Influence of Hepatitis C Virus driven immune responses on the acquisition of operational tolerance in liver transplant recipients

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One of the major constraints of long-term graft survival is the need to administer immunosuppressant (IS) drugs to prevent rejection of transplanted tissue, which is associated with severe side effects like renal and metabolic toxicity, infection and malignancies. Therefore, induction of transplantation tolerance constitutes the optimal solution for post transplantation treatment. Clinically defined “operational” tolerance comprises graft acceptance sustained for years in the absence of IS without functional graft impairment. In humans, liver transplantation represents a unique model to investigate the acquisition of operational tolerance, given that up to 20% of recipients can completely discontinue IS drugs maintaining normal liver function. A potential limitation to widespread withdrawal of IS in liver transplantation is the fact that almost 50% of recipients are chronically infected with Hepatitis C Virus (HCV) which can alter or break the ability to attain tolerance. We propose here to elucidate the molecular and cellular components of HCV-induced immune responses influencing tolerance acquisition in liver transplant recipients. In addition we will test the hypothesis that IS-withdrawal will lead to decreased liver damage by promoting cellular anti-HCV-responses.