Differential expression of Organ Transplant Rejection related genes after xenokidney from 1KO.1TG vs. 3KO.7TG donor pigs
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PROVIDER: PRJNA1117941 | ENA |
REPOSITORIES: ENA
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Project description:Antibody-mediated rejection, caused by antibodies against the donor human leukocyte antigen (HLA) molecules plays a fundamental role in graft rejection in transplantation. Most significant is transplant patients who generate antibodies against the donor HLA-DQ have the highest risk of rejection. In this study, we investigated the role of indirect CD4 T cell epitopes in the formation of donor-specific antibodies (DSA). Using antigen mapping techniques in kidney and heart transplant recipients with HLA-DQ DSA, we identified two polymorphic hotspots in the HLA-DQ gene that generated alloreactive CD4 T cell responses. To study the functional significance of indirect CD4 T cells, we first mapped epitopes recognised by H2-Kb C57Bl6 mice against a skin graft from H2-Kd Balb/c mice. We identified a CD4 T cell epitope, specific for amino acids 287-301 derived from the H2-Kd protein, that generated tetramer-binding Kd287+ CD4 T cells during rejection. Importantly, the transfer of Kd287+ CD4 T cells into T cell-deficient mice was sufficient to drive an antibody response against the donor H2-Kd molecule. Lastly, we found that administration of systemic high-dose donor H2-Kd peptides combined with CTLA4-Ig reduced the formation of Kd287+ CD4 T cells and diminished DSA formation. Together, these findings demonstrate that the identification of donor antigens indicates the potential for inducing donor-specific immune tolerance in transplantation.
2024-09-17 | GSE277075 | GEO
Project description:Introduction: Responses to allogeneic human leukocyte antigen (HLA) molecules limit the survival of transplanted organs. The changes in T-cell alloreactivity that contribute to this process, however, are not fully understood. We defined a set of donor reactive T-cell clones (DRTC) with the goal to elucidate signatures of kidney allograft rejection. Methods: DRTC were identified pretransplant using an anti-donor mixed lymphocyte reaction assay: CFSE-diluting CD4+ and CD8+ DRTC were flow-sorted, and the TCR sequences were identified using Adaptive Immunosequencing. DRTC were then tracked in post-transplant biopsies, blood, and urine samples in a cohort of kidney transplant recipients. Results: In patients with an abnormal biopsy, the majority of CD8+ DRTC found within the allograft were detected in the circulating pre-transplant repertoire. Circulating CD8+ DRTC were more abundant pre- and post-transplant in patients that received non-lymphodepletional induction and developed an abnormal biopsy when compared to stable patients. Additionally, DRTC were detected as early as two weeks post-transplant in the urine of some patients, with some of these clones subsequently identified in follow-up kidney biopsy samples. Discussion: The findings of our study add to our understanding of T-cell alloreactivity following kidney transplantation and provide evidence for the role of pre-defined alloreactive T-cells in the development of allograft rejection.
2025-02-10 | GSE288648 | GEO
Project description:We used DNA microarrays (HG-U95Av2 GeneChips) to determine gene expression profiles for kidney biopsies and peripheral blood lymphocytes (PBLs) in transplant patients. Sample classes include kidney biopsies and PBLs from patients with 1) healthy normal donor kidneys, 2) well-functioning transplants with no clinical evidence of rejection, 3) kidneys undergoing acute rejection, and 4) transplants with renal dysfunction without rejection. Nomenclature for samples is as follows: 1) all sample names include either BX or PBL to indicate that they were derived from biopsies or PBLs respectively, 2) C indicates samples from healthy normal donors, 3) TX indicates samples from patients with well-functioning transplants with no clinical evidence of rejection, 3) AR indicates samples from transplant patients with kidneys undergoing acute rejection, 4) NR indicates samples from transplant patients with renal dysfunction without rejection. Abbreviations used to describe patient samples include the following: BX - Biopsy; PBL- Peripheral Blood Lymphocytes; CsA -Cyclosporine; MMF - Mycophenolate Mofetil; P - Prednisone; FK - Tacrolimus; SRL - Sirolimus; CAD -Cadaveric; LD - Live Donor; Scr - Serum Creatinine; ATN - Acute Tubular Necrosis CNI - Calcineurin Inhibitor; FSGS - Focal Segmental Glomerulosclerosis several array data sets did not pass quality control and were not analyzed. These include AR1PBL, NR4BX, and NR6PBL Keywords = DNA microarrays, gene expression, kidney, rejection, transplant Keywords: other. This dataset is part of the TransQST collection.
