Multiparameter Immune Profiling of Operational Tolerance in Liver Transplantation

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Multiparameter Immune Profiling of Operational Tolerance in Liver Transplantation

aLiver Transplant Unit, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain bLiver Transplant Unit, Surgical Clinic, University of Rome 'Tor Vergata,' Rome, Italy cChildren´s Hospital Bioinformatics Program, Harvard Medical School, Boston, MA dCliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium eLiver Transplant Unit, Hospital Vall d´Hebró, Autonomous University of Barcelona, Barcelona, Spain fDepartment of Immunology, King´s College Hospital, London, UK gINSERM U643, CHU Hotel-Dieu, Nantes, France

*Corresponding author: A. Sánchez-Fueyo, afueyo@...

Abstract

Immunosuppressive drugs can be completely withdrawn in up to 20% of liver transplant recipients, commonly referred to as 'operationally' tolerant. Immune characterization of these patients, however, has not been performed in detail, and we lack tests capable of identifying tolerant patients among recipients receiving maintenance immunosuppression. In the current study we have analyzed a variety of biological traits in peripheral blood of operationally tolerant liver recipients in an attempt to define a multiparameter 'fingerprint' of tolerance. Thus, we have performed peripheral blood gene expression profiling and extensive blood cell immunophenotyping on 16 operationally tolerant liver recipients, 16 recipients requiring on-going immunosuppressive therapy, and 10 healthy individuals. Microarray profiling identified a gene expression signature that could discriminate tolerant recipients from immunosuppression-dependent patients with high accuracy. This signature included genes encoding for γδ T-cell and NK receptors, and for proteins involved in cell proliferation arrest. In addition, tolerant recipients exhibited significantly greater numbers of circulating potentially regulatory T-cell subsets (CD4+CD25+ T-cells and Vδ1+ T cells) than either non-tolerant patients or healthy individuals. Our data provide novel mechanistic insight on liver allograft operational tolerance, and constitute a first step in the search for a non-invasive diagnostic signature capable of predicting tolerance before undergoing drug weaning.