Early isolated v-lesion may not truly represent a rejection of kidney allograft
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PROVIDER: PRJNA472352 | ENA |
REPOSITORIES: ENA
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Project description:Intimal arteritis is known to be a negative prognostic factor for kidney allograft survival. Although Banff classification assesses isolated v-lesion (IV) as a T-cell mediated rejection, its origin and significance remain unclear. To help resolve if IV truly represents acute rejection, molecular study was performed. Transcriptome of early IV, T cell-mediated vascular rejection (TCMRV) and nonrejection histologic findings was compared using microarrays (Illumina Human HT-12 v4 Expression BeadChips). The enrichment of deregulated genes was analysed using DAVID. Differential gene expression analysis identified 310 genes to be deregulated in TCMRV compared to IV. Gene enrichment analysis categorized deregulated genes to be associated with immune and inflammatory response. Principal component and unsupervised hierarchical cluster analysis revealed clear distinction of TCMRV samples but showed similarity of IV with control group. RT-qPCR validation on external sample set (n=20) confirmed upregulation of genes involved in immune response in TCMRV compared to IV. Based on stepwise logistic regression SLA2 gene represented the strongest group classifier [OR 0.106 (95 % CI 0.01- 0.774), p=0.03] with ROC AUC 0.906 [95% CI (0.769-1.0), p=0.003)]. IV reveals weak immunologic signature compared to TCMRV but shows similarity with non-rejection findings. Early IV in a DSA- and C4d- negative patients may feature non-rejection origin and reflect injury distinct from alloimmune response. Study calls for reassessment of current Banff histopathology criteria which considers an intimal arteritis to be TCMR irrespective of TI and supports use of molecular diagnostics as a part of integrative approach.
2018-05-22 | GSE114712 | GEO
Project description:Rat corneal allograft rejection models were established to investigate the effects and mechanisms of resveratrol on corneal allograft rejection after corneal transplantation.
2023-07-10 | GSE236626 | GEO
Project description:Acute allograft rejection is a leading cause for the failure of organ allotransplantation. Identifying the genes involved in the rejection process provides clues to study the mechanisms, and to provide specific gene targets for monitoring, predicting and preventing acute allograft rejection. Using a mice model of skin acute allograft rejection and SAGE method, we analyzed gene expression in the CD4+ T cells of the mice, the cell type known to play critical roles in acute allograft rejection. Our study identifies 402 SAGE tags significantly different from these from the control. From these SAGE tags, we identified 91 increasingly and 85 decreasingly expressed genes, and many genes have not been linked with acute allograft rejection before. Functional classification of these genes shows that apoptosis, transcription regulation, cell growth and maintenance and signal transduction are among the most frequently changed functional groups. Our study provides a genome-wide view for the genes involving acute allograft rejection in the CD4+ T cells, and indicates that acute allograft rejection involves multiple genes in different functional categories. The genes identified from the study provide candidates for further studying the mechanisms and for monitoring, predicting and preventing acute allograft rejection.
2010-03-01 | GSE14540 | GEO
Project description:In this proof-of-concept study, spatial transcriptomics combined with public single-cell RNA sequencing data were used to explore the potential of this technology to study kidney allograft rejection. We aimed to map gene expression patterns within diverse pathological states by examining biopsies classified across non-rejection, T cell-mediated acute rejection, and interstitial fibrosis and tubular atrophy (IFTA). Our results revealed distinct immune cell signatures, including those of T and B lymphocytes, monocytes, mast cells, and plasma cells, and their spatial organization within the renal interstitium. We also mapped chemokine receptors and ligands to study immune-cell migration and recruitment. Finally, our analysis demonstrated differential spatial enrichment of transcription signatures associated with kidney allograft rejection across various biopsy regions. Interstitium regions displayed higher enrichment scores for rejection-associated gene expression patterns than did tubular areas, which had negative scores. This implies that these signatures are primarily driven by processes unfolding in the renal interstitium. Overall, this study highlights the value of spatial transcriptomics for revealing cellular heterogeneity and immune signatures in renal transplant biopsies, and demonstrates its potential for studying the molecular and cellular mechanisms associated with rejection. However, certain limitations must be borne in mind regarding the development and future applications of this technology.
