Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation.
SourceJournal of Clinical Investigation, 122, 1, (2012), pp. 368-382
Article / Letter to editor
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Laboratory of Genetic, Endocrine and Metabolic Diseases
Journal of Clinical Investigation
SubjectIGMD 7: Iron metabolism N4i 1: Pathogenesis and modulation of inflammation; N4i 1 - pathogenesis and modulation of inflammation Oncol 5 - Aetiology, screening and detection
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.
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