Immunomodulation as a therapeutic option for bronchial asthma – evaluation, mechanism and translation of canonical Wnt signalling effects

• Applicant: Professor Dr. Christian Taube, since 3/2024
• Subject Area: Pneumology, Thoracic Surgery ; Clinical Immunology and Allergology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 471723504

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 needed. Recent studies in mice models were able to show that the activation of canonical Wnt/β –Catenin signalling attenuates the development of allergic airway disease. On cellular levels the activation of Wnt signalling directly modulates dendritic cells (DC). Futhermore, application of Wnt1 Ligand has a direct impact on respiratory epithelial cells. However, the underlying mechanisms are still unclear and the therapeutic capacity of Wnt1 is unknown. The current project is a logical extension of our longstanding work on Wnt signalling in asthma. Key objective of the work is to identify the immunomodulatory mechanisms of Wnt1 and to evaluate the therapeutic potential of Wnt1 in translational models. In the first part of the project the impact of Wnt1 on DC and their interaction with T cells will be analysed. Therefore, to reveal intracellular processes responsible for Wnt mediated immune regulation Chip-analysis of Wnt treated DC will be performed. Furthermore, we will test the impact of Wnt1 on central cellular functions of DC, like activation, antigen processing and their interaction with T cells in co-culture models. The second objective will be to assess the effect of a treatment with Wnt1 ligands on respiratory epithelial cell functions. Here, the impact of Wnt1 on barrier function, cytokine and mucus secretion, differentiation and healing processes will be determined. In third objective the suitability and potential of a recombinant Wnt1 based therapy will be tested in clinically relevant murine in vivo models. In addition, for translation into humans the Wnt1 treatment will be tested in a humanised mouse model, which allows the analysis of humane immune cells of asthmatic patients in an in vivo situation. The depicted experiments are important preclinical investigations to identify immunomodulatory function of Wnt signalling and to evaluate the potential of Wnt1 ligands as a future therapeutic option for asthma.

• DFG Programme: Research Grants
• Ehemalige Antragsteller: Dr. Sebastian Reuter, from 8/2022 until 3/2024; Dr. Hendrik Übner, until 7/2022