The role of regulatory T cells and Th1/Th17/Th22 cells in the pathogenesis of Non-Alcoholic Fatty Liver Disease and Non-Alcoholic SteatoHepatitis in mice and humans.

Non-Alcoholic Fatty Liver Disease (NAFLD) is a chronic liver disease defined by the accumulation of fat in the hepatocytes. In case of additional inflammation and signs of hepatocyte degeneration the disease is called Non-Alcoholic SteatoHepatitis (NASH), which represents a more severe disease subtype. Given the clear correlation between NAFLD and obesity and diabetes, and the increasing incidence of the latter two, NAFLD constitutes a major health concern. Moreover, NAFLD is one of the major causes of liver cirrhosis and can lead to liver cancer. The pathogenesis of NASH is poorly understood, and several organs and tissues (the gut, the visceral and subcutaneous adipose tissue) have been implicated. In the current project characterization of immune cells (regulatory T cells and Th1/Th17/Th22 by flowcytometry and immunohistochemistry) and cytokine profiles (ELISA on serum and RT-PCR on tissue) will be examined in peripheral and portal venous blood, liver tissue, mesenteric lymph nodes, subcutaneous and abdominal adipose tissue of mice fed a high-fat diet (a well established model of NASH) vs. mice fed a control diet for 20 weeks, in order to study the immunological alterations (focused on Tregs and Th17) in these different tissue compartments involved in NASH pathogenesis. In a second set of experiments one group of mice fed a high fat diet for 20 weeks will subsequently be switched for an additional 12 weeks to a normal diet, followed again by characterization of aforementioned immune cells and cytokines at the different sites, in order to study the evolution of the immunological alterations at the different sites, their potential reversal and their relation with (the evolution of) NASH histology. A second and third group will continue on high fat diet or on high fat diet supplemented with an antioxidant (resveratrol), to study the therapeutic effects of the latter on NASH in relation to its effects on the immune cell population. In a third set of experiments the effects of adoptive transfer of Tregs from mice fed the control diet to the mice fed the high-fat diet will be studied, in order to further substantiate their role in NASH pathogenesis. Lastly, given the results of the preclinical research were significant, we will study the immune cell populations and cytokine profiles in peripheral and hepatic venous blood and in liver biopsy specimens of well-characterized NAFLD patients (translational study).

Keywords:T CELL SUBSETS

Disciplines:Gastro-enterology and hepatology, Immunology