2024-05-02 | GSE245870 | GEO
Project description:Lung allograft rejection results in the accumulation of low molecular weight hyaluronic acid (LMW-HA), which further propagates inflammation and tissue injury. We have previously shown that therapeutic lymphangiogenesis in a murine model of lung allograft rejection reduced tissue LMW-HA and was associated with improved transplant outcomes. Herein we investigated the use of 4-Methylumbelliferone (4-MU), a known inhibitor of HA synthesis, to alleviate acute allograft rejection in a murine model of lung transplantation. We found that treating mice with 4-MU from day 20-30 post-transplant was sufficient to significantly improve outcomes, characterized by a reduction in T-cell mediated lung inflammation, LMW-HA content and improved pathology scores. In vitro, 4-MU directly attenuated activation, proliferation, and differentiation of naïve CD4+ T-cells into Th1 cells. As 4-MU has already been demonstrated to be safe for human use, we believe examining 4-MU for the treatment of acute lung allograft rejection may be of clinical significance.
2021-12-15 | GSE183142 | GEO
Project description:The data set contains 67 array (lymphochip cDNA array), published in N Engl J Med 2003 Jul 10;349(2):125-38. PMID: 12853585. TITLE: Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. BACKGROUND: The causes and clinical course of acute rejection vary, and it is not possible to predict graft outcome reliably on the basis of available clinical, pathological, and genetic markers. We hypothesized that previously unrecognized molecular heterogeneity might underlie some of the variability in the clinical course of acute renal allograft rejection and in its response to treatment. METHODS: We used DNA microarrays in a systematic study of gene-expression patterns in biopsy samples from normal and dysfunctional renal allografts. A combination of exploratory and supervised bioinformatic methods was used to analyze these profiles. : We found consistent differences among the gene-expression patterns associated with acute rejection, nephrotoxic effects of drugs, chronic allograft nephropathy, and normal kidneys. The gene-expression patterns associated with acute rejection suggested at least three possible distinct subtypes of acute rejection that, although indistinguishable by light microscopy, were marked by differences in immune activation and cellular proliferation. Since the gene-expression patterns pointed to substantial variation in the composition of immune infiltrates, we used immunohistochemical staining to define these subtypes further. This analysis revealed a striking association between dense CD20+ B-cell infiltrates and both clinical glucocorticoid resistance (P=0.01) and graft loss (P<0.001). CONCLUSIONS: Systematic analysis of gene-expression patterns provides a window on the biology and pathogenesis of renal allograft rejection. Biopsy samples from patients with acute rejection that are indistinguishable on conventional histologic analysis reveal extensive differences in gene expression, which are associated with differences in immunologic and cellular features and clinical course. The presence of dense clusters of B cells in a biopsy sample was strongly associated with severe graft rejection, suggesting a pivotal role of infiltrating B cells in acute rejection. A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Disease State: normal vs disease Keywords: disease_state_design Using regression correlation
2003-07-01 | E-GEOD-343 | biostudies-arrayexpress
Project description:Intimal arteritis is known to be a negative prognostic factor for kidney allograft survival. Isolated v-lesion (IV) is defined as intimal arteritis with minimal tubulointerstitial inflammation (TI). Although the Banff classification assesses IV as T cell-mediated rejection (TCMR), clinical, and prognostic significance of early IV (early IV, eIV) with negative C4d and donor-specific antibodies (DSA) remains unclear. To help resolve if such eIV truly represents acute rejection, a molecular study was performed. The transcriptome of eIV (n=6), T cell-mediated vascular rejection with rich TI (T cell-mediated vascular rejection, TCMRV, n=4) and non-rejection histologic findings (n=8) was compared using microarrays. A total of 310 genes were identified to be deregulated in TCMRV compared with eIV. Gene enrichment analysis categorized deregulated genes to be associated primarily with T-cells associated biological processes involved in an innate and adaptive immune and inflammatory response. Comparison of deregulated gene lists between the study groups and controls showed only a 1.7% gene overlap. Unsupervised hierarchical cluster analysis revealed clear distinction of eIV from TCMRV and showed similarity with a control group. Up-regulation of immune response genes in TCMRV was validated using RT-qPCR in a different set of eIV (n=12) and TCMRV (n=8) samples. The transcriptome of early IV (< 1 month) with negative C4d and DSA is associated with a weak immune signature compared with TCMRV and shows similarity with normal findings. Such eIV may feature non-rejection origin and reflect an injury distinct from an alloimmune response. The present study supports use of molecular methods when interpreting kidney allograft biopsy findings.
