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 intragraft expression of genes involved in the regulation of iron homeostasis. Furthermore, as compared with nontolerant 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.

Inflammatory macrophage–associated 3-gene signature predicts subclinical allograft injury and graft survival

“…The data sets comprised 1,697 biopsy samples from renal (11 data sets, 1,571 samples), cardiac (3 data sets, 94 samples), and lung transplants (1 data set, 32 samples; Table 1). Four of these data sets included only protocol biopsies (7,(17)(18)(19)(20), six included only for-cause biopsies (21)(22)(23)(24)(25)(26), and five included both protocol and for-cause biopsies (7,(27)(28)(29). We curated each data set to identify allograft biopsies from AR and stable (STA) patients.…”

A Three-Gene Assay for Monitoring Immune Quiescence in Kidney Transplantation

“…7,8 These patients are conventionally called operationally tolerant (TOL) and provide a unique repertoire for study and development of monitoring methods that help to differentiate transplant recipients receiving immunosuppression with differing immune thresholds and thus help identify patients who may safely minimize their immunosuppression. Transcriptional studies in peripheral blood by our group and others have identified gene signatures for TOL after kidney [7][8][9] and liver 10,11 transplantation. But these studies are limited by insufficient cross-validations in independent cohorts, and, importantly, the frequency of a TOL signature is poorly defined in stable transplant recipients receiving immunosuppression.…”

“…Figure 3A), and canonical pathway analyses identified the complement system (P=0.03) and the B cell activating factor signaling pathway (P=0.04) associated with these genes (Supplemental Figure 3B). BNC2, which encodes for a DNA-/metal-binding protein, has previously been associated with peripheral gene expression profiling of operationally tolerant liver transplant recipients 10 ; KLF6 belongs to the Krueppellike family of transcription factors, which participate in diverse aspects of leukocyte growth, development, differentiation, and activation of cells of myeloid lineages. 17 Finally, CYP1B1 belonged to the cytochrome P450 family of monooxygenases that catalyzes reactions involved in drug metabolism and synthesis of cholesterol, steroids, and lipids.…”

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“…In addition, tissue genes involved in iron homeostasis have been recently identified, which are shown before liver transplant in recipients who developed COT. 25 No prospective studies have been performed to validate the efficiency of utilizing a biomarker to successfully accomplish COT. Such investigational efforts are required in the future to move forward the concept of COT in solid-organ transplant.…”