Transplant tissue specfic exosome platform for noninvasive monitoring of immunologic rejection
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PROVIDER: PRJNA348761 | ENA |
REPOSITORIES: ENA
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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
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:This SuperSeries is composed of the SubSeries listed below.
2016-10-18 | GSE88846 | GEO
Project description:Transplant tissue specfic exosome platform for noninvasive monitoring of immunologic rejection [mRNA]
| PRJNA348763 | ENA
Project description:Transplant tissue specfic exosome platform for noninvasive monitoring of immunologic rejection [miRNA]
| PRJNA348762 | ENA
Project description:In transplantation, there is a critical need for noninvasive biomarker platforms for monitoring immunologic rejection. We hypothesized that transplanted tissues release donor-specific exosomes into recipient circulation and that the quantitation and profiling of donor intra-exosomal cargoes may constitute a biomarker platform for monitoring rejection. Here, we have 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, we quantified islet transplant exosomes in recipient blood over long-term follow-up using anti-HLA antibody, which was detectable only in xenoislet recipients of human islets. Transplant islet exosomes were purified using anti-HLA antibody-conjugated beads, and their cargoes contained the islet endocrine hormone markers insulin, glucagon, and somatostatin. Rejection led to a marked decrease in transplant islet exosome signal along with distinct changes in exosomal microRNA and proteomic profiles prior to appearance of hyperglycemia. In the clinical settings of islet and renal transplantation, donor exosomes with respective tissue specificity for islet ? cells and renal epithelial cells were reliably characterized in recipient plasma over follow-up periods of up to 5 years. Collectively, these findings demonstrate the biomarker potential of transplant exosome characterization for providing a noninvasive window into the conditional state of transplant tissue.
| S-EPMC5373894 | 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 Using regression correlation
2003-07-01 | E-GEOD-343 | biostudies-arrayexpress
Project description:BackgroundEndomyocardial biopsy remains the gold standard for distinguishing types of immunologic injury-acute versus antibody-mediated rejection (AMR). Exosomes are tissue-specific extracellular microvesicles released by many cell types, including transplanted heart. Circulating transplant heart exosomes express donor-specific human leukocyte antigen (HLA) I molecules. As AMR is mediated by antibodies to donor HLAs, we proposed that complement deposition that occurs with AMR at tissue level would also occur on circulating donor heart exosomes.MethodsPlasma exosomes in 4 patients were isolated by column chromatography and ultracentrifugation. Donor heart exosomes were purified using anti-donor HLA I antibody beads and complement C4d protein expression was assessed in this subset as marker for AMR.ResultsThree patients had no rejection episodes. Circulating donor heart exosomes showed troponin protein and mRNA expression at all follow-up time points. One patient developed AMR on day 14 endomyocardial biopsy that was treated with rituximab, IVIG/plasmapheresis. Time-specific detection of C4d protein was seen in donor heart exosome subset in this patient, which resolved with treatment. C4d was not seen in other 3 patients' donor exosomes.ConclusionsAnti-donor HLA I specificity enables characterization of circulating donor heart exosomes in the clinical setting. Further characterization may open the window to noninvasively diagnose rejection type, such as AMR.
| S-EPMC7575166 | biostudies-literature
Project description:BACKGROUND: Assessment of gene expression in peripheral blood may provide a noninvasive screening test for allograft rejection. We hypothesized that changes in peripheral blood expression profiles would correlate with biopsy-proven rejection and would resolve after treatment of rejection episodes. METHODS AND RESULTS: We performed a case-control study nested within a cohort of 189 cardiac transplant patients who had blood samples obtained during endomyocardial biopsy (EMB). Using Affymetrix HU133A microarrays, we analyzed whole-blood expression profiles from 3 groups: (1) control samples with negative EMB (n=7); (2) samples obtained during rejection (at least International Society for Heart and Lung Transplantation grade 3A; n=7); and (3) samples obtained after rejection, after treatment and normalization of the EMB (n=7). We identified 91 transcripts differentially expressed in rejection compared with control (false discovery rate <0.10). In postrejection samples, 98% of transcripts returned toward control levels, displaying an intermediate expression profile for patients with treated rejection (P<0.0001). Cluster analysis of the 40 transcripts with >25% change in expression levels during rejection demonstrated good discrimination between control and rejection samples and verified the intermediate expression profile of postrejection samples. Quantitative real-time polymerase chain reaction confirmed significant differential expression for the predictive markers CFLAR and SOD2 (UniGene ID No. 355724 and No. 384944). CONCLUSIONS: These data demonstrate that peripheral blood expression profiles correlate with biopsy-proven allograft rejection. Intermediate expression profiles of treated rejection suggest persistent immune activation despite normalization of the EMB. If validated in larger studies, expression profiling may prove to be a more sensitive screening test for allograft rejection than EMB. Experiment Overall Design: Case- control study with three groups. Patients with rejection (r1-r7), follow-up samples after treatment of rejection (post1-7), and controls with no rejection (con1-7)
2008-06-14 | E-GEOD-5967 | biostudies-arrayexpress
Project description:The survival rate following lung transplantation is among the lowest of all solid-organ transplants, and current diagnostic tests often fail to distinguish between infection and rejection, the two primary posttransplant clinical complications. We describe a diagnostic assay that simultaneously monitors for rejection and infection in lung transplant recipients by sequencing of cell-free DNA (cfDNA) in plasma. We determined that the levels of donor-derived cfDNA directly correlate with the results of invasive tests of rejection (area under the curve 0.9). We also analyzed the nonhuman cfDNA as a hypothesis-free approach to test for infections. Cytomegalovirus is most frequently assayed clinically, and the levels of CMV-derived sequences in cfDNA are consistent with clinical results. We furthermore show that hypothesis-free monitoring for pathogens using cfDNA reveals undiagnosed cases of infection, and that certain infectious pathogens such as human herpesvirus (HHV) 6, HHV-7, and adenovirus, which are not often tested clinically, occur with high frequency in this cohort.
| S-EPMC4629384 | biostudies-literature