Break Down Barriers: Respiratory epithelial cells as modulators of dendritic cells during the pathogen associated allergic sensitization and acute asthma exacerbation

打破障碍：在病原体相关的过敏致敏和哮喘急性发作期间，呼吸道上皮细胞作为树突状细胞的调节剂

• 批准号: 504226880
• 负责人: Dr. Hendrik Übner
• 金额: --
• 依托单位: Klinik für Pneumologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2022
• 资助国家: 德国
• 起止时间: 2021-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/504226880?language=en
• 关键词: Break; Down; Barriers; Respiratory; epithelial

Bronchial Asthma is a chronic inflammatory disease of the airways. In Germany, more than 4 million people suffer from Asthma. Since treatment approaches are currently primarily symptom-orientated a better understanding for disease underlying mechanisms is required and new therapeutic approaches are urgently needed. During asthma pathogenesis viral infections of the airways are key players with a huge impact on allergic sensitization and the induction of potentially life-threatening acute exacerbations. With their barrier function and mucus production respiratory epithelial cells are the first line of defence against pathogens. If the barrier breaks, epithelial cells are able to secrete several immunomodulatory substances, like alarmins. Hereby, they have a great impact on the early immune response as well as on dendritic cell (DC) activation and the following imprinting of the adoptive immune system. Despite we know about the importance of communication between epithelial cells and the immune system, adequate in vitro models are still missing to elucidate details. Aim of this project is to further develop air liquid interface (ALI) cell culture techniques to a reproducible co-culture of primary human bronchial epithelial cells (HBEC) and DC. With this model, the impact of epithelial infection with Respiratory Syncytial Virus (RSV) on DC activation and allergen uptake will be analysed. Beside the analysis of direct effects of RSV infection of epithelial cells by measuring its barrier function, differentiation or mucus secretion and the composition of secreted pro- or anti-inflammatory molecules will be characterized. We hypothesise, that the mixture of different epithelial cytokines are able to modulate and fine-tune central functions of DCs. This could influence asthma related pathogenic processes like allergen uptake and processing, cytokine secretion of DCs, and thereby activation and priming of t cell responses. The major limitation of missing complexity of in vitro cell cultures could be overcome by further development of such co-culture systems. This would help to reduce animal experiments as well. By exclusively usage of primary human cells this model contains a high translational capacity and could be able to identify new therapeutic targets during the early phase of immune activation.

支气管哮喘是一种慢性气道炎症性疾病。在德国，有超过400万人患有哮喘。由于目前的治疗方法主要以症状为导向，因此需要更好地了解疾病的潜在机制，并迫切需要新的治疗方法。在哮喘发病过程中，呼吸道的病毒感染是对过敏致敏和诱发潜在危及生命的急性加重有巨大影响的关键因素。呼吸道上皮细胞具有屏障功能和分泌粘液，是抵御病原体的第一道防线。如果屏障被破坏，上皮细胞能够分泌几种免疫调节物质，如警报器。因此，它们对早期免疫反应以及树突状细胞（DC）的激活和随后的过继免疫系统的印记有很大的影响。尽管我们知道上皮细胞和免疫系统之间通讯的重要性，但仍然缺乏足够的体外模型来阐明细节。本项目旨在进一步发展气液界面（ALI）细胞培养技术，实现人支气管上皮细胞（HBEC）和DC的可重复共培养。利用该模型，将分析呼吸道合胞病毒（RSV）上皮感染对DC激活和过敏原摄取的影响。除了通过检测其屏障功能来分析RSV感染对上皮细胞的直接影响外，还将研究其分化或粘液分泌以及分泌的促炎或抗炎分子的组成。我们假设，不同上皮细胞因子的混合物能够调节和微调dc的中枢功能。这可能影响哮喘相关的致病过程，如过敏原的摄取和加工，dc的细胞因子分泌，从而激活和启动t细胞反应。体外细胞培养缺乏复杂性的主要限制可以通过进一步发展这种共培养系统来克服。这也将有助于减少动物实验。通过专门使用原代人细胞，该模型具有很高的翻译能力，并且能够在免疫激活的早期阶段识别新的治疗靶点。