Fibrogenesis in chronic hepatitis C

Infection with the hepatitis C virus (HCV) can lead to chronic liver damage. The progression of HCV-infection to fibrosis, cirrhosis and liver failure is only partly dependent on the virus itself, but strongly influenced by other factors e.g. the host`s immune response, preexisting liver diseases or other infectious diseases (e.g. HIV coinfection). HCV-induced liver disease is caused by destruction of hepatocytes but also by excessive accumulation of extracellular matrix (ECM) molecules leading to scarring of the liver. These ECM-molecules are produced by the so called hepatic stellate cells (HSC). Depending on the cytokine microenvironment, HSC can produce ECM-molecules or enzymes that break down ECM-molecules (matrix-metalloproteinases) and therefore reverse the process of fibrogenesis. In the proposed project, we will compare the cytokine profile in patients with slow progression of fibrosis (HCV monoinfection) with the profile of rapid progressors (HCV-monoinfection, HCV/HIV or HCV/schistosoma mansoni coinfection). We will isolate T- and NK-cells from the peripheral blood and cultivate these cells together with HCV fragments. The secreted cytokines will be characterized. The supernatant of the cell culture will then be used to cultivate HSC, thus imitating the scenario of HCV-infection in vitro. The read-out will be done by analyses of various EMC-molecules and matrix-metalloproteinases. With this project we will elucidate not only the cytokine network involved in fibrogenesis but we also aim at establishing a diagnostic approach to distinguish between rapid and slow progressors. This is of utmost clinical interest because only early antiviral therapy even in spite of side effects can prevent liver cirrhosis in patients with rapid disease progression.