Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance.
Long-term allograft survival generally requires lifelong immunosuppression (IS). Rarely, recipients display spontaneous "operational tolerance" with stable graft function in the absence of IS. The lack of biological markers of this phenomenon precludes identification of potentially tolerant patients in which IS could be tapered and hinders the development of new tolerance-inducing strategies. The objective of this study was to identify minimally invasive blood biomarkers for operational tolerance and use these biomarkers to determine the frequency of this state in immunosuppressed patients with stable graft function. Blood gene expression profiles from 75 renal-transplant patient cohorts (operational tolerance/acute and chronic rejection/stable graft function on IS) and 16 healthy individuals were analyzed. A subset of samples was used for microarray analysis where three-class comparison of the different groups of patients identified a "tolerant footprint" of 49 genes. These biomarkers were applied for prediction of operational tolerance by microarray and real-time PCR in independent test groups. Thirty-three of 49 genes correctly segregated tolerance and chronic rejection phenotypes with 99% and 86% specificity. The signature is shared with 1 of 12 and 5 of 10 stable patients on triple IS and low-dose steroid monotherapy, respectively. The gene signature suggests a pattern of reduced costimulatory signaling, immune quiescence, apoptosis, and memory T cell responses. This study identifies in the blood of kidney recipients a set of genes associated with operational tolerance that may have utility as a minimally invasive monitoring tool for guiding IS titration. Further validation of this tool for safe IS minimization in prospective clinical trials is warranted.
Brouard
Sophie
S
Institut National de la Santé et de la Recherche Médicale, U643, Centre Hospitalier Universitaire de Nantes, Institut de Transplantation et de Recherche en Transplantation, and Université de Nantes, Faculte de Medicine, F-44000 Nantes, France.
Mansfield
Elaine
E
Braud
Christophe
C
Li
Li
L
Giral
Magali
M
Hsieh
Szu-chuan
SC
Baeten
Dominique
D
Zhang
Meixia
M
Ashton-Chess
Joanna
J
Braudeau
Cécile
C
Hsieh
Frank
F
Dupont
Alexandre
A
Pallier
Annaik
A
Moreau
Anne
A
Louis
Stéphanie
S
Ruiz
Catherine
C
Salvatierra
Oscar
O
Soulillou
Jean-Paul
JP
Sarwal
Minnie
M
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism*; D002453:Cell Cycle; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism; D023001:Transplantation Tolerance / Q000235:genetics*; D014184:Transplantation, Homologous
D015415:Biomarkers; D007166:Immunosuppressive Agents; D016212:Transforming Growth Factor beta