title: 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.affiliation: Liver Unit, Hospital Clinic Barcelona, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain.
authors.forename: Felix
authors.initials: F
authors.lastname: Bohne
authors.forename: Marc
authors.initials: M
authors.lastname: Martínez-Llordella
authors.forename: Juan-José
authors.initials: JJ
authors.lastname: Lozano
authors.forename: Rosa
authors.initials: R
authors.lastname: Miquel
authors.forename: Carlos
authors.initials: C
authors.lastname: Benítez
authors.forename: María-Carlota
authors.initials: MC
authors.lastname: Londoño
authors.forename: Tommaso-María
authors.initials: TM
authors.lastname: Manzia
authors.forename: Roberta
authors.initials: R
authors.lastname: Angelico
authors.forename: Dorine W
authors.initials: DW
authors.lastname: Swinkels
authors.forename: Harold
authors.initials: H
authors.lastname: Tjalsma
authors.forename: Marta
authors.initials: M
authors.lastname: López
authors.forename: Juan G
authors.initials: JG
authors.lastname: Abraldes
authors.forename: Eliano
authors.initials: E
authors.lastname: Bonaccorsi-Riani
authors.forename: Elmar
authors.initials: E
authors.lastname: Jaeckel
authors.forename: Richard
authors.initials: R
authors.lastname: Taubert
authors.forename: Jacques
authors.initials: J
authors.lastname: Pirenne
authors.forename: Antoni
authors.initials: A
authors.lastname: Rimola
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tisone
authors.forename: Alberto
authors.initials: A
authors.lastname: Sánchez-Fueyo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D023181:Antimicrobial Cationic Peptides / Q000097:blood; D005260:Female; D005293:Ferritins / Q000097:blood; D015870:Gene Expression; D020869:Gene Expression Profiling; D064451:Hepcidins; D006706:Homeostasis; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D016031:Liver Transplantation / Q000276:immunology* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011446:Prospective Studies
chemical_list: D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; D064451:Hepcidins; D007166:Immunosuppressive Agents; D005293:Ferritins; D007501:Iron