Gene Expression Test for Operational Renal Allograft Tolerance
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE45218 | GEO | 2015/01/08
SECONDARY ACCESSION(S): PRJNA215714
REPOSITORIES: GEO
Similar Datasets
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: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:Operational tolerance after solid organ transplantation is defined as stable graft acceptance without immunosuppression while maintaining normal immunocompetence against immunological insults. However, it is not clear yet which cellular and molecular pathways are driving tolerance in these patients and how this state can be induced in order to improve graft survival. Several transcriptomic analysis have shown that transcription signatures in blood can reflect the immunological state associated with operational tolerance in kidney transplant. Nonetheless, epigenetic dynamics orchestrating these transcription signatures have not yet been studied. Here, we performed genome-wide analysis of DNA methylation of kidney transplant recipients with chronic rejection and operational tolerance. Our data showed that chronic rejection and operational tolerance recipients have differential DNA methylation in 2737 genes, indicating that each patient group has a specific epigenetic signature associated with transplant outcome. In addition, we observed that operational tolerance is associated with DNA demethylation in genes involved in immune function, including B cell activation (e.g. ST6GAL1, MS4A1 and MEF2C) and the Th17 differentiation program (e.g. LY9 and BATF), while in CR patients is mostly associated intracellular signaling and ubiquitination pathways. Finally, we used weighted gene co-expression network analysis (WGCNA) to select the more defining epigenetic changes associated with operational tolerance. By this method, we select 12 genomic regions specifically hypomethylated (HIVEP2, HOMER1, UTRN, PTPRO, SP100 and JAZF1) or hypermethylated (EMZ8, EZR-AS, WDR20, NADSYN1, TBCD and MED17) in tolerant patients. Analysis of these genes in stable transplant recipients with immunosuppression showed that these patients have a similar methylation signature to operational tolerance recipients. Overall, these results demonstrate that DNA methylation in blood can mirror the immune status associated with kidney transplant outcome and provides a starting point for understanding the epigenetic mechanisms associated with operational tolerance.
2021-08-12 | GSE156359 | GEO
Project description:Defining a methylation signature associated with operational tolerance in renal transplant
| PRJNA657602 | ENA
Project description:mmunosuppressive drugs can be completely withdrawn in up to 20% of liver transplant recipients, commonly referred to as ‘operationally’ 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 ‘fingerprint’ 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.
2008-06-25 | GSE11881 | GEO
Project description:Immune responses induced by ongoing and/or past infections prevent the establishment of transplantation tolerance in experimental animal models. How host-pathogen interactions influence allograft tolerance in humans has not been investigated before. The spontaneous development of operational tolerance in liver transplant recipients with chronic hepatitis C virus (HCV) infection constitutes a unique setting to address this question. We conducted a clinical trial of immunosuppression withdrawal in stable HCV-infected liver recipients to elucidate: i) the mechanisms through which allograft tolerance is established in the presence of an ongoing inflammatory response; and ii) how is influenced by anti-HCV heterologous immune responses. Enrolled patients gradually discontinued their immunosuppressive drugs over 6-9 months, and those who maintained normal allograft status 12 months after drug withdrawal were considered operationally tolerant. Successful drug withdrawal was associated with intra-hepatic over-expression of type I interferon and immune-regulatory genes, and correlated with an expansion of exhausted PD1/CTLA4/2B4-positive HCV-specific circulating CD8+ T cells. These findings were already present before immunosuppression was discontinued and were specific for HCV infection. In contrast, the magnitude of HCV-induced inflammatory gene expression and the scope of anti-HCV effector T cell responses did not influence drug withdrawal outcome. Our data indicate that in humans persistent viral infections do not necessarily preclude the development of transplantation tolerance. At least in HCV-infected liver allografts, mechanisms associated with the capacity of the virus to evade adaptive immunity could contribute to the restraining of alloimmune responses and the establishment of transplantation tolerance. Transcriptomic study from the following liver tissue samples: 12 tolerant before immunosuppression (IS), 13 non-tolerant before IS, 4 from non-tolerant at the time of rejection, 13 from tolerant patients 12 months after IS discontinuation. Additionally, 8 liver tissue samples obtained from healthy living liver donors undergoing partial hepatectomy were included as non-transplanted controls.
2014-12-23 | E-GEOD-52420 | biostudies-arrayexpress
Project description:The Australian Chronic Allograft Dysfunction (AUSCAD) study is an ongoing single centre cohort study at Westmead hospital in Australia. In this section of the study, we aimed to identify biomarkers for allograft rejection in kidney transplant recipients, 3-months after their transplant. Our study recruited 123 patients, each having protocol renal allograft biopsies taken 3-months post transplantation.
