Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

MOLECULAR CHARACTERIZATION OF LIVER ALLOGRAFTS FROM OPERATIONALLY TOLERANT TRANSPLANT RECIPIENTS (Illumina)

ABSTRACT: In clinical organ transplantation complete cessation of immunosuppressive therapy can be successfully accomplished in selected recipients providing a proof-of-principle that allograft tolerance is attainable in humans. The intra-graft molecular pathways associated with human allograft tolerance, however, have not been comprehensively studied before. In this study we analyzed sequential liver tissue samples collected from liver recipients enrolled in a prospective multicenter immunosuppressive withdrawal clinical trial. Tolerant and non-tolerant recipients differed in the intra-graft expression of genes involved in the regulation of iron homeostasis.These results point to a critical role of iron homeostasis in the regulation of intra-graft alloimmune responses in humans and provide a set of novel biomarkers to conduct drug-weaning trials in liver transplantation. The complete database comprised the expression measurements of 48766 probes in liver biopsies. The liver biopsy specimens available for the study were obtained: a) before immunosuppressive drugs were discontinued from tolerant (TOL, n=24) and non-tolerant (Non-TOL, n=29) recipients; b) at the time of rejection from non-tolerant recipients (Non TOL REJ, n=18); In addition, liver tissue samples were also collected from the following control patient groups: a) liver transplant recipients with chronic hepatitis due to recurrent hepatitis C virus infection (HEPC, n=12); b) liver transplant recipients with typical acute cellular rejection taking place during the immediate post-transplant period (REJ, n=9); c) liver transplant recipients under maintenance immunosuppression with normal liver function and normal liver histology 1 year after transplantation (CONT-Tx, n=8); and d) non-transplanted patients undergoing surgery for colorectal liver metastases (CONT, n=10).

ORGANISM(S): Homo sapiens

SUBMITTER: Juanjo Lozano

PROVIDER: E-GEOD-26625 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation.

Bohne Felix F Martínez-Llordella Marc M Lozano Juan-José JJ Miquel Rosa R Benítez Carlos C Londoño María-Carlota MC Manzia Tommaso-María TM Angelico Roberta R Swinkels Dorine W DW Tjalsma Harold H López Marta M Abraldes Juan G JG Bonaccorsi-Riani Eliano E Jaeckel Elmar E Taubert Richard R Pirenne Jacques J Rimola Antoni A Tisone Giuseppe G Sánchez-Fueyo Alberto A

The Journal of clinical investigation 20111212 1

Following organ transplantation, lifelong immunosuppressive therapy is required to prevent the host immune system from destroying the allograft. This can cause severe side effects and increased recipient morbidity and mortality. Complete cessation of immunosuppressive drugs has been successfully accomplished in selected transplant recipients, providing proof of principle that operational allograft tolerance is attainable in clinical transplantation. The intra-graft molecular pathways associated ...[more]

PMID: 22156196

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Project description:Immune responses induced by ongoing and/or past infections prevent the establishment of transplantation tolerance in experimental animal models. How host-pathogen interactions influence allograft tolerance in humans has not been investigated before. The spontaneous development of operational tolerance in liver transplant recipients with chronic hepatitis C virus (HCV) infection constitutes a unique setting to address this question. We conducted a clinical trial of immunosuppression withdrawal in stable HCV-infected liver recipients to elucidate: i) the mechanisms through which allograft tolerance is established in the presence of an ongoing inflammatory response; and ii) how is influenced by anti-HCV heterologous immune responses. Enrolled patients gradually discontinued their immunosuppressive drugs over 6-9 months, and those who maintained normal allograft status 12 months after drug withdrawal were considered operationally tolerant. Successful drug withdrawal was associated with intra-hepatic over-expression of type I interferon and immune-regulatory genes, and correlated 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 inflammatory gene expression and the scope of anti-HCV effector T cell responses did not influence drug withdrawal outcome. Our data indicate that in humans persistent viral infections do not necessarily preclude the development of transplantation tolerance. At least in HCV-infected liver allografts, mechanisms associated with the capacity of the virus to evade adaptive immunity could contribute to the restraining of alloimmune responses and the establishment of transplantation tolerance. Transcriptomic study from the following liver tissue samples: 12 tolerant before immunosuppression (IS), 13 non-tolerant before IS, 4 from non-tolerant at the time of rejection, 13 from tolerant patients 12 months after IS discontinuation. Additionally, 8 liver tissue samples obtained from healthy living liver donors undergoing partial hepatectomy were included as non-transplanted controls.

Dataset Information

MOLECULAR CHARACTERIZATION OF LIVER ALLOGRAFTS FROM OPERATIONALLY TOLERANT TRANSPLANT RECIPIENTS (Illumina)

Publications

Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation.

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