title: Hepatic Infiltrates in Operational Tolerant Patients After Liver Transplantation Show Enrichment of Regulatory T Cells Before Proinflammatory Genes Are Downregulated.
abstract: Immunosuppression can be discontinued from selected and stable patients after liver transplantation resulting in spontaneous operational tolerance (SOT), although the underlying mechanisms remain elusive. Thus, we analyzed serial liver biopsy specimens from adult liver recipients enrolled in a prospective multicenter immunosuppression withdrawal trial that used immunophenotyping and transcriptional profiling. Liver specimens were collected before the initiation of weaning, at the time of rejection, or at 1 and 3 years after complete drug discontinuation. Unexpectedly, the tolerated grafts developed portal tract expansion with increased T cell infiltration after immunosuppression withdrawal. This was associated with transient and preferential accumulation of CD4(+) FOXP3(+) cells and a trend toward upregulation of immune activation and regulatory genes, without signs of rejection. At the same time, no markers of endothelial damage or activation were noted. Portal infiltrates persisted at 3 years but were characterized by decreased expression of genes associated with chronic immunological damage. Further, SOT was not associated with a progressive liver fibrosis up to 5 years. These data suggest that SOT involves several mechanisms: a long-lasting local immune cell persistence with a transient regulatory T cells accumulation followed by a downregulation of immune-activated genes over years. These results have important implications for designs and follow-up of weaning trials.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.|Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Taubert
authors.affiliation: Institute of Liver Studies, Liver Sciences Department, MRC Centre for Transplantation, School of Life Sciences & Medicine, King's College London University, King's College Hospital, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Danger
authors.affiliation: Liver Unit, Hospital Clinic Barcelona, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain.
authors.forename: M-C
authors.initials: MC
authors.lastname: Londoño
authors.affiliation: Department of Biostatistics, Institute of Psychiatry, Psychology & Neuroscience King's College London, London, UK.|Department of Experimental Immunobiology, MRC Centre for Transplantation, King's College London, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Christakoudi
authors.affiliation: Liver Unit, Hospital Clinic Barcelona, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Martinez-Picola
authors.affiliation: Institute of Liver Studies, Liver Sciences Department, MRC Centre for Transplantation, School of Life Sciences & Medicine, King's College London University, King's College Hospital, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Rimola
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: M P
authors.initials: MP
authors.lastname: Manns
authors.affiliation: Institute of Liver Studies, Liver Sciences Department, MRC Centre for Transplantation, School of Life Sciences & Medicine, King's College London University, King's College Hospital, London, UK.|Liver Unit, Hospital Clinic Barcelona, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Sánchez-Fueyo
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.|Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Jaeckel
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000032:analysis; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000235:genetics* / Q000276:immunology*; D006085:Graft Survival; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000378:metabolism*; D008107:Liver Diseases / Q000601:surgery; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D023001:Transplantation Tolerance / Q000276:immunology*
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators