As barrier to the outside world the lung is in constant contact with innocuous environmental
antigens, but is also the entrance site for many pathogens. Similarly, as one of the main sites of
entrance of food antigens through the portal vein, the liver plays a central role in oral tolerance
but the liver is also a major infection site. Importantly, loss of immune tolerance against
environmental or oral antigens causes severe clinical complications, including allergic asthma or inflammatory bowel disease. Dendritic Cells (DCs) and Macrophages (MFs) play an essential role in the regulation of immune responses. Thus liver and lung DCs and MFs appear to mediate two seemingly incompatible functions: maintaining tolerance against harmless antigens while
retaining the capacity to response powerfully to invading pathogens. This Odysseus project is
based on the hypothesis that the different functional tasks performed by DCs and MFs in the
lungs and the liver are in fact mediated by distinct subsets of DCs and MFs. Unfortunately current
available research tools cannot properly address the contribution of the individual DC or MF
subsets in the regulation of pulmonary and hepatic immune responses. Therefore, this project
proposes to utilize state-of-the-art techniques to generate the first knock-in mouse models that
will allow to unambiguously study the specific role of the major lung MF subset, i.e. Alveolar
Macrophages, the major liver MF subset, i.e. Kupffer Cells and the major antigen-presenting cells
upon inflammation, i.e. Monocyte-derived DCs, in vivo. This research project should lead to a
better understanding of the functional role of these distinct MF and DC subsets in the regulation
of specific pulmonary and hepatic immune responses, including allergic asthma, flu infection, oral tolerance and non-alcoholic fatty liver disease, which ultimately could lead to the design of more efficient immune intervention strategies to fight lung and liver diseases.