Allergen-specific immunotherapy induces the suppressive secretoglobin 1A1 in cells of the lower airways. Allergen-specific immunotherapy induces the suppressive secretoglobin 1A1 in cells of the lower airways

While several systemic immunomodulatory effects of allergen-specific immunotherapy (AIT) have been discovered, local anti-inflammatory mechanisms in the respiratory tract are largely unknown. We sought to elucidate local and epithelial mechanisms underlying allergen-specific immunotherapy in a genome-wide approach. We induced sputum in hay fever patients and healthy controls during the pollen peak season and stratified patients by effective allergen-immunotherapy or as untreated. Sputum was directly processed after induction and subjected to whole transcriptome RNA microarray analysis. Nasal secretions were analyzed for Secretoglobin1A1 (SCGB1A1) and IL-24 protein levels in an additional validation cohort at three defined time points during the three-year course of AIT. Subsequently, RNA was extracted and subjected to an array-based whole transcriptome analysis. AIT inhibited pro-inflammatory CXCL8, IL24 and CCL26 mRNA expression, while SCGB1A1, IL7, CCL5, CCL23 and WNT5B mRNAs were induced independently of the asthma status and allergen season. In our validation cohort, local increase of SCGB1A1 occurred concomitantly with the reduction of local IL-24 in upper airways during the course of AIT. Additionally, SCGB1A1 was identified as a suppressor of epithelial gene expression.AIT induces a yet unknown local gene expression footprint in the lower airways that on one hand appears to be a result of multiple regulatory pathways and on the other hand reveals SCGB1A1 as novel anti-inflammatory mediator of long-term allergen specific therapeutic intervention in the local environment. Overall design: Induced sputa were performed in healthy controls, allergic rhinitis with and without concomittant asthma in and out of grass pollen season. Some of the patients received allergen-specific immunotherapy (AIT).

尽管学界已明确变应原特异性免疫治疗（allergen-specific immunotherapy, AIT）存在多种系统性免疫调节效应，但其呼吸道局部抗炎机制仍有待进一步阐明。本研究旨在通过全基因组研究策略，阐明变应原特异性免疫治疗的局部及上皮细胞调控机制。我们于花粉高峰期招募花粉症患者与健康对照，采集其诱导痰液，并根据是否接受有效变应原特异性免疫治疗将患者分为治疗组与未治疗组。痰液样本于诱导完成后即刻进行处理，并开展全转录组RNA芯片分析。此外，我们在另一项验证队列中，于变应原特异性免疫治疗三年疗程的三个预设时间点，检测了鼻分泌物中分泌球蛋白1A1（Secretoglobin1A1, SCGB1A1）与IL-24的蛋白水平。随后，我们提取RNA并开展基于芯片的全转录组分析。变应原特异性免疫治疗可抑制促炎因子CXCL8、IL24及CCL26的mRNA表达，同时上调SCGB1A1、IL7、CCL5、CCL23与WNT5B的mRNA水平，且该调控效应不受哮喘患病状态及花粉季的影响。在验证队列中，随着变应原特异性免疫治疗的推进，上呼吸道局部SCGB1A1水平升高的同时伴随IL-24水平的降低。此外，本研究证实SCGB1A1可作为上皮细胞基因表达的负调控因子。变应原特异性免疫治疗可在下呼吸道诱导出一种尚未被报道的局部基因表达特征：该特征一方面源于多条调控通路的协同作用，另一方面则揭示SCGB1A1可作为一种新型抗炎介质，介导长期变应原特异性免疫治疗在局部微环境中的抗炎效应。实验设计：本研究于牧草花粉季及非花粉季，分别采集健康对照、伴或不伴哮喘的变应性鼻炎患者的诱导痰液，其中部分患者接受了变应原特异性免疫治疗（AIT）。