| S-EPMC6365629 | biostudies-literature
Project description:The data set contains 67 array (lymphochip cDNA array), published in N Engl J Med 2003 Jul 10;349(2):125-38. PMID: 12853585. TITLE: Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. BACKGROUND: The causes and clinical course of acute rejection vary, and it is not possible to predict graft outcome reliably on the basis of available clinical, pathological, and genetic markers. We hypothesized that previously unrecognized molecular heterogeneity might underlie some of the variability in the clinical course of acute renal allograft rejection and in its response to treatment. METHODS: We used DNA microarrays in a systematic study of gene-expression patterns in biopsy samples from normal and dysfunctional renal allografts. A combination of exploratory and supervised bioinformatic methods was used to analyze these profiles. : We found consistent differences among the gene-expression patterns associated with acute rejection, nephrotoxic effects of drugs, chronic allograft nephropathy, and normal kidneys. The gene-expression patterns associated with acute rejection suggested at least three possible distinct subtypes of acute rejection that, although indistinguishable by light microscopy, were marked by differences in immune activation and cellular proliferation. Since the gene-expression patterns pointed to substantial variation in the composition of immune infiltrates, we used immunohistochemical staining to define these subtypes further. This analysis revealed a striking association between dense CD20+ B-cell infiltrates and both clinical glucocorticoid resistance (P=0.01) and graft loss (P<0.001). CONCLUSIONS: Systematic analysis of gene-expression patterns provides a window on the biology and pathogenesis of renal allograft rejection. Biopsy samples from patients with acute rejection that are indistinguishable on conventional histologic analysis reveal extensive differences in gene expression, which are associated with differences in immunologic and cellular features and clinical course. The presence of dense clusters of B cells in a biopsy sample was strongly associated with severe graft rejection, suggesting a pivotal role of infiltrating B cells in acute rejection. A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Disease State: normal vs disease Keywords: disease_state_design
2003-07-01 | GSE343 | GEO
Project description:Acute renal allograft rejection is an important complication in kidney transplantation. Accurate diagnosis of rejection events is necessary for timely response and treatment. We illustrate the usefulness and biological relevance of selected multivariate approaches to detect rejection from genomic and proteomic signals. The data was used to study gene expression changes using whole genome microarray analysis of peripheral blood from subjects with acute rejection (n=20) and non-rejecting controls (n=20) to obtain insight into the molecular and biological causation of acute renal allograft rejection when combined with proteomics (iTRAQ) data for the same patients/time-points.
2014-04-26 | GSE46474 | GEO
Project description:Compromised renal function after renal allograft transplantation often results in anemia in the recipient. Molecular mechanisms leading to anemia during acute rejection are not fully understood; inadequate erythropoietin production and iron deficiency have been reported to be the main contributors. To increase our understanding of the molecular events underlying anemia in acute rejection, we analyzed the gene expression profiles of peripheral blood lymphocytes (PBL) from four pediatric renal allograft recipients with acute rejection and concurrent anemia, using DNA microarrays containing 9000 human cDNA clones (representing 7469 unique genes). In these anemic rejecting patients, an 'erythropoiesis cluster' of 11 down-regulated genes was identified, involved in hemoglobin transcription and synthesis, iron and folate binding and transport. Additionally, some alloimmune response genes were simultaneously down-regulated. An independent data set of 36 PBL samples, some with acute rejection and some with concurrence of acute rejection and anemia, were analyzed to support a possible association between acute rejection and anemia. In conclusion, analysis using DNA microarrays has identified a cluster of genes related to hemoglobin synthesis and/or erythropoeisis that was altered in kidneys with renal allograft rejection compared with normal kidneys. The possible relationship between alterations in the expression of this cluster, reduced renal function, the alloimmune process itself, and other influences on the renal transplant awaits further analysis. A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Keywords: disease_state_design
2006-01-06 | GSE3976 | GEO