2004-07-14 | E-GEOD-1563 | biostudies-arrayexpress
Project description:PBMC samples from heart transplant patients were profiled. Sample classification was based on endomyocardial biopsy at the time of sample collection. Keywords = Transplant Keywords = Transplantation Keywords = Heart Transplant Keywords = Graft Rejection Keywords = Rejection Keywords = PBMC Keywords = Immune Response Keywords = Peripheral Blood
2010-06-10 | E-GEOD-2445 | biostudies-arrayexpress
Project description:We used DNA microarrays (HG-U95Av2 GeneChips) to determine gene expression profiles for kidney biopsies and peripheral blood lymphocytes (PBLs) in transplant patients. Sample classes include kidney biopsies and PBLs from patients with 1) healthy normal donor kidneys, 2) well-functioning transplants with no clinical evidence of rejection, 3) kidneys undergoing acute rejection, and 4) transplants with renal dysfunction without rejection. Nomenclature for samples is as follows: 1) all sample names include either BX or PBL to indicate that they were derived from biopsies or PBLs respectively, 2) C indicates samples from healthy normal donors, 3) TX indicates samples from patients with well-functioning transplants with no clinical evidence of rejection, 3) AR indicates samples from transplant patients with kidneys undergoing acute rejection, 4) NR indicates samples from transplant patients with renal dysfunction without rejection. Abbreviations used to describe patient samples include the following: BX - Biopsy; PBL- Peripheral Blood Lymphocytes; CsA -Cyclosporine; MMF - Mycophenolate Mofetil; P - Prednisone; FK - Tacrolimus; SRL - Sirolimus; CAD -Cadaveric; LD - Live Donor; Scr - Serum Creatinine; ATN - Acute Tubular Necrosis CNI - Calcineurin Inhibitor; FSGS - Focal Segmental Glomerulosclerosis several array data sets did not pass quality control and were not analyzed. These include AR1PBL, NR4BX, and NR6PBL Keywords = DNA microarrays, gene expression, kidney, rejection, transplant Keywords: other
2004-07-14 | GSE1563 | GEO
Project description:PBMC samples from heart transplant patients were profiled. Sample classification was based on endomyocardial biopsy at the time of sample collection. Keywords = Transplant Keywords = Transplantation Keywords = Heart Transplant Keywords = Graft Rejection Keywords = Rejection Keywords = PBMC Keywords = Immune Response Keywords = Peripheral Blood Keywords: other
2005-09-01 | GSE2445 | GEO
Project description:Transplant rejection is a major factor limiting allograft survival. CircRNAs are reported to be strongly associated with various diseases pathogenesis. However, the potential role of circRNAs in cardiac transplant rejection are rarely reported. Here, differentially expressed mRNAs and circRNAs were determined by microarrays in allogeneic cardiac allografts. Functional analysis was then performed and a full-scale functional blueprint of the circRNA-associated-ceRNA networks was constructed. Among the circRNA networks, circ23123 expression was negatively linked with cytolytic molecules of CD8+ T cells by targeting miR155-SOCS1 axis. We illustrated a new comprehensive view of circRNAs and their potential functional impact in cardiac transplantation. It may provide a prospective for therapeutic strategy on organ transplant rejection in the future.
