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

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 4

In contrast to Non-TOL recipients, TOL patients exhibit mild hepatocyte stainable iron in their liver biopsies.

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In contrast to Non-TOL recipients, TOL patients exhibit mild hepatocyte ...
(A) Total iron score (TIS) values derived from TOL and Non-TOL liver biopsy samples collected at baseline (left panel). Significant differences between TOL and Non-TOL samples were only detected in hepatocytes (middle panel) and not in mesenchymal (Kupffer and endothelial) cells (right panel). (B) Plot showing the influence of individual gene expression measurements on iron stores as assessed by TIS (left panel) and on ferritin serum levels (right panel). Bars above the reference line indicate influential genes. Red indicates negative association; green indicates positive association. Reference line is the expected influence under the null hypothesis. (C) Visualization (original magnification, ×200) of CD4+, CD8+ and FoxP3+ infiltrating cells in a representative portal tract from a liver biopsy with the use of CD4- (red), CD8- (green), and FoxP3-specific (blue) monoclonal antibodies. The right panel shows the negative control employing the secondary fluorescent antibodies only. (D) Number of CD4+, CD8+, and FoxP3+ lymphocytes per portal tract area in biopsy samples obtained from TOL and Non-TOL individuals. All analyses were conducted on liver biopsy samples collected before immunosuppressive drugs were withdrawn. Box plots display medians for each category (center line), interquartile range (box upper and lower boundaries), and minimum and maximum (whiskers).