Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Indices of Tolerance (IOT): Cross-platform biomarkers that identify kidney transplant tolerance

ABSTRACT: Being able to identify patients in whom immunological tolerance has been established or is developing would allow an individually tailored approach to post-transplant management of kidney allograft recipients. Ex vivo immunological monitoring was performed on samples from five groups of European renal transplant recipients (“IOT samples”): ten drug-free tolerant recipients who were functionally stable despite remaining immunosuppression-free for more than one year (Tol-DF); also functionally stable patients on minimal immunosuppression (<10 mg/day prednisone, s-LP); stable patients maintained with calcineurin inhibitors (s-CNI); stable patients maintained on CNI-free immunosuppression regimen (s-nCNI); patients showing signs of chronic rejection (CR) and healthy controls (HC). Among the investigation of other biomarkers and bioassays, gene expression profiles were generated on custom Agilent 8x15K 60mer oligonucleotide microarrays (“RISET 2.0”) on the IOT cohort (training set) and on an independent cohort of patients from the ITN (USA) that contained similar groups of patients and included 23 tolerant recipients (“ITN samples”, test set). Set of genes were identified, whose expression on whole blood allowed the identification of 100% of the tolerant recipients in the training set and 84% in the test set. Keywords: classification of clinical samples, tolerance prediction IOT samples: 13 samples from 10 Tol-DF patients, 16 samples from 11 s-LP patients, 8 samples from 8 s-nCNI patients, 40 samples from 28 s-CNI patients, 10 samples from 9 CR patients, and 8 samples from 8 HC donors were analysed on a custom Agilent 8x15K 60mer oligonucleotide microarray encomprising 5069 probes in triplicates. The microarray is dedicated to transplantation research and was designed based on current literature and published and unpublished data provided by the RISET consortium. For the probe selection procedure we specially focused on the detection of multiple transcript variants of a gene, on optimized hybridization properties of the probes, and on the avoidance of crosshybridization. The sampling dates of replicate samples from the same patient range from one day to 1.5 years. ITN samples: 31 samples from 23 Tol-DF patients, 14 samples from 11 s-LP patients, 52 samples from 34 s-CNI patients, 25 samples from 18 CR patients, and 20 samples from 20 HC donors were analysed on the same microarray platform and served as test set. The samples of the two cohorts differ in the protocol of RNA preparation.

ORGANISM(S): Homo sapiens

SUBMITTER: Stefan Tomiuk

PROVIDER: E-GEOD-14655 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans.

Sagoo Pervinder P Perucha Esperanza E Sawitzki Birgit B Tomiuk Stefan S Stephens David A DA Miqueu Patrick P Chapman Stephanie S Craciun Ligia L Sergeant Ruhena R Brouard Sophie S Rovis Flavia F Jimenez Elvira E Ballow Amany A Giral Magali M Rebollo-Mesa Irene I Le Moine Alain A Braudeau Cecile C Hilton Rachel R Gerstmayer Bernhard B Bourcier Katarzyna K Sharif Adnan A Krajewska Magdalena M Lord Graham M GM Roberts Ian I Goldman Michel M Wood Kathryn J KJ Newell Kenneth K Seyfert-Margolis Vicki V Warrens Anthony N AN Janssen Uwe U Volk Hans-Dieter HD Soulillou Jean-Paul JP Hernandez-Fuentes Maria P MP Lechler Robert I RI

The Journal of clinical investigation 20100524 6

Identifying transplant recipients in whom immunological tolerance is established or is developing would allow an individually tailored approach to their posttransplantation management. In this study, we aimed to develop reliable and reproducible in vitro assays capable of detecting tolerance in renal transplant recipients. Several biomarkers and bioassays were screened on a training set that included 11 operationally tolerant renal transplant recipients, recipient groups following different immu ...[more]

