A peripheral blood gene expression signature diagnoses subclinical acute rejection [discovery]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE120396 | GEO | 2019/09/11
REPOSITORIES: GEO
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Project description:Histological features of acute rejection can be detected in surveillance biopsies despite stable graft function and can negatively impact graft outcomes. However, routine surveillance biopsies for detection of subclinical rejection are not generally performed due to potential risks and costs associated with repeated biopsies. Noninvasive biomarkers are required to facilitate early detection of acute rejection and borderline changes. We examined the impact of histological abnormalities at 3-month in surveillance biopsies on graft outcomes in kidney transplant recipients from the prospective Genomics of Chronic Allograft Rejection (GoCAR) study. We then performed RNA sequencing on whole blood collected at the time of biopsy in 88 patients (22 vs. 66) to identify transcripts associated with histological abnormalities. Subjects with subclinical ACR or borderline ACR at 3 month (ACR-3) had higher risk of subsequent clinical acute rejection at 12 and 24 month (P < 0.05), more rapid functional decline (P < 0.05) and a decreased graft survival in adjusted cox analysis (P < 0.01) than patients with no abnormalities on 3-month biopsy. We then identified a 17-gene signature in peripheral blood that accurately diagnosed ACR-3. The gene set was then validated for diagnosis of ACR-3 using microarray data (N=65; 12 vs. 53; 26 overlapping with the RNAseq cohort).
2019-09-11 | GSE120397 | GEO
Project description:The significance of borderline changes (BL) in kidney allograft biopsies is widely debated. We examined differences in gene expression patterns between early clinical biopsy tissue and 3-month protocol biopsy tissue, all of which had histological BL changes and identified specific molecular BL patterns associated with poor graft outcome. The expression profiles were analyzed in training set of patients and next data were validated in validation cohort using RT-qPCR. Using the Illumina microarray technology, we observed greater expression of immunity- and inflammation-related genes in tissues from early clinical biopsies compared to 3-month protocol biopsies with BL findings. In tissues with early clinically manifested BL changes, graft deterioration within 24 months due to chronic rejection was associated with increased activation of immune, defense, and inflammatory processes, specifically with higher donor age and expression of macrophage receptor CLEC5A. In the 3-month protocol biopsies with BL changes, graft dysfunction was associated with increased expression of fibrinogen complex transcripts. This study highlights the molecular differences between clinical and subclinical biopsies with similar histological findings. The data also support a recommendation for frequent patient monitoring, especially in those who received grafts from expanded criteria donors (ECDs).
2013-12-19 | GSE52694 | GEO
Project description:The significance of borderline changes (BL) in kidney allograft biopsies is widely debated. We examined differences in gene expression patterns between early clinical biopsy tissue and 3-month protocol biopsy tissue, all of which had histological BL changes and identified specific molecular BL patterns associated with poor graft outcome. The expression profiles were analyzed in training set of patients and next data were validated in validation cohort using RT-qPCR. Using the Illumina microarray technology, we observed greater expression of immunity- and inflammation-related genes in tissues from early clinical biopsies compared to 3-month protocol biopsies with BL findings. In tissues with early clinically manifested BL changes, graft deterioration within 24 months due to chronic rejection was associated with increased activation of immune, defense, and inflammatory processes, specifically with higher donor age and expression of macrophage receptor CLEC5A. In the 3-month protocol biopsies with BL changes, graft dysfunction was associated with increased expression of fibrinogen complex transcripts. This study highlights the molecular differences between clinical and subclinical biopsies with similar histological findings. The data also support a recommendation for frequent patient monitoring, especially in those who received grafts from expanded criteria donors (ECDs). The experiments were performed with total RNA derived from the renal graft biopsy samples of 28 different patients who had undergone a kidney transplantation. Only the patients with diagnosis of borderline changes early (M-bM-^IM-$2 months) or protocolar (3 months) were included in the study. RNA profiles of patients with stable and deteriorated graft function during 2 years after transplantation were compared. As microarray platform, Illumina HumanHT-12 v4.0 Expression BeadChips (Illumina) was used. The chip scanning was performed with a BeadStation 500 instrument (Illumina Inc), and the raw data were extracted with the BeadStudio Data Analysis Software (Illumina). The R software lumi package was used to further process the raw data. The quantile method was used for normalization.
