SFB 738 - Research Project B2

Immunological and viral determinants of graft hepatitis C after LTX in the context of novel antiviral therapies

"Complementing to conquer! By studying the basic immunological and virological mechanisms of graft hepatitis C after liver transplantation, the research of our groups draw from our expertise in both translational immunology and virology to address a fundamental quandary faced by transplant clinicians."

Thomas von Hahn - principal investigator

Our Vision

Liver transplantation is the surgical removal of a patient's diseased liver and replacing it with a wholly or partially healthy one from another individual. In most patients with severe liver disease, this treatment option is most often the only cure. Generally, outcomes for liver transplantation are very good, but may vary significantly depending on factors including the indication for liver transplant. In many cases, hepatitis C virus (HCV) infection (a leading cause of liver transplantation) has been implicated in particularly poor outcomes after liver transplantation. For patients with this infection, long-term survival is determined by both immunological acceptance of the graft and the control of viral replication. The advent of the recently introduced interferon-free treatment of HCV with the direct-acting antiviral (DAA) drugs has presented a therapy revolution that may lead to complete viral clearance in a far majority of hepatitis C patients after liver transplantation. However, the immunological consequence of HCV elimination in the context of liver transplantation is still completely unknown. More also, the clinical implications of treatment failures which are now increasingly observed in liver transplant recipients as a result of the resistance to different DAA combinations or altered drug metabolism are virtually unexplored. For this funding period, the overall focus of our research groups is geared towards improving our understanding of immunological and virological mechanisms of graft hepatitis C after liver transplantation. We believe that such insight is ultimately required for the improvement in the clinical management of transplanted patients.

Our Goals

Regulatory T cells (Tregs) play a significant role in immune homeostasis and are particularly critical after transplantation. In the past two funding periods we could demonstrate that HCV infection alters Treg cell phenotype and function and that distinct Treg cell properties can differentiate between rejection and recurrent graft hepatitis C. By further performing a biomarker screening early after liver transplantation we identified follistatin and IL-16 as factors that are independently associated with long-term graft loss. In this funding period we aim to continue these efforts by investigating the effects of DAA therapies on Tregs and other immune cells in the post-transplant setting. Here, we hypothesize that IFN-free cure of HCV infection reduces Treg cell frequency and restores not only NK cell function but also T cell responses - which in turn might lead to undesirable side effects including rejection episodes. We further aim to extend the biomarker screening project of the past funding period to intrahepatic mRNA signatures as well as to non-HCV patients. This will be followed by a detailed investigation of the specific role of follistatin and IL-16 as well as other novel biomarker hits in the pathogenesis of graft hepatitis. Specifically, our aim here will be to test if follistatin and IL-16 may have direct pro- or antiviral effects on the whole HCV replication cycle. Furthermore, we want to characterize viral populations causing viral reinfection after liver transplantation and relapse after DAA therapy in liver transplant recipients. Here too, our focus will be to determine if the frequency, specificity and pathogenicity of HCV resistance-associated variants differ in immunosuppressed HCV infected patients from non-immunosuppressed patients and further identify other factors that are associated with these unfavorable events. Our investigations are most likely to unravel novel therapeutic targets to improve graft survival in liver transplant recipients with or without hepatitis C and further identify strategies to improve preventive strategies.

Principal Investigators Project B2

Prof. Dr. med. Thomas von Hahn

Klinik für Gastroenterologie, Hepatologie und Endokrinologie
Medizinische Hochschule Hannover
Carl-Neuberg-Str.1
30625 Hannover
Tel.: +49 511 532-4585

VonHahn.Thomas@mh-hannover.de

Prof. Dr. med. Heiner Wedemeyer

Klinik für Gastroenterologie, Hepatologie und Endokrinologie
Medizinische Hochschule Hannover
Carl-Neuberg-Str.1
30625 Hannover
Tel.: +49 511 532-6814

Wedemeyer.Heiner@mh-hannover.de