Gene expression profiling in B lymphocytes from transplanted patients
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Richard Danger
PROVIDER: E-GEOD-39899 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:The achievement of a drug-free operational tolerance for renal transplanted patients is a major goal in organ transplantation. Previous gene expression profiling in peripheral blood mononuclear cells (PBMC) identified genes associated with operational tolerance. The identification of a common pattern of B cell-related genes associated with tolerance encourage us to analyze gene expression in purified B cell from operationally tolerant patients (TOL=10) compared to renal transplanted patients with stable graft function (STA=12) under immunosuppression and also compared to healthy volunteers (HV=10) who have no immunosuppressive treatment and no graft. Microarray analyses exhibited an absence of gene signature associated with tolerance in purified B cell compared to STA or HV. These results suggest that the B cell signatures observed in PBMC may be due to an increase number of total B cells rather than specific B cell characteristics in operationally tolerant patients.
2015-08-01 | GSE39899 | GEO
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.
2015-10-06 | GSE49198 | GEO
Project description:Survival of solid organ grafts depends on life-long immunosuppression, which results in increased rates of infection and malignancy. Induction of tolerance to allografts would represent the optimal solution for controlling both chronic rejection (CR) and side effects of immunosuppression. Although spontaneous ‘‘operational tolerance’’ can occur in human kidney transplantation, the lack of noninvasive peripheral blood biological markers of this rare phenomenon precludes the identification of potentially tolerant patients in whom immunosuppression could be tapered as well as the development of new tolerance inducing strategies. Here, the potential of high throughput microarray technology to decipher complex pathologies allowed us to study the peripheral blood specific gene expression profile and corresponding EASE molecular pathways associated to operational tolerance in a cohort of human kidney graft recipients. In comparison with patients with CR, tolerant patients displayed a set of 343 differentially expressed genes, mainly immune and defense genes, in their peripheral blood mononuclear cells (PBMC), of which 223 were also different from healthy volunteers. Using the expression pattern of these 343 genes, we were able to classify correctly >80% of the patients in a cross-validation experiment and classified correctly all of the samples over time. Collectively, this study identifies a unique PBMC gene signature associated with human operational tolerance in kidney transplantation. 250 samples were analyzed, replicates included: some patients from the TOL and CR groups were sampled twice with an interval between the two different time points of at least 16 months (mean 25.8 months, range 16–31 months). All the samples were analyzed in duplicate or quadruplicate. 1. TOL (n = 21). patients with stable graft function (blood creatinemia<150 mmol/L, proteinuria<1 g/24 h) for at least 1 year (mean 6.4 years,range 1.6–17.2 years) after complete interruption of immunosuppressive therapy. 2. STA (n = 190). Patients with stable kidney graft function under immunosuppressive therapy. 3. CR (n = 31). Patients having a progressive degradation of their renal function (blood creatinemia ≥150 mmol/L, proteinuria ≥1 g/24 h). CR was diagnosed on a graft biopsy according to the updated Banff criteria. CR was defined by histological signs of chronic allograft arteriopathy (arterial intimal fibrosis with mononuclear cell infiltration) and/or transplant glomerulopathy with glomerular double contours. 4. HV (n = 8). Subjects having normal blood formulae and no infectious or other concomitant pathology for at least 6 months before the study.
2017-02-09 | GSE47755 | GEO
Project description: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.
2017-02-09 | GSE47683 | GEO
Project description:Genomic Analysis of more than 400 patients from multi-center transplant programs and clinical trials provides a non-invasive QPCR based gene expression test for operational renal allograft tolerance 3 group comparison of blood from TOL, CAN and Non-transplant healthy controls (HD) allografts. Biological replicates: 16 TOL, 10 CAN and 5 HC
2015-01-08 | E-GEOD-45218 | biostudies-arrayexpress
Project description:mmunosuppressive drugs can be completely withdrawn in up to 20% of liver transplant recipients, commonly referred to as âoperationallyâ tolerant. Immune characterization of these patients, however, has not been performed in detail, and we lack tests capable of identifying tolerant patients among recipients receiving maintenance immunosuppression. In the current study we have analyzed a variety of biological traits in peripheral blood of operationally tolerant liver recipients in an attempt to define a multiparameter âfingerprintâ of tolerance. Thus, we have performed peripheral blood gene expression profiling and extensive blood cell immunophenotyping on 16 operationally tolerant liver recipients, 16 recipients requiring on-going immunosuppressive therapy, and 10 healthy individuals. Microarray profiling identified a gene expression signature that could discriminate tolerant recipients from immunosuppression-dependent patients with high accuracy. This signature included genes encoding for ?d T-cell and NK receptors, and for proteins involved in cell proliferation arrest. In addition, tolerant recipients exhibited significantly greater numbers of circulating potentially regulatory T-cell subsets (CD4+CD25+ T-cells and Vd1+ T cells) than either non-tolerant patients or healthy individuals. Our data provide novel mechanistic insight on liver allograft operational tolerance, and constitute a first step in the search for a non-invasive diagnostic signature capable of predicting tolerance before undergoing drug weaning. Experiment Overall Design: The complete database comprised the expression measurements of 54 675 genes for nine operationally tolerant (TOL) and eight immunosuppression-dependent (ID) samples.
