Preclinical evaluation of the Helicobacter pylori molecule vacuolating cytotoxin A (VacA) as a therapeutic approach for allergic airway disease
Final Report Abstract
The incidence and prevalence of immunological diseases, such as asthma, has risen substantially in recent decades. Worldwide, the number of patients suffering from asthma is estimated to be about 300 million. Since a modifìcation of the underlying pathophysiology has not been possible so far, treatment has remained purely symptomatic. New concepts and approaches are being worked on, which should enable a causal therapy of asthma in the future. Asthma is a heterogeneous syndrome with different clinical and immunological phenotypes. These are characterized by dysregulation of innate and adaptive immunity leading to chronic inflammatory responses and lung remodeling processes, which are ultimately responsible for the pathophysiology of the disease. Since regulatory T cells (Tregs) play a central role in suppressing immunological inflammatory processes, their activation may represent a novel intervention strategy to treat chronic inflammatory airway diseases such as asthma. ln preliminary work we could already demonstrate that neonatal infections with Helicobacter pylori (H. pylori) can suppress the development of allergic asthma in mice. Among other things, vacuolating cytotoxin A (VacA) produced by H. pylori was responsible for this effect. VacA plays an important role in the induction of Tregs in infected mice. The aim of this application was to further explore the therapeutic efficacy of VacA in asthma and to investigate whether the protein could also be suitable for treatment in humans. Using an acute, a therapeutic and a chronic murine model of allergic airway disease, we were able to demonstrate that VacA not only has a prophylactic effect, but can also be used therapeutically to treat asthma. ln this context, the development of allergic airway disease can be suppressed without side effects after intraperitoneal, but also after oral and intranasal application of the molecule. Detailed analyses of the immunophenotype showed that the administration of VacA leads to a modification of dendritic cells, tissue resident T memory cells and Tregs. The central role of Tregs, whose induction is mainly observed at the site of application, for the therapeutic efficacy of VacA was confirmed by depletion experiments. Analyses in the humanized mouse model, and human in vitro DC/ T cell interaction experiments indicate that VacA can also modulate the immune function of human cells. The data suggest that VacA may also suppress exaggerated immunological responses in humans via DC-mediated induction of regulatory T cells, and thus may be suitable as a new therapeutic option for the treatment of asthma.
Publications
-
ln an acute allergic airway disease murine model, H. pylori derived VacA treatment attenuates the asthma phenotype of adult mice. Herbsttagung der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin; Sektion 14; Hannover 2021
Jonas Raspe
-
Das vakuolisierende Zytotoxin A (VacA) als neuer Therapieansatz für die Behandlung von Asthma. Pneumologie, 76(S 01), S79-S80.
Raspe, J.; Beckert, H.; Westendorf, A. M.; Pastille, E.; Cover, T. L.; Müller, A.; Taube, C. & Reuter, S.
-
Helicobacter Pylori Derived Vacuolating Cytotoxin A (VacA) Modulates the Allergen Specific Interaction of Dendritic Cells with T Cells. A32. UPDATES IN THE MOLECULAR AND CELLULAR UNDERPINNINGS OF ASTHMA, A1274-A1274. American Thoracic Society.
Raspe, J.; Beckert, H.; Cover, T.L.; Müller, A.; Taube, C. & Reuter, S.
-
Vacuolating Cytotoxin A (VacA) - Therapeutic Potential of a Helicobacter Derived Molecule for Asthma. C21. DRILLING DOWN ON INFLAMMATORY MECHANISMS IN ASTHMA VIA HUMAN CELLS AND MURINE MODELS, A3749-A3749. American Thoracic Society.
Reuter, S.; Raspe, J.; Beckert, H.; Westendorf, A.; Pastille, E.; Cover, T.; Müller, A. & Taube, C.
-
Das Helicobacter pylori Protein vakuolisierendes Zytotoxin A (VacA) moduliert murin und human die Interaktion zwischen dendritischen Zellen und T Zellen. Pneumologie, 77(S 01), S71-S71.
Raspe, J.; Contoyannis, A.; Schmitz, M.; Übner, H.; Cover, T.; Müller, A.; Taube, C. & Reuter, S.
-
Therapeutic properties of Helicobacter pylori-derived vacuolating cytotoxin A in an animal model of chronic allergic airway disease. Respiratory Research, 24(1).
Raspe, Jonas; Schmitz, Mona S.; Barbet, Kimberly; Caso, Georgia C.; Cover, Timothy L.; Müller, Anne; Taube, Christian & Reuter, Sebastian
-
Treatment with Helicobacter pylori-derived VacA attenuates allergic airway disease. Frontiers in Immunology, 14.
Reuter, Sebastian; Raspe, Jonas; Uebner, Hendrik; Contoyannis, Alexandros; Pastille, Eva; Westendorf, Astrid M.; Caso, Georgia C.; Cover, Timothy L.; Müller, Anne & Taube, Christian
-
Microbes little helpers and suppliers for therapeutic asthma approaches. Respiratory Research, 25(1).
Reuter, Sebastian; Raspe, Jonas & Taube, Christian
