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Hepatic Infiltrates in Operational Tolerant Patients After Liver Transplantation Show Enrichment of Regulatory T Cells Before Proinflammatory Genes Are Downregulated

Research output: Contribution to journalArticle

Richard Taubert, Richard Amaud Eric David Danger, María-Carlota Londono, Sofia Christakoudi, Marta Martinez-Picola, Antoni Rimola, Michael Manns, Alberto Sanchez Fueyo, Elmer Jaeckel

Original languageEnglish
JournalAmerican Journal of Transplantation
Early online date18 Feb 2016
DOIs
Accepted/In press26 Sep 2015
E-pub ahead of print18 Feb 2016

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  • AJT-2015-Taubert_revised

    AJT_2015_Taubert_revised.pdf, 598 KB, application/pdf

    Uploaded date:11 Mar 2016

    Version:Accepted author manuscript

King's Authors

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.

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