2020-12-16 | GSE163261 | GEO
Project description:Histologic diagnosis of T cell-mediated rejection in kidney transplant biopsies has limited reproducibility because it is based on non-specific lesions using arbitrary rules that are subject to differing interpretations. We used microarray results from 403 indication biopsies previously given histologic diagnoses to develop a molecular classifier that assigned a molecular T cell-mediated rejection score to each biopsy. Independent assessment of the biopsies by multiple pathologists confirmed considerable disagreement on the presence of TCMR features: 79-88% accuracy and 35-69% sensitivity. The agreement of the molecular T cell-mediated rejection score with the histology diagnosis was similar to agreement among individual pathologists: accuracy 89%, sensitivity 51%. However, the score also predicted the consensus among pathologists, being highest when all agreed. Many discrepancies between the scores and the histologic diagnoses were in situations where histology is unreliable e.g. scarred biopsies. The score correlated with histologic lesions and gene sets associated with T cell-mediated rejection. The transcripts most often selected by the classifier were expressed in effector T cells, dendritic cells, or macrophages or inducible by interferon-gamma. Thus the T cell-mediated rejection score offers an objective assessment of kidney transplant biopsies, predicting the consensus opinion among multiple pathologists, and offering insights into underlying disease mechanisms. Antibody-mediated rejection is a major cause of kidney transplant failure, but the current diagnostic system misses most cases due to dependency on subjective non-standardized tests. We hypothesized that molecular features could provide a test to address this problem. We classified 403 biopsies by a reference standard based on microcirculation lesions and donor-specific HLA antibody, and used microarray analysis to develop a classifier that assigned each biopsy a score reflecting the probability of antibody-mediated rejection. The scores correlated with donor-specific antibody and histologic lesions: 42/45 biopsies with antibody-mediated rejection scores >0.5 had both donor-specific antibody and microcirculation lesions. Intermediate scores (0.2-0.5) were more ambiguous, but became more specific combined with donor-specific antibody. Compared to diagnoses based on histology-plus-donor-specific antibody, the scores had sensitivity 0.67; specificity 0.90. Donor-specific antibody improved the specificity to 0.97. The score correlated not only with diagnoses of individual pathologists but with the consensus among multiple pathologists. The classifier used transcripts expressed in endothelial cells (e.g. CDH13, DARC, ROBO4) and NK cells (e.g. CX3CR1, FGFBP2), as well as IFNG-inducible transcripts e.g. CXCL11. Thus the molecular phenotype of antibody-mediated rejection provides not only an objective test that predicts microcirculation lesions and donor-specific HLA antibody, but also offers mechanistic insights. All consenting renal transplant patients undergoing biopsies for cause as standard of care. 403 samples and 8 controls (nephrectomies). This dataset is part of the TransQST collection.
2013-02-13 | E-GEOD-36059 | biostudies-arrayexpress
Project description:In transplantation, there is a critical need for non-invasive biomarker platforms for monitoring immunologic rejection. We hypothesized that transplanted tissues release donor specific exosomes into recipient circulation/ bodily fluids, and that the quantitation and profiling of their intra-exosomal cargoes would constitute a novel biomarker platform for monitoring rejection. We tested this hypothesis in a human into mouse xenogeneic islet transplant model, and validated the concept in clinical settings of islet and renal transplantation. In the xenogeneic model, islet transplant exosomes in recipient blood were quantified over long-term follow-up using anti-human leukocyte antigen (HLA) antibody that is only expressed on human islets (p=1.6x10-14). Transplant islet exosomes were purified using anti-HLA antibody conjugated beads and their cargoes contained bona fide islet endocrine hormone markers insulin, glucagon, and somatostatin. Rejection led to significant decrease in transplant islet exosome signal (p=4x10-15), along with distinct changes in its microRNA and proteomic profiles prior to appearance of hyperglycemia. In the clinical settings of islet (n=5) and renal (n=5) transplantation, donor exosomes with respective tissue specificity for islet β cells and renal epithelial cells were reliably characterized in recipient plasma over follow-up (up to 5 years; p=0.0001). Collectively, these findings demonstrate the biomarker potential of transplant exosome characterization for providing a non-invasive window into the conditional state of the transplant tissue.
2016-10-18 | GSE88844 | GEO
Project description:In transplantation, there is a critical need for non-invasive biomarker platforms for monitoring immunologic rejection. We hypothesized that transplanted tissues release donor specific exosomes into recipient circulation/ bodily fluids, and that the quantitation and profiling of their intra-exosomal cargoes would constitute a novel biomarker platform for monitoring rejection. We tested this hypothesis in a human into mouse xenogeneic islet transplant model, and validated the concept in clinical settings of islet and renal transplantation. In the xenogeneic model, islet transplant exosomes in recipient blood were quantified over long-term follow-up using anti-human leukocyte antigen (HLA) antibody that is only expressed on human islets (p=1.6x10-14). Transplant islet exosomes were purified using anti-HLA antibody conjugated beads and their cargoes contained bona fide islet endocrine hormone markers insulin, glucagon, and somatostatin. Rejection led to significant decrease in transplant islet exosome signal (p=4x10-15), along with distinct changes in its microRNA and proteomic profiles prior to appearance of hyperglycemia. In the clinical settings of islet (n=5) and renal (n=5) transplantation, donor exosomes with respective tissue specificity for islet β cells and renal epithelial cells were reliably characterized in recipient plasma over follow-up (up to 5 years; p=0.0001). Collectively, these findings demonstrate the biomarker potential of transplant exosome characterization for providing a non-invasive window into the conditional state of the transplant tissue.
2016-10-18 | GSE88845 | GEO