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| Status |
Public on Feb 09, 2017 |
| Title |
Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Long-term allograft survival generally requires lifelong immunosuppression. Rarely, recipients display spontaneous operational tolerance with stable graft function in the absence of immunosuppression. The lack of biological markers of this phenomenon precludes identification of potentially tolerant patients in which immunosuppression 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 utilize these biomarkers to determine the frequency of this state in immunosupressed 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 immunosuppression) 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. 33/49 genes correctly segregated tolerance and chronic rejection phenotypes with 99% and 86% specificity. The signature is shared with 1/12 and 5/10 stable patients on triple immunosuppression and low dose steroid monotherapy respectively. The gene signature suggests a pattern of reduced co-stimulatory 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 immunosuppression titration. Further validation of this tool for safe immunosuppression minimization in prospective clinical trials is warranted.
67 samples were analyzed, no replicates included: 1. TOL (n = 12). patients with long-term stable graft function, without immunosuppression for at least 2 years 2. MIS (n = 10). Patients with stable graft function on steroid monotherapy (<10 mg/day) for 4.6. Calcineurin inhibitors and CellCept were removed in these patients because of previous posttransplant lymphoproliferative disease (n = 6), cancer (n = 2), or uncontrolled infectious disease (n = 2). 3. STA (n = 12). Patients with stable kidney graft function at >5 years posttransplantation while under mycophenolate mofetil or azathioprine and maintenance steroids with (n = 5) or without (n = 7) an associated calcineurin inhibitor. 4. AR (n = 14). Patients experiencing rapid decline (>20% from baseline) in graft function and biopsy-proven AR. 5. CR (n = 11). Patients having a progressive degradation of their renal function (creatinine clearance of <60 ml per min per 1.73 m2 and/or proteinuria of >1.5 g/day) and histological signs CR. 6. N (n = 8). These subjects all had normal blood formulae and no infectious or other concomitant pathology for at least 6 months before the study.
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| Overall design |
67 PBL (Peripheral Blood Leukocytes) samples from 6 groups (TOL, MIS, STA, AR, CR, N) were analyzed by microarray.
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| Contributor(s) |
Brouard S, Mansfield E, Braud C, Li L, Giral M, Hsieh S, Baeten D, Zhang M, Ashton-Chess J, Braudeau C, Hsieh F, Dupont A, Pallier A, Moreau A, Louis S, Ruiz C, Salvatierra O, Soulillou J, Sarwal M |
| Citation(s) |
17873064 |
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| Submission date |
Jun 05, 2013 |
| Last update date |
Feb 09, 2017 |
| Contact name |
Daniel BARON |
| E-mail(s) |
daniel.baron@univ-nantes.fr
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| Organization name |
Institut national de la santé et de la recherche médicale-INSERM
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| Department |
UMR1064 - Centre de Recherche en Transplantation & Immunologie
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| Lab |
Tolerance et regulation lymphocytaire
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| Street address |
30 Bd Jean Monnet
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| City |
Nantes |
| State/province |
Loire-Atlantique (44) |
| ZIP/Postal code |
44093 |
| Country |
France |
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| Platforms (1) |
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| Samples (67)
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| Relations |
| BioProject |
PRJNA207105 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE47683_RAW.tar |
438.5 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
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