HCV-Induced Immune Responses Influence the Development of Operational Tolerance After Liver Transplantation in Humans


F. Bohne et al. HCV-Induced Immune Responses Influence the Development of Operational Tolerance After Liver Transplantation in Humans. Sci. Transl. Med. 6, 242ra81 (2014)


Pathogen-induced immune responses prevent the establishment of transplantation tolerance in experimental animal models. Whether this occurs in humans as well remains unclear. The development of operational tolerance in liver transplant recipients with chronic hepatitis C virus (HCV) infection allows us to address this question. We conducted a clinical trial of immunosuppression withdrawal in HCV-infected adult liver recipients to elucidate (i) the mechanisms through which allograft tolerance can be established in the presence of an ongoing inflammatory response and (ii) whether anti-HCV heterologous immune responses influence this phenomenon. Of 34 enrolled liver recipients, drug withdrawal was successful in 17 patients (50%). Tolerance was associated with intrahepatic overexpression of type I interferon and immunoregulatory genes and with an expansion of exhausted PD1/CTLA4/2B4-positive HCV-specific circulating CD8+ T cells. These findings were already present before immunosuppression was discontinued and were specific for HCV infection. In contrast, the magnitude of HCV-induced proinflammatory gene expression and the breadth of anti-HCV effector T cell responses did not influence drug withdrawal outcome. Our data suggest that in humans, persistent viral infections exert immunoregulatory effects that could contribute to the restraining of alloimmune responses, and do not necessarily preclude the development of allograft tolerance.


Read abstract online in Science Translational Medicine

Felix Bohne1,2,*, María-Carlota Londoño1,*, Carlos Benítez1, Rosa Miquel3, Marc Martínez-Llordella4, Carolina Russo5, Cecilia Ortiz6, Eliano Bonaccorsi-Riani4, Christian Brander7, Tanja Bauer5, Ulrike Protzer2, Elmar Jaeckel8, Richard Taubert8, Xavier Forns1, Miquel Navasa1, Marina Berenguer6, Antoni Rimola1, Juan-José Lozano9,† and Alberto Sánchez-Fueyo1,4,†‡


1Liver Unit, Hospital Clinic Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Barcelona 08036, Spain.

2Institute of Virology, Technische Universität München–Helmholtz Zentrum München, Munich 81675, Germany.

3Department of Pathology, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona 08036, Spain.

4Institute of Liver Studies, MRC Centre for Transplantation, King’s College London, London SE5 9RS, UK.

5Clinical Cooperation Group Monitoring, Helmholtz Zentrum München, Munich 81675, Germany.

6Liver Unit, Hospital La Fe Valencia, CIBERehd, University of Valencia, Valencia 46026, Spain.

7Irsicaixa AIDS Research Institute, Institució Catalana de Recerca i Estudis Avançats, Barcelona 08916, Spain.

8Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Hannover 30625, Germany.

9Bioinformatics Platform, CIBERehd, Barcelona 08036, Spain.

Grupos de IrsiCaixa vinculados: Inmunidad Celular y Genética del huésped