Translational Medicine, Genentech Inc, South San Francisco, California, USA.
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Clin Exp Allergy. 2023 Nov;53(11):1187-1197. doi: 10.1111/cea.14406. Epub 2023 Oct 4.
Similar immune responses in the nasal and bronchial mucosa implies that nasal allergen challenge (NAC) is a suitable early phase experimental model for drug development targeting allergic rhinitis (AR) and asthma. We assessed NAC reproducibility and the effects of intranasal corticosteroids (INCS) on symptoms, physiology, and inflammatory mediators.
20 participants with mild atopic asthma and AR underwent three single blinded nasal challenges each separated by three weeks (NCT03431961). Cohort A (n = 10) underwent a control saline challenge, followed by two allergen challenges. Cohort B (n = 10) underwent a NAC with no treatment intervention, followed by NAC with 14 days pre-treatment with saline nasal spray (placebo), then NAC with 14 days pre-treatment with INCS (220 μg triamcinolone acetonide twice daily). Nasosorption, nasal lavage, blood samples, forced expiratory volume 1 (FEV1), total nasal symptom score (TNSS), peak nasal inspiratory flow (PNIF) were collected up to 24 h after NAC. Total and active tryptase were measured as early-phase allergy biomarkers (≤30 min) and IL-13 and eosinophil cell counts as late-phase allergy biomarkers (3-7 h) in serum and nasal samples. Period-period reproducibility was assessed by intraclass correlation coefficients (ICC), and sample size estimates were performed using effect sizes measured after INCS.
NAC significantly induced acute increases in nasosorption tryptase and TNSS and reduced PNIF, and induced late increases in nasosorption IL-13 with sustained reductions in PNIF. Reproducibility across NACs varied for symptoms and biomarkers, with total tryptase 5 min post NAC having the highest reproducibility (ICC = 0.91). Treatment with INCS inhibited NAC-induced IL-13 while blunting changes in TNSS and PNIF. For a similar crossover study, 7 participants per treatment arm are needed to detect treatment effects comparable to INCS for TNSS.
NAC-induced biomarkers and symptoms are reproducible and responsive to INCS. NAC is suitable for assessing pharmacodynamic activity and proof of mechanism for drugs targeting allergic inflammation.
鼻腔和支气管黏膜的相似免疫反应表明，鼻过敏原挑战（NAC）是一种适合开发针对过敏性鼻炎（AR）和哮喘的早期实验模型。我们评估了 NAC 的重现性以及鼻内皮质类固醇（INCS）对症状、生理学和炎症介质的影响。
20 名轻度特应性哮喘和 AR 患者接受了三次单盲鼻腔挑战，每次间隔 3 周（NCT03431961）。队列 A（n=10）接受了生理盐水对照挑战，然后进行了两次过敏原挑战。队列 B（n=10）接受了 NAC，没有治疗干预，然后用 14 天的盐水鼻腔喷雾（安慰剂）预处理，然后用 14 天的 INCS（220μg 曲安奈德，每天两次）预处理。在 NAC 后长达 24 小时收集鼻吸、鼻冲洗、血液样本、用力呼气 1 秒量（FEV1）、总鼻症状评分（TNSS）、峰值鼻吸气流量（PNIF）。在血清和鼻腔样本中测量总和活性类胰蛋白酶作为早期过敏生物标志物（≤30 分钟），IL-13 和嗜酸性粒细胞计数作为晚期过敏生物标志物（3-7 小时）。使用 INCS 测量的效应大小进行样本量估计，通过组内相关系数（ICC）评估周期-周期重现性。
NAC 显著诱导急性鼻吸 tryptase 和 TNSS 增加，PNIF 降低，并诱导晚期鼻吸 IL-13 增加，PNIF 持续降低。NAC 之间的症状和生物标志物重现性不同，NAC 后 5 分钟的总 tryptase 具有最高的重现性（ICC=0.91）。INCS 治疗抑制了 NAC 诱导的 IL-13，同时减弱了 TNSS 和 PNIF 的变化。对于类似的交叉研究，每个治疗组需要 7 名参与者来检测与 INCS 类似的治疗效果，以检测针对过敏炎症的药物的药效学活性和机制证明。
NAC 诱导的生物标志物和症状具有重现性，并且对 INCS 有反应。NAC 适用于评估针对过敏炎症的药物的药效学活性和机制证明。
