Role of Dendritic Cells in Hepatitis C Virus Infection

Research project P 14641 Role of Dendritic Cells in Hepatisis C Virus Infection Herbert TILG 09.10.2000 Several lines of recent evidence indicate that clearance of hepatitis C virus during acute infection is associated with a strong, broad and specific HCV-directed T lymphocyte response, while chronic infection is characterized by a much weaker T cell response, inefficient to clear the virus but clinically relevant in promoting prolonged hepatic injury. Furthermore, it has been demonstrated that successfull treatment of chronic hepatitis with IFN-alpha and ribavirin results in the induction of HCV genotypes common in our region, this treatment is far from being curative for all patients, and thus evaluation of new treatment options in vitro is warranted. Dendritic cells (DCs) are the only cell type capable to induce a primary T lymphocyte immune response and therefore play a central role in immunology. In the treatment of various types of cancer, several clinical trial on the use of tumour-spacific DCs have provided promising results. However, the role of DCs in HCV infection is only poorly unserstood. The aim of our project is to gain clues in understanding of factors drivin a strong T lymphocyte-mediated HCV- specific immune response. To this end we plan to investigate molecular mechanisms of IFN-alpha as a current approach to induce an HCV-specific T cell response. As a possible new treatment approach, we plan to investigate HCV-promed DCs for their capability to drive a specific T lymphocyte response. For this purpose, we want to determine immunologically relevant parts of HCV and a cytokine-microenvironment for the priming of DCs and the induction of specific and efficient immune responses. As an important prerequisite, DCs derived from HCV patients have to be compared for overall quantity and various biological functions to DCs derived form healthy controls. Furthermore, the effect of HCV on DC funtion shall be addressed. Our studies should provide valuable insights into the development of primary T lymphocyte responses toward HCV, the interacion of HCV wich DCs, and some clues in understanding the molecular mechanisms of IFN-alpha in the treatment of HCV infection. Furthermore, these experiments could provide important clues for the future development of prophylactic and therapeutic vaccination strategies for HCV infection.

Cytokines (mediators of the immune system) play a key role in diseases of liver and gut. These mediators regulate especially various inflammatory conditions and an improved understanding of their role is of major interest for a better treatment of various diseases. One of those key cytokines is interferon-alpha (IFNa). This cytokine is mainly used in the treatment of chronic viral hepatitis B and C. The mode of action of IFNa is currently incompletely understood and our research group is involved in this type of research since many years. We described earlier that IFNa has various anti-inflammatory and immunomodulatory actions. Therefore, anti-inflammatory potential of this cytokine could open new clinical fields where this cytokine might be of interest. In this project (P14641) we were interested whether IFNa is able to affect synthesis of interleukin-16 (IL-16). IL-16 is a cytokine which is of particular importance for the physiology of T cells. T cells play a key role in chronic viral hepatitis and also in other chronic inflammatory disorders such as inflammatory bowel diseases. Previously we have demonstrated that IFNa is able to enhance apoptosis (programmed cell death). Now we can demonstrate that via induction of apoptosis (induction of various caspases) IFNa is also able to induce secretion and synthesis of IL-16. Therefore, via enhancement of apoptosis IFNa is able to induce/upregulate an important immunomodulatory cytokine such as IL-16. Furthermore, we identified another new anti-inflammatory mechanism of IFNa. IL-18, a proinflammatory cytokine, is regulated endogenously via its physiologc antagonist, namely IL-18 binding protein (IL-18BP). We could demonstrate both in vitro and in IFNa - treated patients with chronic hepatitis C, that IFNa is able to induce large amounts of IL-18BP, thereby decreasing free circulating IL-18. Therefore, this could be another important mode of action of this clinically important cytokine. These findings had major clinical implications as after having this knowledge we started a Phase I/II clinical trial in four European countries to test whether IFNa is able to control inflammation in a chronic inflammatory condition, namely ulcerative colitis. In this pilot study we could indeed demonstrate that IFNa shows some efficacy in patients with chronic inflammation. Therefore, our Research Project nicely demonstrates the utility of a "bench-to-bedside" concept and will open new clinical indications for IFNa in human diseases.