- Dr Marc Martinez-Llordella, Principal Investigator
- Prof. Alberto Sanchez-Fueyo, Collaborator
- Dr Juan-Jose Lozano, Collaborator
- Dr Kosh Agarwal, Collaborator
- Prof. John O'Grady, Collaborator
- King's College, London, UK
- Influence of HCV infection on the specific immune responses against donor antigens after liver transplantation
HCV chronically infects around 200 million people worldwide and constitutes the leading indication for liver transplantation in the Western hemisphere. HCV infection is present in almost 50% of liver recipients and universally recurs following liver transplantation, leading to persistent liver allograft T cell infiltration. Evidences from experimental animal models indicate that immune responses to pathogens enhance alloreactivity and hamper the induction of transplantation tolerance. However, in liver transplant recipients with chronic HCV infection successful immunosuppression withdrawal, known as operational tolerance, can be accomplished as frequently as in HCV-negative recipients. Therefore, this constitutes the only clinical setting to study the influence of virus-induced responses on the donor-specific immunogenicity. Our preliminary studies suggest that, in contrast to what would have been anticipated, in some HCV-infected recipients HCV-induced immune responses promote, rather than hinder, the establishment of allograft tolerance. We propose here to analyze in depth the mechanisms through which persistent HCV infection may suppress anti-donor reactivity, and how viral eradication with new therapies may disrupt the immunoregulation acquired. Circulating and expanded liver-infiltrated T cells will be employed for functional and phenotypic analysis. Our findings will provide the first description of how innate and adaptive anti-viral immune responses shape donor-specific responses in human transplantation. Knowledge gained from these studies will have implications for the management of immunosuppressive therapy in HCV-infected recipients, and in patients infected with other persistent infections such as HBV and HIV. Furthermore, elucidation of whether the use of direct anti-viral agents fully restores anti-donor reactivity in transplants recipients with persistent HCV infection may have immediate clinical implications, since it may influence how immunosupression is man-aged following viral eradication.