| World-wide more than 1 million patients die annually of liver failure or hepatocellular carcinoma as a consequence of chronic hepatitis B (HBV) infection. Chronic HBV infection is the result of a complex interaction between a replicating non-cytopathic virus and a down-regulated antiviral immune response. Regulatory T cells (Treg) represent a unique lineage of T cells with a critical role in maintaining immune homeostasis. The central hypothesis of this project is that regulatory T cells (Treg) induce immune tolerance in chronic HBV infection. To investigate the contribution of Treg in persistent HBV infection we will study multiple pathways. In the dendritic cell (DC) pathway we will analyse the interaction between Treg and DCs, an important family of antigen presenting cells, which are functionally impaired in chronic HBV infection. We will determine whether Treg induce tolerance to HBV through induction of HBV tolerant Cs from DC progenitors. Vice versa we will assess whether HBV tolerant DCs induce Treg from naive T cells. In the effector T cell pathway we will investigate whether Treg induce HBV tolerance directly through suppression of HBV-specific CD4+ and CD8+ T cells. These in vitro studies will be followed by a study in humans assessing the effect of therapy-induced HBV reduction on both pathways of Treg-induced HBV tolerance. Finally, to reverse the inadequate immune response to the virus we will induce HBV-specific activation of DC progenitors and functionally deplete Treg from blood of chronic HBV patients. It is our aim to develop a therapeutic strategy through vaccination with ex vivo modulated DC progenitors and in vivo depletion of Treg to reverse HBV tolerance and thereby resolve chronic HBV-related liver disease. This project will elucidate key pathways of tolerance induction by Treg in persistent infections and will pave the way for novel therapeutic strategies of many immunology-based disorders. |