2013-12-19 | E-GEOD-52694 | biostudies-arrayexpress
Project description:CONTEXT Slowly progressive chronic tubulo-interstitial damage jeopardizes long-term renal allograft survival. Both immune and non-immune mechanisms are thought to contribute, but the most promising targets for timely intervention have not been identified. OBJECTIVE In the current study we seek to determine the driving force behind progressive histological damage of renal allografts, without the interference of donor pathology, delayed graft function and acute graft rejection. DESIGN We used microarrays to examine whole genome expression profiles in renal allograft protocol biopsies, and analyzed the correlation between gene expression and the histological appearance over time. The gene expression profiles in these protocol biopsies were then compared with gene expression of biopsies with acute T-cell mediated rejection. PATIENTS Human renal allograft biopsies (N=120) were included: 96 rejection-free protocol biopsies and 24 biopsies with T-cell mediated acute rejection. RESULTS In this highly cross-validated study, we demonstrate the significant association of established, ongoing and future chronic histological damage with regulation of adaptive immune gene expression (T-cell and B-cell transcript sets) and innate immune response gene expression (dendritic cell, NK-cell, mast cell and granulocyte transcripts). We demonstrate the ability of gene expression analysis to perform as a quantitative marker for ongoing inflammation with a wide dynamic range: from subtle subhistological inflammation prior to development of chronic damage, over moderate subclinical inflammation associated with chronic histological damage, to marked inflammation of Banff-grade acute T-cell mediated rejection. CONCLUSION Progressive chronic histological damage after kidney transplantation is associated with significant regulation of both innate and adaptive immune responses, months before the histological lesions appear. This study therefore corroborates the hypothesis that quantitative inflammation below the diagnostic threshold of classic T-cell or antibody-mediated rejection is associated with early subclinical stages of progressive renal allograft damage. We used microarrays to examine whole genome expression profiles in renal allograft protocol biopsies, and analyzed the correlation between gene expression and the histological appearance over time. The gene expression profiles in these protocol biopsies were then compared with gene expression of biopsies with acute T-cell mediated rejection. Human renal allograft biopsies (N=120) were included: 96 rejection-free protocol biopsies and 24 biopsies with T-cell mediated acute rejection.
2011-12-10 | E-GEOD-25902 | biostudies-arrayexpress
Project description:CONTEXT Slowly progressive chronic tubulo-interstitial damage jeopardizes long-term renal allograft survival. Both immune and non-immune mechanisms are thought to contribute, but the most promising targets for timely intervention have not been identified. OBJECTIVE In the current study we seek to determine the driving force behind progressive histological damage of renal allografts, without the interference of donor pathology, delayed graft function and acute graft rejection. DESIGN We used microarrays to examine whole genome expression profiles in renal allograft protocol biopsies, and analyzed the correlation between gene expression and the histological appearance over time. The gene expression profiles in these protocol biopsies were then compared with gene expression of biopsies with acute T-cell mediated rejection. PATIENTS Human renal allograft biopsies (N=120) were included: 96 rejection-free protocol biopsies and 24 biopsies with T-cell mediated acute rejection. RESULTS In this highly cross-validated study, we demonstrate the significant association of established, ongoing and future chronic histological damage with regulation of adaptive immune gene expression (T-cell and B-cell transcript sets) and innate immune response gene expression (dendritic cell, NK-cell, mast cell and granulocyte transcripts). We demonstrate the ability of gene expression analysis to perform as a quantitative marker for ongoing inflammation with a wide dynamic range: from subtle subhistological inflammation prior to development of chronic damage, over moderate subclinical inflammation associated with chronic histological damage, to marked inflammation of Banff-grade acute T-cell mediated rejection. CONCLUSION Progressive chronic histological damage after kidney transplantation is associated with significant regulation of both innate and adaptive immune responses, months before the histological lesions appear. This study therefore corroborates the hypothesis that quantitative inflammation below the diagnostic threshold of classic T-cell or antibody-mediated rejection is associated with early subclinical stages of progressive renal allograft damage.
