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.

中文翻译：

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在抗原驱动的混合性粒细胞哮喘模型中用皮质类固醇治疗中和 IL-17A 的治疗效果。

许多过敏性哮喘小鼠模型在类固醇无反应的严重疾病中表现出以嗜酸性粒细胞为主的细胞学，而不是混合粒细胞学。因此，我们寻求实施一种新的抗原驱动、混合粒细胞、严重过敏性哮喘小鼠模型，以确定疾病过程的生物标志物和潜在的治疗目标。C57BL/6J、IL-6-/- 和 IL-6R-/- 小鼠在第 1 天注射完全弗氏佐剂和屋尘螨抗原 (CFA/HDM) 的乳液。在第 19-22 天鼻内 HDM 攻击期间施用抗 IL-17A 或抗 IL-17A。在第 23 天，CFA/HDM 模型引发混合支气管肺泡灌洗 (BAL) 细胞结构（通常为 80% 中性粒细胞和 10% 嗜酸性粒细胞）、气道对乙酰甲胆碱的高反应性 (AHR)、扩散障碍、肺损伤、与 HDM 驱动的过敏性气道疾病的嗜酸性粒细胞模型相比，体重减轻、皮质类固醇抵抗和血清淀粉样蛋白 A (SAA)、促炎细胞因子和 Th1/Th17 细胞因子水平升高。IL-6 或 IL-6R 缺陷小鼠中的 BAL 细胞主要是嗜酸性粒细胞，并且与升高的 Th2 和降低的 Th1/Th17 细胞因子产生有关，同时缺乏 SAA。然而，即使给予地塞米松，AHR 仍存在于 IL-6 缺陷小鼠中。然而，抗 IL-17A 和全身性皮质类固醇的联合给药显着减轻了整体和中性粒细胞气道炎症，并且还减少了 AHR 和体重减轻。