Subproject A10

The pathogenesis of autoimmune liver diseases is incompletely understood. Autoimmune cholangitis almost exclusively develops in patients with inflammatory bowel disease, suggesting involvement of the gut-associated lymphatic tissue in the pathogenesis of the liver disease. Migration of effector T-cells between gut and liver in terms of an enterohepatic circuit is a well-documented phenomenon in humans but suitable mouse models to investigate its basis are lacking. Establishment of a mouse model of the enterohepatic circuit would allow the investigation of underlying pathophysiological mechanisms and might identify potential therapeutic approaches.

In the course of a previous project funded by the DFG, transgenic mice were developed, which express the model antigen ovalbumin either in hepatocytes or in cholangiocytes. This previous work has demonstrated that the model is suited for the investigation of the mechanisms of antigen presentation and cross-presentation as well as the development of autoimmunity in the liver.

In the present project, characteristics of the enterohepatic circuit of antigen specific T-cells and the potential to block their migration will be investigated. T-cells activated either in the gut or in the liver will be purified and used for transfer experiments to elucidate their migratory properties. Using antibodies against specific homing receptors, we aim to clarify whether the enterohepatic circuit can be blocked therapeutically. In further experiments, we will investigate whether the tolerogenic expression of an antigen in the liver leads to a spread of tolerance and to amelioration of an immune response directed against the same antigen in the gut. To address how liver-induced tolerance may be broken, double transgenic mice will be generated, which express the same antigen in the liver as well as in the gut. Using these animals, we aim to specify whether an organ-specific inflammatory process may lead to the loss of tolerance and to autoimmunity beyond the limit of the primarily inflamed organ.