed-granulocytic asthma

Abstract

Many mouse models of allergic asthma exhibit eosinophil-predominant cellularity rather than the mixed granulocytic cytology in steroid-unresponsive severe disease. Therefore, we sought to implement a novel mouse model of antigen-driven, mixed-granulocytic, severe allergic asthma to determine biomarkers of the disease process and potential therapeutic targets. C57BL/6J, IL-6-/-, and IL-6R-/- mice were injected with an emulsion of Complete Freund's Adjuvant and House Dust Mite antigen (CFA/HDM) on day 1. Dexamethasone, a lymphocyte-depleting biological, or anti-IL-17A were administered during intranasal HDM challenge on days 19-22. On day 23, the CFA/HDM model elicited mixed bronchoalveolar lavage (BAL) cellularity (typically 80% neutrophils and 10% eosinophils), airway hyperresponsiveness (AHR) to methacholine, diffusion impairment, lung damage, body weight loss, corticosteroid resistance, and elevated levels of serum amyloid A (SAA), pro-inflammatory cytokines, and Th1/Th17 cytokines compared to eosinophilic models of HDM-driven allergic airway disease. BAL cells in IL-6- or IL-6R-deficient mice were predominantly eosinophilic and associated with elevated Th2 and reduced Th1/Th17 cytokine production, along with an absence of SAA. Nevertheless, AHR remained in IL-6-deficient mice even when administered dexamethasone. However, combined administration of anti-IL-17A and systemic corticosteroid significantly attenuated both overall and neutrophilic airway inflammation, and also reduced AHR and body weight loss. Inhibition of IL-17A combined with systemic corticosteroid treatment during antigen-driven exacerbations may provide a novel therapeutic approach to prevent the pathological pulmonary and constitutional changes that greatly impact patients with the mixed-granulocytic endotype of severe asthma.

Has2 Regulates the Development of Ovalbumin-Induced Airway Remodeling and Steroid Insensitivity in Mice

“…Notably, this refractory airway inflammation was relieved by combined therapy with steroid and anti-IL-17A antibodies (Figure 6C). Recent literature reported that combined administration of anti-IL-17A Ab and corticosteroid significantly attenuated steroidinsensitive airway inflammation, AHR, and body weight loss (42). Furthermore, Pathinayake et al reported that heightened ER stress is associated with severe eosinophilic and neutrophilic inflammation in asthma and ER stress genes displayed a significant correlation with classic Th2 genes and Th17 (IL-17F/CXCL1) genes (43).…”

Early IL-17A Prevention Rather Than Late IL-17A Neutralization Attenuates Toluene Diisocyanate-Induced Mixed Granulocytic Asthma

“…Plus, we speculated that IL-17A mab could be administered when the asthmatics initially need systemic steroid treatment, in line with the findings of a work conducted in a HDM/CFA-induced mixed granulocytic asthma model showing that combined administration of anti-IL-17A and systemic corticosteroid significantly attenuated both overall and neutrophilic airway inflammation. 15 Actually, the challenging task of targeting severe asthma is further complicated by the complex pathobiology of asthma., but it still hits us that interfere with IL-17A signaling during an earlier phase would be more beneficial to severe asthmatics in clinical practice. However, the exact time-point of intervention is needed to be further explored in the future.…”

“… 13 14 Even the latest study found that IL-17A blocking antibody significantly inhibited airway neutrophil infiltration, but promoted eosinophil accumulation in a HDM/complete Freunds adjunvant (CFA)-induced mixed granulocytic asthma model. 15 In addition, IL-17A directly enhances IL-13-driven airway inflammation. 16 17 Indeed, researchers have already detected elevated IL-17A concentrations in TDI-induced asthma model and discovered that IL-17A neutralization could alleviate TDI-induced airway inflammation and remodeling.…”

The Diagnostic Utility of Interleukin-13 and Interleukin-17A using the ELISA Technique in Asthmatic Children

“…7 When Th2 pathway is downregulated by corticosteroids, the Th17 pathway is activated. 8,9 Medical diagnostic tests should have the ability to confirm the presence of a disease and the capacity to discriminate between those with disease and healthy individuals. Sensitivity and specificity with a single cutoff point are among the most widely used characteristics for diagnostic accuracy.…”