title: HCV-induced immune responses influence the development of operational tolerance after liver transplantation in humans.
abstract: 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.
authors: Liver 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. Institute of Virology, Technische Universität München-Helmholtz Zentrum München, Munich 81675, Germany.
authors: Felix
authors: F
authors: Bohne
authors: Liver 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.
authors: María-Carlota
authors: MC
authors: Londoño
authors: Liver 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.
authors: Carlos
authors: C
authors: Benítez
authors: Department of Pathology, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona 08036, Spain.
authors: Rosa
authors: R
authors: Miquel
authors: Institute of Liver Studies, MRC Centre for Transplantation, King's College London, London SE5 9RS, UK.
authors: Marc
authors: M
authors: Martínez-Llordella
authors: Clinical Cooperation Group Monitoring, Helmholtz Zentrum München, Munich 81675, Germany.
authors: Carolina
authors: C
authors: Russo
authors: Liver Unit, Hospital La Fe Valencia, CIBERehd, University of Valencia, Valencia 46026, Spain.
authors: Cecilia
authors: C
authors: Ortiz
authors: Institute of Liver Studies, MRC Centre for Transplantation, King's College London, London SE5 9RS, UK.
authors: Eliano
authors: E
authors: Bonaccorsi-Riani
authors: Irsicaixa AIDS Research Institute, Institució Catalana de Recerca i Estudis Avançats, Barcelona 08916, Spain.
authors: Christian
authors: C
authors: Brander
authors: Clinical Cooperation Group Monitoring, Helmholtz Zentrum München, Munich 81675, Germany.
authors: Tanja
authors: T
authors: Bauer
authors: Institute of Virology, Technische Universität München-Helmholtz Zentrum München, Munich 81675, Germany.
authors: Ulrike
authors: U
authors: Protzer
authors: Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Hannover 30625, Germany.
authors: Elmar
authors: E
authors: Jaeckel
authors: Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Hannover 30625, Germany.
authors: Richard
authors: R
authors: Taubert
authors: Liver 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.
authors: Xavier
authors: X
authors: Forns
authors: Liver 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.
authors: Miquel
authors: M
authors: Navasa
authors: Liver Unit, Hospital La Fe Valencia, CIBERehd, University of Valencia, Valencia 46026, Spain.
authors: Marina
authors: M
authors: Berenguer
authors: Liver 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.
authors: Antoni
authors: A
authors: Rimola
authors: Bioinformatics Platform, CIBERehd, Barcelona 08036, Spain.
authors: Juan-José
authors: JJ
authors: Lozano
authors: Liver 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. Institute of Liver Studies, MRC Centre for Transplantation, King's College London, London SE5 9RS, UK. sanchez_fueyo@kcl.ac.uk.
authors: Alberto
authors: A
authors: Sánchez-Fueyo
mesh_terms: D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000276:immunology; D016174:Hepacivirus / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007109:Immunity; D007165:Immunosuppression Therapy; D007370:Interferon Type I / Q000378:metabolism; D016031:Liver Transplantation; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology
chemical_list: D015415:Biomarkers; D007370:Interferon Type I; D016692:Receptors, Antigen, T-Cell, gamma-delta; C521523:T-cell receptor Vdelta2, human