Kurzfassung

Asthma is a widespread inflammatory disease of the lungs and the most common chronic disease in childhood. It is characterized by the loss of immune tolerance to harmless environmental antigens (allergens) and its pathophysiology involves recurring inflammation of the airways, intermittent airflow obstruction, and bronchial hyper-responsiveness. To develop effective therapies, it is crucial to understand how the immune system of the lungs is regulated and how tolerance is maintained;...Asthma is a widespread inflammatory disease of the lungs and the most common chronic disease in childhood. It is characterized by the loss of immune tolerance to harmless environmental antigens (allergens) and its pathophysiology involves recurring inflammation of the airways, intermittent airflow obstruction, and bronchial hyper-responsiveness. To develop effective therapies, it is crucial to understand how the immune system of the lungs is regulated and how tolerance is maintained; particularly with respect to restoring tolerance after the immunological balance has been disrupted.
Dendritic cells (DCs) play a critical role both in the initiation of an effective immune response, as well as in the maintenance of tolerance. The challenge for DCs is to ensure protective immunity against dangerous pathogens, while maintaining immune homeostasis against harmless antigens. The lung contains two main DC populations, expressing either CD11b or CD103, that have different functions in the activation of effector or regulatory T cells (Tregs). Especially CD103+ DCs play an important role in maintaining pulmonary tolerance due to their ability to induce Foxp3+ Tregs. Next to DCs, alveolar macrophages (MΦ) play a central role in lung homeostasis, tissue remodeling, and host defense by the continuous clearance of cellular debris. In addition, they participate in the induction of tolerance by restraining DC and T cell activation and facilitating the development of Foxp3+ Tregs via secretion of TGF-β and retinoic acid (RA). However, after pathogenic stimulation MΦ acquire a pro-inflammatory phenotype and contribute to inflammatory processes in the lung by increased phagocytic capacity and the production of pro-inflammatory cytokines. The molecular signals that enable DCs and MΦ to mediate immune tolerance are still largely unknown. However, β-catenin, the central component of the Wnt signaling pathway was shown to promote the tolerogenic potential of DCs. Furthermore, DC-specific deletion of β -catenin increased the susceptibility of mice to DSS-induced colitis. These data make β-catenin in DCs a promising candidate for future therapeutic intervention. However, to what extent CD11c-specific β-catenin signals are able to modulate pulmonary tolerance and attenuate the development of allergic asthma is not known. To this aim, we will apply cell specific conditional gene targeting to generate mice with either a CD11c-specific deficiency of β-catenin or a constitutively active form of β-catenin.
The aim of this research project is to unravel the underlying mechanisms by which β-catenin signaling induces the tolerogenic phenotype in CD11c+ antigen presenting cells (APCs). Furthermore, this project will address the therapeutic potential of DCs harboring constitutively active β-catenin in the regulation of allergic asthma and the restoration of immune tolerance in the lung.» weiterlesen» einklappen