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

肝脏在平衡耐受性和免疫力方面起着至关重要的作用。为了防止自身免疫性或传染性疾病发展为不可逆的肝损伤，需要进一步了解如何控制这种平衡。在此背景下，本项目侧重于分析人类自然杀伤T细胞的不同亚型及其在炎症性肝病（如自身免疫性肝炎）中的作用。健康人群和慢性丙型肝炎患者作为对照。我们将研究，除了I型NKT细胞外，人类外周血和肝脏中是否存在硫脂反应型NKT细胞，以及这些细胞是否能被硫脂激活。此外，还将测试具有Th1或Th17特征的I型NKT细胞是否被募集到肝脏，从而在活动性自身免疫性肝炎中具有致病性。我们将分析参与促炎人类I型NKT细胞肝内募集的趋化因子/趋化因子受体，以找到阻断炎症过程进展的治疗靶点。据推测，人类硫脂反应型ⅱ型NKT细胞在功能上表现出调节潜能（IL-4, IL-10），并且在活动性自身免疫性肝炎期间，它们在肝脏中的数量减少。我们将研究人类硫脂反应型ⅱ型NKT细胞是否与小鼠相似，发挥免疫调节功能。本项目旨在首次在人体中鉴定该细胞群，并在体外检测其对潜在致病性I型NKT细胞和效应T细胞的免疫调节作用。因此，不仅将描述一种新的人类调节细胞群，而且还将有未来的免疫调节治疗选择，通过转移扩展的硫脂反应型II型NKT细胞或通过硫脂激活可以阻止炎症过程，如自身免疫性肝炎或慢性丙型肝炎。

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.