2011-12-10 | GSE25902 | GEO
Project description:Aims. Serial invasive endomyocardial biopsies (EMB) remain the gold standard for acute cellular rejection (ACR) diagnosis. However histological grading has several limitations. We aimed to explore the value of myocardial Gene Expression Profiling (GEP) for diagnosing and identifying predictive biomarkers of ACR. Methods. A case-control study nested within a retrospective heart transplant patients cohort included 126 patients with median (IQR) age 50 (41-57) years and 111 (88%) males. Among 1157 EMB performed, 467 were eligible (i.e, corresponding to either ISHLT grade 0 or â¥3A), among which 36 were selected for GEP according to the grading: 0 (CISHLT, n= 13); rejection â¥3A (RISHLT, n=13); 0 one month before ACR (BRISHLT, n=10). Results. We found 294 genes differentially expressed between CISHLT and RISHLT, mainly involved in immune activation, and inflammation. Hierarchical clustering showed a clear segregation of CISHLT and RISHLT groups and heterogeneity of GEP within RISHLT. All EMB presented immune activation, but some RISHLT EMB were strongly subject to inflammation, whereas others, closer to CISHLT, were characterized by structural modifications with lower inflammation level. We identified 15 probes significantly different between BRISHLT and CISHLT, including the gene of the muscular protein TTN. This result suggests that structural alterations precede inflammation in ACR. Linear Discriminant Analysis based on these 15 probes was able to identify the histological status of every 36 samples. Conclusion. Myocardial GEP is a helpful method to accurately diagnose ACR, and predicts rejection one month before its histological occurrence. These results should be considered in cardiac allograft recipientsâ care.
2017-03-07 | E-MTAB-5136 | biostudies-arrayexpress
Project description:The molecular basis of calcineurin inhibitor toxicity (CNIT) in kidney transplantation (KT) and its contribution to chronic allograft dysfunction (CAD) with interstitial fibrosis (IF) and tubular atrophy (TA) were evaluated. Molecular signatures characterizing CNIT samples were identified. The recognized CNIT gene signature was most common in patients with decreased graft function and histological evidence of IF/TA. To test CNIT contribution to CAD progression, kidney biopsies from transplant recipients with histological diagnosis of CNIT (n=14), acute rejection (ACR, n=13), and CAD with IF/TA (n=10), including 18 Normal allografts, were analyzed using gene expression microarrays.
2014-06-01 | E-GEOD-53605 | biostudies-arrayexpress
Project description:Acute cellular rejection (ACR) is the major cause of intestinal graft loss. Little is known about the genetic response occurring in small bowel transplantation (SBTx) during ACR. We report the case of a 44 year-old female with short gut syndrome following multiple surgeries for familial adenomatous polyposis that underwent living-related SBTx. We obtained for the first time a gene expression profile of the intestinal graft during ACR. Microarray analysis revealed increased transcript levels for genes that match identically to an IFN? signature reported for activated plasmacytoid dendritic cells and T-cell chemotaxis and cytolysis correlating with the diagnosis of ACR. Experiment Overall Design: sam1, sam2, sam3 (without signs of rejection) Experiment Overall Design: sam4, sam5, sam6 (with signs and symptoms of rejection , histology showed increasing lymphocyte infiltration in the lamina propria and epithelium)
2008-04-03 | E-GEOD-5838 | biostudies-arrayexpress
Project description:Genesets for the IL-17 pathway and Th17 T-helper cell subtype showed increasing enrichment in 33 pre-transplant donor biopsies and 33 matching post-transplant biopsies from patients with increasing Banff grades of acute rejection (no signficant abnormalities, n=17; borderline, n=4; ARIA, n=7; ARIB, n=6) in gene set analysis using SAM (GSA, FDR 0.5; 1000 permutations, log rank regression) for a total of 3307 publically available and manually curated gene-sets. 14 genes of the IL-17 pathway gene-set and 132 genes of the Th17 gene set segregated patients according to their histological diagnosis by unsupervised hierarchical clustering and principal component analysis. This study demonstrates a significant role for the IL-17 pathway in the development of acute renal allograft rejection. Therapeutically targeting the IL-17 pathway presents a promising option in transplantation medicine and can be acchieved through drug reposittioning. Keywords: IL-17 pathway, drug repositioning, gene set enrichment analysis A total of 66 human renal allograft protocol biopsies were included in this study, 33 biopsies obtained at implantation prior to revascularization and 33 protocol biopsies obtained after transplantation. Whole genome expression profiles were assessed using microarrays. This dataset is part of the TransQST collection.
2014-01-01 | E-GEOD-34437 | biostudies-arrayexpress
Project description:Acute cellular rejection (ACR) is the major cause of intestinal graft loss. Little is known about the genetic response occurring in small bowel transplantation (SBTx) during ACR. We report the case of a 44 year-old female with short gut syndrome following multiple surgeries for familial adenomatous polyposis that underwent living-related SBTx. We obtained for the first time a gene expression profile of the intestinal graft during ACR. Microarray analysis revealed increased transcript levels for genes that match identically to an IFN? signature reported for activated plasmacytoid dendritic cells and T-cell chemotaxis and cytolysis correlating with the diagnosis of ACR. Keywords: disease state analysis
2008-03-12 | GSE5838 | GEO