PMID: 20501943

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Project description:This study corresponds to a re-analysis and meta-analysis of the five transcriptomic studies related to spontaneous tolerance to renal allograft in human. It examines the transcriptome of peripheral blood samples from six distinct clinical groups: healthy volunteers (HV); tolerant patients (TOL); stable patients on minimal immunosuppression (MIS) or maintained on classical immunosuppressive therapy (STA); patients showing either signs of chronic rejection (CR) or acute rejection (AR). The initial studies are the following: -Study 1 from Braud C. et al. (J Cell Biochem., 2008) published under GEO accession number GSE47755 and comprising 250 unique samples (8 HV; 21 TOL; 190 STA; 31 CR). -Study 2 from Brouard S. et al. (Proc Natl Acad Sci U S A., 2007) published under GEO accession number GSE47683 and comprising 67 unique samples (8 HV; 12 TOL; 10 MIS; 12 STA; 11 CR; 14 AR). - Study 3 from Lozano JJ. et al. (Am J Transplant., 2011) published under GEO accession number GSE22707 and comprising 42 unique samples (6 HV; 12 TOL; 12 STA; 12 CR). - Study 4 from Newell KA. et al. (J Clin Invest., 2010) published under GEO accession number GSE22229 and comprising 58 unique samples (12 HV; 19 TOL; 27 STA). - Study 5 from Sagoo P. et al. (J Clin Invest. 2010) published under GEO accession number GSE14655 and comprising two distinct cohorts of patients. The IOT (“Indices of Tolerance”) cohort (5a) corresponds to a European group of patients and totalizes 74 unique samples (8 HV; 10 TOL; 11 MIS; 36 STA; 9 CR). The ITN (“Immune Tolerance in Transplantation”) cohort (5b) corresponds to an American group of patients and totalizes 105 unique samples (20 HV; 22 TOL; 11 MIS; 34 STA; 18 CR). The final data matrix corresponds to the combination of the data from the five independent studies and examines the expression of 1846 meta-genes (MG) across 596 unique blood samples. The 1846 meta-genes correspond to the genes being measured across the five datasets and form a virtual microarray platform (TOL-HUMAN-G1846). The 596 examined samples can be divided into 62 HV, 96 TOL, 32 MIS, 311 STA, 81 CR, and 14 AR.

Project description:Background: Despite significant improvements in short-term kidney transplant survival, comparable increases in 5 and 10-year outcomes have not been achieved. Chronic allograft nephropathy (CAN) is a major cause of late graft loss. Toxic nephropathy and inadequate long-term immunosuppression are possible factors. We performed a randomized prospective trial comparing calcineurin inhibitor (CNI)-free to CNI-based immunosuppression to determine the impact on renal function, structure, and gene expression. Methods: Sixty-one kidney recipients received mycophenolate mofetil (MMF), and prednisone (P). Randomized patients received concentration-controlled sirolimus or cyclosporine. Two years post-transplant 55 patients underwent renal function studies, 48 (87%) underwent transplant biopsies; all classified by Banff scoring and 41 by DNA microarrays. Findings: Comparing sirolimus/MMF/P to cyclosporine/MMF/P at two years, there was a significantly lower serum creatinine (1.35 vs. 1.81 mg/dl; p=0.008), significantly higher Cockroft-Gault glomerular filtration rate (GFR) (80.4 vs. 63.4 cc/min; p=0.008), iothalamate GFR (60.6 vs. 49.2 cc/min; p= 0.018), and Banff 0 (normal) biopsies (66.6 vs. 20.8%; p=0.013). Regression analysis of calculated GFR’s from 1 to 36 months yielded a positive slope for sirolimus of 3.36 ml/min/year, and a negative slope for cyclosporine of –1.58 ml/min/year (p=0.008). Gene expression profiles of kidney biopsies with higher Banff CAN scores confirmed significant up regulation of genes responsible for immune/inflammation and fibrosis/tissue remodeling. Interpretation: At two years the sirolimus-treated patients have better renal transplant function, a diminished prevalence of CAN, and down regulated expression of genes responsible for the progression of CAN. All may provide for an alternative natural history with improved graft survival. Keywords = Cyclosporine Keywords = Sirolimus Keywords = Transplantation Keywords = DNA microarrays Keywords = calcineurin inhibitors Keywords: parallel sample. This dataset is part of the TransQST collection.

Dataset Information

Indices of Tolerance (IOT): Cross-platform biomarkers that identify kidney transplant tolerance

Publications

Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans.

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