Human Natural Killer T cells Type I and Type II and their Role in Inflammatory Liver Disease such as Autoimmune Hepatitis

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The liver has a crucial role in balancing tolerance and immunity. Further knowledge about how to steer this balance is needed in order to prevent autoimmune or infectious disease from progressing to irreversible liver damage. In this context, this project focusses on the analysis of different subtypes of human natural killer T cells and their roles in inflammatory liver disease such as autoimmune hepatitis. Healthy humans and patients with chronic hepatitis C serve as controls.It will be examined, if, aside from type I NKT cells, sulfatide-reactive type II NKT cells are present in human peripheral blood and liver and if these can be activated by sulfatide ex-vivo. Furthermore, it will be tested, whether type I NKT cells with Th1 or Th17 profile are recruited into the liver and thus are pathogenic in active autoimmune hepatitis. The chemokines/chemokine receptors involved in intrahepatic recruitment of proinflammatory human type I NKT cells will be analyzed in order to find a therapeutic target for blocking progession of the inflammatory process.It is hypothesized that human sulfatide-reactive type II NKT cells show functionally a regulatory potential (IL-4, IL-10) and that they are decreased in numbers in the liver during active autoimmune hepatitis. It will be examined whether human sulfatide-reactive type II NKT cells, in similarity to the murine, exert an immunoregulatory function. This project aims to identify this cell population for the first time in humans and to examine its immunoregulatory effect on potentially pathogenic type I NKT cells and effector T cells in vitro. Thus, not only a new human regulatory cell population would be described, but also there would be the future option of immune-modulating therapy by transfer of expanded sulfatide-reactive type II NKT cells or by activation with sulfatide that could stop inflammatory processes such as autoimmune hepatitis or chronic hepatitis C.