The intrahepatic T cell profile and its polarization in development and progression of non-alcoholic steatohepatitis (NASH)

• Applicant: Dr. Hannah Drescher
• Subject Area: Gastroenterology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 425970635

Non-alcoholic fatty liver disease (NAFLD) is a chronic and progressive liver disease, the most common in western countries and evolving to be the leading causes for liver transplantation. NAFLD is accompanied by a specific sequence of hepatic alterations that begin with simple steatosis which can progress to more advanced stages like non-alcoholic steatohepatitis (NASH), liver fibrosis and cirrhosis and finally the development of hepatocellular carcinoma (HCC). Considering that more than 20% of the general population in industrialized nations have a fatty liver with the risk of progressing to NASH and that there is currently no pharmacological treatment available, the need for studies on disease pathogenesis and for the development of novel therapeutic options is evident. One emerging focus of investigation is the role of CD4+ T cells, most notably their polarization towards a TH17 profile in the progression from simple steatosis to a more advanced disease state of steatohepatitis. However, more studies using human patient samples are needed to further confirm the exact role and mechanism of action for CD4+ T cells in NAFLD/NASH. To date, most studies have been cross-sectional, given the very slow progression from NAFLD to NASH. It would be a major improvement to study patients longitudinally, however who will actually progress is hard to predict and the required long-term follow-up has made such studies impractical. The observation that chemotherapy, for example with regiments containing 5-FU, Oxaliplatin or most pronounced Irinotecan, induce hepatic steatosis and steatohepatitis frequently and rapidly opens the opportunity to prospectively and longitudinally study patients with progressive fatty liver disease. Patients receiving chemotherapy for hepatic metastasis also allow sampling of liver tissue pre and post chemotherapy during diagnostic biopsies and liver resections. Based on our hypotheses that changes in CD4+ T cell polarization, but potentially also other intrahepatic immune cell populations, are associated with the progression of fatty liver disease we will characterize intrahepatic CD4+ T cells pre and post chemotherapy insult. In addition, we will utilize a novel unbiased single cell sequencing approach to extent our analysis of these valuable human samples to all intrahepatic immune cell populations. At the end of the study we will have determined whether TH17 polarization is indeed operative in this human model for NASH pathogenesis, and will also have generated additional novel hypotheses regarding the role of other intrahepatic immune cells.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Georg M. Lauer