Molecular phenotyping of rejection in mucosal biopsies from lung transplant recipients
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE125004 | GEO | 2019/11/19
REPOSITORIES: GEO
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Project description:We previously developed molecular assessment systems for lung transplant transbronchial biopsies (TBBs) with high surfactant and bronchial mucosal biopsies (3BMBs). Unsupervised machine learning identified T cell-mediated rejection (TCMR) based on expression of validated rejection-associated transcripts (RATs). The relationship to patient outcomes is not known. We aimed to establish whether molecular TCMR in TBBs and 3BMBs has implications for future graft loss. Molecular TCMR scores assigned in all TBBs or high surfactant TBBs agreed closely, indicating that variation in alveolar content in TBBs does not prevent detection of TCMR. Molecular assessments of 3BMB-3BMB pairs showed less variation than TBB-TBB pairs. TBB TCMR scores correlated with those in 3BMB. In both formats, molecular TCMR was associated with increased risk of graft loss whereas the presence of histologic rejection or donor-specific antibodies was not. Molecular TCMR can be detected in TBBs or 3BMBs and is associated with future risk of graft loss. TCMR emerges as a n important contributor to risk of failure. ClinicalTrials.gov NCT02812290.
2020-10-07 | GSE150156 | GEO
Project description:Molecular phenotyping of rejection in mucosal biopsies from lung transplant recipients
| PRJNA514864 | ENA
Project description:Improved understanding of lung transplant disease states is essential because failure rates are high, often due to chronic lung allograft dysfunction. However, histologic assessment of lung transplant transbronchial biopsies (TBBs) is difficult and often uninterpretable even with 10 pieces. All 242 single-piece TBBs produced reliable transcript measurements. Paired TBB pieces available from 12 patients showed significant similarity but also showed some sampling variance. Alveolar content, as estimated by surfactant transcript expression, was a source of sampling variance. To offset sampling variation, for analysis we selected 152 single-piece TBBs with high surfactant transcripts. Unsupervised archetypal analysis identified four idealized phenotypes (archetypes) and scored biopsies for their similarity to each: normal, T cell-mediated rejection (TCMR; T cell transcripts), antibody-mediated rejection (ABMR)-like (endothelial transcripts), and injury (macrophage transcripts). Molecular TCMR correlated with histologic TCMR. The relationship of molecular scores to histologic ABMR could not be assessed because of the paucity of ABMR in this population. Molecular assessment of single-piece TBBs can be used to classify lung transplant biopsies and correlated with rejection histology. Two or three pieces for each TBB will probably be needed to offset sampling variance.
2019-08-16 | GSE125478 | GEO
Project description:Molecular T-cell mediated rejection in transbronchial and mucosal lung transplant biopsies
| PRJNA631267 | ENA
Project description:The samples are a part of a study aiming at diagnosing ulcerative colitis from genome-wide gene expression analysis of the colonic mucosa. Colonic mucosal samples were collected as endoscopic pinch biopsies from ulcerative colitis patients and from control subjects. Samples with and without macroscopic signs of inflammation were collected from the patients. Keywords: Disease state analysis
2007-10-31 | GSE9452 | GEO
Project description:The samples are a part of a study aiming at diagnosing ulcerative colitis from genome-wide gene expression analysis of the colonic mucosa. Colonic mucosal samples were collected as endoscopic pinch biopsies from ulcerative colitis patients and from control subjects. Samples with and without macroscopic signs of inflammation were collected from the patients. Experiment Overall Design: The series contain eight UC samples with macroscopic signs of inflammation, 13 UC smaples without macroscopic signs of inflammation, five control subjects.
2008-06-20 | E-GEOD-9452 | biostudies-arrayexpress
Project description:Transplanted lungs suffer worse outcomes than other organ transplants with many developing chronic lung allograft dysfunction (CLAD), diagnosed by physiologic changes. Histology of transbronchial biopsies (TBB) yields little insight, and the molecular basis of CLAD is not defined. We hypothesized that gene expression in TBBs would reveal the nature of CLAD and distinguish CLAD from changes due simply to time posttransplant. Time was associated with increased expression of inflammation genes e.g. CD1E and immunoglobulins. After correcting for time, CLAD manifested not as inflammation but as parenchymal response-to-wounding, with increased expression of genes such as HIF1A, SERPINE2, and IGF1 that are increased in many injury and disease states and cancers, associated with development, angiogenesis, and epithelial response-to-wounding in pathway analysis. Fibrillar collagen genes were increased in CLAD, indicating matrix changes, and normal transcripts were decreased – dedifferentiation. Gene-based classifiers predicted CLAD with AUC 0.70 (no time-correction) and 0.87 (time-corrected). CLAD-related gene sets and classifiers were strongly prognostic for graft failure and correlated with CLAD stage. Thus, in TBBs molecular changes indicate that CLAD primarily reflects severe parenchymal injury-induced changes and dedifferentiation.