2024-04-05 | GSE261892 | GEO
Project description:Immune responses induced by ongoing and/or past infections prevent the establishment of transplantation tolerance in experimental animal models. How host-pathogen interactions influence allograft tolerance in humans has not been investigated before. The spontaneous development of operational tolerance in liver transplant recipients with chronic hepatitis C virus (HCV) infection constitutes a unique setting to address this question. We conducted a clinical trial of immunosuppression withdrawal in stable HCV-infected liver recipients to elucidate: i) the mechanisms through which allograft tolerance is established in the presence of an ongoing inflammatory response; and ii) how is influenced by anti-HCV heterologous immune responses. Enrolled patients gradually discontinued their immunosuppressive drugs over 6-9 months, and those who maintained normal allograft status 12 months after drug withdrawal were considered operationally tolerant. Successful drug withdrawal was associated with intra-hepatic over-expression of type I interferon and immune-regulatory genes, and correlated with an expansion of exhausted PD1/CTLA4/2B4-positive HCV-specific circulating CD8+ T cells. These findings were already present before immunosuppression was discontinued and were specific for HCV infection. In contrast, the magnitude of HCV-induced inflammatory gene expression and the scope of anti-HCV effector T cell responses did not influence drug withdrawal outcome. Our data indicate that in humans persistent viral infections do not necessarily preclude the development of transplantation tolerance. At least in HCV-infected liver allografts, mechanisms associated with the capacity of the virus to evade adaptive immunity could contribute to the restraining of alloimmune responses and the establishment of transplantation tolerance.
2014-12-23 | GSE52420 | GEO
Project description:Renal transplantation is the preferred treatment of end stage renal disease, but allograft survival is limited by development of interstitial fibrosis and tubular atrophy in response to various stimuli. Much effort has been put into identifying new protein markers of fibrosis to support the diagnosis. In present work, we performed an in-depth quantitative proteomics analysis of allograft biopsies from 31 prevalent renal transplant patients and identified correlated the quantified proteins with the volume fraction of fibrosis as determined by a morphometric method. Linear regression analysis identified four proteins that were highly associated with the degree of interstitial fibrosis, namely Coagulation Factor XIII A chain (estimate 18.7, adjusted p<0.03), Uridine Phosphorylase 1 (estimate 19.4, adjusted p<0.001), Actin-related protein 2/3 subunit 2 (estimate 34.2, adjusted p<0.05) and Cytochrome C Oxidase Assembly Factor 6 homolog (estimate -44.9, adjusted p<0.002) even after multiple testing. Proteins that were negatively associated with fibrosis (p < 0.005) were primarily related to normal metabolic processes and respiration, whereas proteins that were positively associated with fibrosis (p < 0.005) were involved in catabolic processes, cytoskeleton organization and immune response. The identified proteins may be candidates for further validation with regards to renal fibrosis. The results support the notion that cytoskeleton organization and immune responses are prevalent processes in renal allograft fibrosis.
2020-05-26 | PXD017867 | Pride
Project description:The aim of this study was to investigate the role of infiltrating macrophages in renal allograft fibrosis. Forty-six protocol renal allograft biopsies obtained one-year after transplantation were stained with Sirius Red to quantify fibrosis and double stained with CD68 and CD206 to identify the proportion of alternately activated (M2) macrophages. 23 protocol biopsies obtained 12 months post transplant were analyzed for gene expression by microarray, which was correlated with macrophage infiltration and the severity of fibrosis. Phenotypic analysis showed 92% of infiltrating macrophages exhibited an M2 phenotype with CD68+CD206+ dual staining. Gene microarrays demonstrated a distinct alloimmune response despite the lack of rejection and inflammatory infiltrate with upregulation of interferon-γ-response genes. This suggests that following initiation of Th1 driven macrophage proliferation or infiltration, M2 macrophages contribute to tubular injury and progression of fibrosis. 23 protocol renal biopsies were obtained from patients at 12 month post transplant. The study population was divided into two groups according to the number of infiltrating macrophages (CD68 positive cells) (Group I: Recipients with a low number of infiltrating macrophages, CD68 positive cells < 400/mm2; Group II: Recipients with a high number of infiltrating macrophages, CD68 positive cells ≥ 400/mm2). Additional analyses were undertaken by dividing the group into those with fibrosis (ci score >1) and those without. To correlate gene expression with kidney fibrosis, or intensity of CD68 infiltrate, Spearman correlations analysis of the gene expression data with 12 month IFTA was performed and the correlation co-efficiency and its p value calculated. Gene Ontology enrichment and IPA pathway and network analysis (Ingenuity System Inc.) were performed on the associated genes. All p-values were two-sided, and p < 0.05 was considered significant.
2015-01-28 | E-GEOD-65326 | biostudies-arrayexpress