Abstract：
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.
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.
摘要：
背景：鼻腔和支气管粘膜中的类似免疫反应意味着鼻腔过敏原攻击（NAC）是针对过敏性鼻炎（AR）和哮喘的药物开发的合适的早期实验模型。我们评估了NAC的可重复性和鼻内皮质类固醇（INCS）对症状的影响，生理学,和炎症介质。
方法：20名患有轻度特应性哮喘和AR的参与者接受了三次单盲鼻攻击，每次间隔三周（NCT03431961）。队列A（n=10）接受了对照盐水攻击，接下来是两个过敏原挑战。队列B（n=10）接受了NAC，没有治疗干预，然后是NAC，用生理盐水鼻喷雾剂（安慰剂）治疗14天，然后用INCS（220μg曲安奈德，每日两次）预处理14天的NAC。鼻吸附,鼻腔灌洗,血液样本,用力呼气容积1(FEV1),总鼻部症状评分（TNSS），在NAC后24小时内收集峰值鼻吸气流量（PNIF）。血清和鼻部样本中的总的和活性的类胰蛋白酶被测量为早期变态反应生物标志物(≤30分钟),IL-13和嗜酸性粒细胞计数被测量为晚期变态反应生物标志物(3-7小时)。周期再现性通过组内相关系数(ICC)评估，和样本量估计使用INCS后测量的效应大小进行。
结果：NAC显著诱导了鼻吸收类胰蛋白酶和TNSS的急性增加，并降低了PNIF，并诱导鼻吸IL-13的后期增加，PNIF持续减少。NAC的可重复性因症状和生物标志物而异，NAC后5分钟的总胰蛋白酶具有最高的可重复性（ICC=0.91）。INCS治疗抑制了NAC诱导的IL-13，同时抑制了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TNSS的INCS相当的治疗效果。
结论：NAC诱导的生物标志物和症状是可重复的，并且对INCS有反应。NAC适用于评估药物靶向过敏性炎症的药效学活性和机制证明。
方法：20名患有轻度特应性哮喘和AR的参与者接受了三次单盲鼻攻击，每次间隔三周（NCT03431961）。队列A（n=10）接受了对照盐水攻击，接下来是两个过敏原挑战。队列B（n=10）接受了NAC，没有治疗干预，然后是NAC，用生理盐水鼻喷雾剂（安慰剂）治疗14天，然后用INCS（220μg曲安奈德，每日两次）预处理14天的NAC。鼻吸附,鼻腔灌洗,血液样本,用力呼气容积1(FEV1),总鼻部症状评分（TNSS），在NAC后24小时内收集峰值鼻吸气流量（PNIF）。血清和鼻部样本中的总的和活性的类胰蛋白酶被测量为早期变态反应生物标志物(≤30分钟),IL-13和嗜酸性粒细胞计数被测量为晚期变态反应生物标志物(3-7小时)。周期再现性通过组内相关系数(ICC)评估，和样本量估计使用INCS后测量的效应大小进行。
结果：NAC显著诱导了鼻吸收类胰蛋白酶和TNSS的急性增加，并降低了PNIF，并诱导鼻吸IL-13的后期增加，PNIF持续减少。NAC的可重复性因症状和生物标志物而异，NAC后5分钟的总胰蛋白酶具有最高的可重复性（ICC=0.91）。INCS治疗抑制了NAC诱导的IL-13，同时抑制了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TNSS的INCS相当的治疗效果。
结论：NAC诱导的生物标志物和症状是可重复的，并且对INCS有反应。NAC适用于评估药物靶向过敏性炎症的药效学活性和机制证明。
