Determining the role of hepatic and circulatory Immune Cells on a single cell level in the Onset and Treatment of severe Alcoholic Hepatitis: The DICOTAH study.

Alcoholic liver disease (ALD) is a leading cause of liver-related mortality worldwide. ALD cirrhosis may suddenly develop into a lifethreatening and distinct clinical syndrome termed severe alcoholic hepatitis (sAH), reaching a short-term mortality of 20% at 1 month. sAH is hallmarked by a marked pro-inflammatory milieu in the liver and the systemic circulation, making it plausible that immunological changes are the main drivers of its sudden disease onset. Corticosteroid therapy is the only available therapeutic option for sAH. However, nearly 50% of patients with sAH will not benefit from corticosteroid treatment. In this project we will address the two key clinical questions of 1) which immunological processes drive the onset of sAH and 2) why a certain sub-cohort of sAH patients fail to respond to corticosteroid therapy. The novelty of this project originates from the 1) unique patient set-up using sequential analyses before and after corticosteroid treatment and 2) the application of single-cell RNA sequencing that has emerged as a powerful technique to decipher the cellular diversity and functions of several tissues. So far, no in depth studies using state-of-the-art high-throughput immunological technologies are performed in this area. A success in this project would provide ground-breaking information paving the way for novel or tailored treatment strategies and towards improving the prognosis of this vulnerable patient population with a high short-term mortality.