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SFB 841:  Liver Inflammation: Infection, Immune Regulation and Consequences

Subject Area Medicine
Biology
Term from 2010 to 2021
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 80750187
 
Final Report Year 2023

Final Report Abstract

A variety of insults, in particular of infectious, metabolic, or autoimmune origin, can cause liver damage and liver inflammation, which is one of the most common medical conditions in the world. Resultant liver cirrhosis is one of the ten leading causes of death. Liver cancer is the most common inflammation-induced cancer in the world, and is now second only to lung cancer as the leading cause of cancer death. At the same time, as the central metabolic organ, the liver fulfils vital functions that need to be maintained even under stress and injury. Thus, the liver features several protective mechanisms, including its unique capacity to regenerate, or its distinctive ability to down-regulate inflammation. Although these features might provide an evolutionary advantage, they can become detrimental in specific situations, such as in infections that become chronic due to a dampened local immune response, or in liver cancer that can be initiated and promoted by the liver’s regenerative and tolerogenic capacity. The central hypothesis of the CRC 841 was that immune regulatory mechanisms in the liver determine the outcome of infectious and inflammatory insults to the liver, as well as the risk of malignant transformation. On the basis of a better understanding of the regulatory mechanisms, we wanted to enable specific therapeutic manipulations. In addition, understanding liver inflammation should provide further insight into general mechanisms of initiation, resolution and consequences of inflammation in health and disease. In bringing together scientists of different disciplines, the CRC 841 established a role model for organ-specific inflammation research at our university. Our multidisciplinary, yet unified and synergistic approach using both advanced mouse models and human disease samples enabled us to obtain several major achievements that also resulted in novel treatment approaches. 1) We have addressed the interrelation between the immune response to pathogens and the clinical disease course, uncovering various mechanisms accounting for chronic inflammation, abscess formation or fibrosis. These studies have contributed to the development of a now approved drug inhibitor of hepatitis B virus and hepatitis D virus infection, and a novel experimental T cell therapy providing clearance of hepatitis B virus infection. 2) We have obtained quantification and functional characterisation of regulatory T cells in the liver of patients with autoimmune diseases, and established TNF and IL-17 as key T effector cell-derived molecules in autoimmune hepatitis and primary sclerosing cholangitis, respectively, resulting in an on-going clinical study providing preliminary evidence for efficacy of anti-TNF as primary therapy in autoimmune hepatitis. 3) We have identified a major mechanism of hepatic immune tolerance exerted by liver sinusoidal endothelial cells, and developed a patented method for selective antigen-delivery to these cells, providing antigen-specific immune tolerance and effective treatment for autoimmune diseases. The approach has been further investigated in our innovative transfer project and is currently translated to clinical studies in several indications by our application partner ‘Topas Therapeutics’. 4) We have investigated the links between metabolism and inflammation, and uncovered miR122 and RORalpha as potential targets for treatment of steatohepatitis. 5) We have uncovered key factors linking liver inflammation with carcinogenesis, including IL-6 and IL-22 signalling, providing potential targets for treatment of liver cancer. In conclusion, we dare say that the CRC 841 has produced significant scientific insights and contributions to major biomedical problems resulting in novel therapies for important diseases.

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