Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation
Felix Bohne, … , Giuseppe Tisone, Alberto Sánchez-Fueyo
Felix Bohne, … , Giuseppe Tisone, Alberto Sánchez-Fueyo
Published December 12, 2011
Citation Information: J Clin Invest. 2012;122(1):368-382. https://doi.org/10.1172/JCI59411.
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Research Article Transplantation

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

Abstract

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 with successful drug withdrawal, however, are not well defined. In this study, we analyzed sequential blood and liver tissue samples collected from liver transplant recipients enrolled in a prospective multicenter immunosuppressive drug withdrawal clinical trial. Before initiation of drug withdrawal, operationally tolerant and non-tolerant recipients differed in the intra-graft expression of genes involved in the regulation of iron homeostasis. Furthermore, as compared with non-tolerant recipients, operationally tolerant patients exhibited higher serum levels of hepcidin and ferritin and increased hepatocyte iron deposition. Finally, liver tissue gene expression measurements accurately predicted the outcome of immunosuppressive withdrawal in an independent set of patients. These results point to a critical role for iron metabolism in the regulation of intra-graft alloimmune responses in humans and provide a set of biomarkers to conduct drug-weaning trials in liver transplantation.

Authors

Felix Bohne, Marc Martínez-Llordella, Juan-José Lozano, Rosa Miquel, Carlos Benítez, María-Carlota Londoño, Tommaso-María Manzia, Roberta Angelico, Dorine W. Swinkels, Harold Tjalsma, Marta López, Juan G. Abraldes, Eliano Bonaccorsi-Riani, Elmar Jaeckel, Richard Taubert, Jacques Pirenne, Antoni Rimola, Giuseppe Tisone, Alberto Sánchez-Fueyo

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Figure 2

Intra-graft microarray gene expression profiling of TOL and Non-TOL recipients before immunosuppression drug withdrawal.

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Intra-graft microarray gene expression profiling of TOL and Non-TOL reci...
(A) Non-supervised between-group analysis (BGA) conducted employing liver tissue expression data from the total filtered 33082 Illumina probeset obtained from the following groups of patients: TOL, Non-TOL, liver recipients with recurrent HCV infection (HEPC), liver recipients with acute cellular rejection (Rej), Ctrl-Tx, and Ctrl. Individuals (dots) and groups (ellipses) are positioned on the 2D plane on the basis of their multiple gene expression measurements. The areas delimited by the ellipses cluster 95% of the points belonging to the estimated binomial expression distribution of each of the groups analyzed. (B) Heatmap display of the 50 genes with the most significantly different expression between TOL and Non-TOL recipients. Rows represent genes, and columns represent samples. The intensity of each color denotes the standardized ratio between each value and the average expression of each gene across all samples. Red pixels correspond to an increased abundance of the transcript in the indicated sample, whereas green pixels indicate decreased transcript levels.