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

• Applicant: Dr. Hendrik Übner
• Subject Area: Clinical Immunology and Allergology ; Pneumology, Thoracic Surgery
• Term: from 2022 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 504226880

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.

• DFG Programme: Research Grants