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Tribbles-1 as a Novel Biomarker of Chronic Antibody-Mediated Rejection

Joanna Ashton-Chess^*, Magali Giral^*, Michael Mengel, Karine Renaudin, Yohann Foucher^*,, Wilfried Gwinner^||, Christophe Braud^*, Emilie Dugast^*, Thibaut Quillard^*, Pamela Thebault^*, Elise Chiffoleau^*, Cécile Braudeau^*, Béatrice Charreau^*, Jean-Paul Soulillou^* and Sophie Brouard^*

^* INSERM, U643, and Centre Hospitalier Universitaire Nantes, Institut de Transplantation et de Recherche en Transplantation, Nantes, France; Université de Nantes, Faculté de Médecine, Nantes, France; Institut für Pathologie and ^|| Abteilung für Nephrologie, Medizinische Hochschule Hannover, Hannover, Germany; CHU Nantes, Service d'Anatomie Pathologique, Nantes, France; and University of Montpellier I, Clinical Research Institute, Department of Biostatistics, Montpellier, France

Correspondence: Pr. Jean-Paul Soulillou, ITERT/INSERM U643, CHU Hôtel Dieu, 30 Bd Jean Monnet, 44093 Nantes, France, Cedex 1. Phone: +33-240-08-74-10; Fax: +33-240-08-74-11; E-mail: jean-paul.soulillou{at}university-nantes.fr, sophie.brouard{at}university-nantes.fr

Received for publication October 1, 2007. Accepted for publication January 2, 2008.

Diagnosis of the specific cause of late allograft injury is necessary if more personalized and efficient immunosuppressive regimens are to be introduced. This study sought previously unrecognized biomarkers for specific histologic diagnoses of late graft scarring by comparison of gene sets from published microarray studies. Tribbles-1 (TRIB1), a human homolog of Drosophila tribbles, was identified to be a potentially informative biomarker. For testing this, mRNA expression in 76 graft biopsies, 71 blood samples, and 11 urine samples were profiled from independent cohorts of renal transplant patients with different histologic diagnoses recruited at two European centers. TRIB1 but not TRIB2 or TRIB3 was found to be a potential blood and tissue biomarker of chronic antibody-mediated rejection, an active immune-mediated form of chronic allograft failure associated with a poor prognosis. TRIB1 mRNA levels in peripheral blood mononuclear cells discriminated patients with chronic antibody-mediated rejection from those with other types of late allograft injury with high sensitivity and specificity. TRIB1 was also upregulated in a rodent model of chronic cardiac vasculopathy, suggesting that this biomarker may be useful in other solid-organ transplants and across species. It was determined that TRIB1 is expressed primarily by antigen-presenting cells and activated endothelial cells. Overall, these data support the potential use of TRIB1 as a biomarker of chronic antibody-mediated allograft failure.

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J. Am. Soc. Nephrol. 2008 19: A4. [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673