2008-10-21 | E-GEOD-11881 | biostudies-arrayexpress
Project description:Operational tolerance (OT) after kidney transplantation is defined as stable graft acceptance without the need for immunosuppression therapy. However, it is not clear which cellular and molecular pathways are driving tolerance in these patients. In this first-of-its-kind pilot study, we assessed the immune landscape associated with OT (Tol) using the single-cell analyses. Peripheral mononuclear cells (PBMCs) from a kidney transplant recipient (KTR) with OT, a healthy individual (HC), and a KTR with normal kidney function standard of care immunosuppression (SOC) were evaluated. B cell proportion was greatest in Tol with the predominance of TCL1A+ naïve B cells; regulatory T cell (Tregs) was also high in Tol with a relatively higher expression of LSGAL1. Putative ligand-receptor-based cell-cell interactions between B cells and Tregs were identified. TGFB-TGFBR interaction, present in both Tol and SOC, leads to the proliferation of Tregs. However, SOC had the lowest proportion of B cells and Tregs with a G1 phase accumulation of B and T cells. Our findings instigate application of this technology on a larger cohort to identify mediators of tolerance.
2023-06-20 | GSE230650 | GEO
Project description:Operational tolerance (OT) after kidney transplantation is defined as stable graft acceptance without the need for immunosuppression therapy. However, it is not clear which cellular and molecular pathways are driving tolerance in these patients. In this first-of-its-kind pilot study, we assessed the immune landscape associated with OT (Tol) using the single-cell analyses. Peripheral mononuclear cells (PBMCs) from a kidney transplant recipient (KTR) with OT, a healthy individual (HC), and a KTR with normal kidney function standard of care immunosuppression (SOC) were evaluated. B cell proportion was greatest in Tol with the predominance of TCL1A+ naïve B cells; regulatory T cell (Tregs) was also high in Tol with a relatively higher expression of LSGAL1. Putative ligand-receptor-based cell-cell interactions between B cells and Tregs were identified. TGFB-TGFBR interaction, present in both Tol and SOC, leads to the proliferation of Tregs. However, SOC had the lowest proportion of B cells and Tregs with a G1 phase accumulation of B and T cells. Our findings instigate application of this technology on a larger cohort to identify mediators of tolerance.
2023-06-20 | GSE217762 | GEO
Project description:Using meta-analysis of eight independent transplant datasets (236 graft biopsy samples) from four organs, we identified a common rejection module (CRM) consisting of 11 genes that were significantly overexpressed in acute rejection (AR) across all transplanted organs. The CRM genes could diagnose AR with high specificity and sensitivity in three additional independent cohorts (794 samples). In another two independent cohorts (151 renal transplant biopsies), the CRM genes correlated with the extent of graft injury and predicted future injury to a graft using protocol biopsies. Inferred drug mechanisms from the literature suggested that two FDA-approved drugs (atorvastatin and dasatinib), approved for non-transplant indications, could regulate specific CRM genes and reduce the number of graft infiltrating cells during acute rejection. We treated mice with HLA-mismatched murine cardiac transplant with atorvastatin and dasatinib and showed reduction of the CRM genes, significant reduction of graft infiltrating cells, and extended graft survival. We further validated the beneficial effect of atorvastatina on graft survival by retrospective analysis of electronic medical records of a single-center cohort of 2,515 renal transplant patients. In conclusion, we identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning and rational drug design. The eight transplant data sets used for discovery include GSE4315, GSE2596, GSE4470, GSE9377, GSE1563, GSE9493, GSE13440, GSE6095. The two additional independent cohorts of 151 transplant biopsies are GSE25902 and GSE1563. Not all samples from all studies were used. Only the samples marked as either AR or STA in each data set were used for analysis. The 101 samples in this study were used as case-control experiment between acute rejection (AR) and stable (STA) in renal transplant. The samples in this series are one of the three independent validation cohorts. The other two cohorts are described in GSE21374 and GSE36059
2013-10-04 | E-GEOD-50058 | biostudies-arrayexpress
Project description:In clinical organ transplantation complete cessation of immunosuppressive therapy can be successfully accomplished in selected recipients providing a proof-of-principle that allograft tolerance is attainable in humans. The intra-graft molecular pathways associated with human allograft tolerance, however, have not been comprehensively studied before. In this study we analyzed sequential liver tissue samples collected from liver recipients enrolled in a prospective multicenter immunosuppressive withdrawal clinical trial. Tolerant and non-tolerant recipients differed in the intra-graft expression of genes involved in the regulation of iron homeostasis.These results point to a critical role of iron homeostasis in the regulation of intra-graft alloimmune responses in humans and provide a set of novel biomarkers to conduct drug-weaning trials in liver transplantation. The complete database comprised the expression measurements of 48766 probes in liver biopsies. The liver biopsy specimens available for the study were obtained: a) before immunosuppressive drugs were discontinued from tolerant (TOL, n=24) and non-tolerant (Non-TOL, n=29) recipients; b) at the time of rejection from non-tolerant recipients (Non TOL REJ, n=18); In addition, liver tissue samples were also collected from the following control patient groups: a) liver transplant recipients with chronic hepatitis due to recurrent hepatitis C virus infection (HEPC, n=12); b) liver transplant recipients with typical acute cellular rejection taking place during the immediate post-transplant period (REJ, n=9); c) liver transplant recipients under maintenance immunosuppression with normal liver function and normal liver histology 1 year after transplantation (CONT-Tx, n=8); and d) non-transplanted patients undergoing surgery for colorectal liver metastases (CONT, n=10).
2012-01-09 | E-GEOD-26625 | biostudies-arrayexpress