Translational studies of the induction and functional role of Th2 polarized CD4+ T-cells in chronic liver damage and hepatic fibrogenesis

点击翻译按钮获取中文摘要

Immune mechanisms are critically involved in liver inflammation and subsequent fibrogenesis and cirrhosis. Extensive research has unravelled that the infiltration and local activation of cellular components of the innate as well as the adaptive immune system are prerequisites for the initiation of profibrotic cascades. This is clinical relevant because the therapeutical options are still limited despite the urgent need for effective antifibrotic treatments. Studies in other organs such as the lung have shown that the Th2 polarization of CD4+ T-helper cells is directly linked to remodeling proceses. During organ fibrosis prototypical Th2 cytokines including IL-4 and IL-13 activate mesenchymal cells which synthesize abundant amounts of extracellular matrix compounds. As a consequence, parenchyma is gradually replaced by connective tissue eventually leading to organ failure. Furthermore, Th2-cells can induce alternatively activated M2 macrophages ,that also display profibrotic properties, through cell-cell interaction, whereby organ fibrosis is further amplified. However, it is still widely unknown, whether the Th2-fibrosis paradigm also applies to the liver. There is robust evidence that Th2-poalrized CD4+ T-cells are critically involved in parasitic liver diseases, but their role in sterile, antigen-independent liver inflammation remains elusive. Aim of this proposed translational project is to dissect the differentiation of T-helper cells at different stages of liver fibrosis and to examine their contribution to matrix depostion in descriptive and functional studies. With the help of a comprehensive collection of tissue specimens of explanted diseased liver with different underlying etiologies, it will be possible to precisely characterize intrahepatic T-cell profiles and the local immune environment in liver fibrosis. In vitro cell-culture assays with primary human cells will allow to study mechanisms of hepatic recruitment and local induction of Th2 differentiated T-helper cells. The analysis of the reciprocal interplay between CD4+ T-cells and liver-resident parenchymal and non-parenchymal cells will be a major focus in the human part of this project. The obtained findings will be validated in experimental antigen-independent liver fibrosis models. At defined time points during fibrogenesis the signature of infiltrating T-cells will be characterized. Knockout animals with a genetic deficiency of Th2 key components will serve to study the functional relevance of this immune response in liver fibrosis. If these animals exhibit less fibrosis adoptive transfer of CD4+ T-cells is planned to unravel whether this cell class or members of the innate immune system, such as innate lymphoid cells or NKT-cells, which can also secrete Th2-related cytokines, essentially booster heptic fibrogenesis. By promoting our understanding of the pathogenesis of liver fibrosis this project may help to develop novel therapeutic tools to combat liver cirrhosis.