2022-01-09 | GSE193150 | GEO
Project description:Acute lung rejection is a risk factor for chronic rejection, jeopardizing the long-term survival of lung transplant recipients. At present, acute rejection is diagnosed by transbronchial lung biopsies, which are invasive, expensive, and subject to significant sampling error. In this study, we sought to identify groups of genes whose collective expression in BAL cells best classifies acute rejection versus no-rejection. BAL samples were analyzed from 32 unique subjects whose concurrent histology showed acute rejection (n=14) or no rejection (n=18). Global BAL cell gene expression was measured using Affymetrix U133A microarrays. The nearest shrunken centroid method with 10-fold cross validation was used to define the classification model. 250 runs of the algorithm were performed to determine the range of misclassification error and the most influential genes in determining classifiers. The estimated overall misclassification rate was below 20%. Seven transcripts were present in every classifier and 52 transcripts were present in at least 70% of classifiers; these transcripts were notable for involvement with T-cell function, cytotoxic CD8 activity, and granulocyte degranulation. The proportions of both lymphocytes and neutrophils in BAL samples increased with increasing probability of acute rejection; this trend was more pronounced with neutrophils. We conclude that there is a prominent acute rejection-associated signature in BAL cells characterized by increased T-cell, CD8+ cytotoxic cell, and neutrophil gene expression; this is consistent with established mechanistic concepts of the acute rejection response. Experiment Overall Design: Lung transplant recipients surviving at least 30 days after transplantation at the University of Minnesota were eligible for enrollment in the study. The study was approved by the Universityâs Institutional Review Board, and all patients provided written informed consent. Subjects underwent scheduled surveillance (n = 22) and clinically indicated (decreased pulmonary function tests or new radiographic abnormalities) bronchoscopies (n = 10), in which 100-200 cc of sterile saline was instilled into a single anatomic location (right middle lobe or lingula), and recovered using gentle suction. 4-6 transbronchial biopsies (TBB) were obtained from the same subsegmental location as the BAL, and 4-6 additional TBB were obtained from the lower lobe of the same lung. After sending samples for clinical tests, approximately 50 ml of the recovered BAL effluent was immediately placed on ice. BAL cell counts and differentials were determined with a hemocytometer. Specimens from subjects with active bronchopulmonary infections (as determined by history, exam, chest radiograph, and the results of routine laboratory tests and cultures) were excluded from analysis. Experiment Overall Design: All biopsy specimens were graded according to standard International Society for Heart and Lung Transplantation criteria8. Vascular and airway cellular infiltrate were scored separately on A (vascular) and B (airway) scales, each score ranging from 0 to 48;23;24. For the purposes of this analysis, acute rejection was defined as a combined A+B score greater than or equal to 2; and no-rejection was defined as a combined A+B score less than 2. Experiment Overall Design: The BAL samples used in this study were selected according to strict criteria that were designed to maximize potential differences in gene expression between acute rejection and non-acute rejection BAL samples; and to minimize bias from confounding factors. Each subject (n=32) was represented by one BAL sample in this study. Control subjects and samples (n=14) were selected according to the following criteria: 1) A+B score was 0 or 1 for all biopsies collected from each subject during his/her post-transplant course; 2) at least three biopsies had been graded from each subject; 3) the subject had survived at least one year post-transplant; 4) the selected BAL sample was culture negative for pathogenic bacteria, fungi, and viruses; and 5) the selected sample was from a patient that had not developed BOS or was collected at least 6 months prior to the development of BOS. Rejection subjects and samples (n=18) were selected according to the following criteria: 1) the BAL sample was culture negative for pathogenic bacteria, fungi, and viruses; 2) for subjects with more than one acute rejection sample, we used the first acute rejection sample (A+B score > 1); 3) BOS grade was 0 at the time of BAL sampling (although some subjects subsequently developed BOS).
2008-06-14 | E-GEOD-6095 | biostudies-arrayexpress
Project description:To identify liver transcripts differentially expressed due to treatment with 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB), we collected RNA from male Harlan Sprague Dawley rats exposed to 0, 0.05, 0.55, 5.50, 55 or 550 mg/kg TBB, 5 days after exposure for animals 7 weeks of age. These samples were interrogated with the Affymetrix Rat Genome 230 2.0 GeneChip array. A total of 1,0,2,2, and 66 gene transcripts were differentially expressed due to TBB treatment after exposure to 0.05, 0.55, 5.50, 55 or 550 mg/kg TBB (false discovery rate (FDR) < 0.05).
2020-07-15 | GSE153361 | GEO