Spatial transcriptome analysis unveils an innate immune activation signature of acute T cell-mediated rejection in kidney transplants
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE252137 | GEO | 2024/02/16
REPOSITORIES: GEO
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Project description:Most kidney transplant patients who undergo biopsies are classified as having no rejection based on consensus thresholds. However, we hypothesized that because these patients have normal adaptive immune systems, T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) may exist as subthreshold activity in some transplants currently classified as no rejection. Subthreshold molecular TCMR and/or ABMR activity molecular activity was detectable as elevated classifier scores in many biopsies classified as no rejection, with ABMR activity in many TCMR biopsies and TCMR activity in many ABMR biopsies. In biopsies classified as no rejection histologically and molecularly, molecular TCMR classifier scores correlated with increases in histologic TCMR features and molecular injury, lower eGFR, and higher risk of graft loss, and molecular ABMR activity correlated with increased glomerulitis and donor-specific antibody. No rejection biopsies with high subthreshold TCMR or ABMR activity had a higher probability of having TCMR or ABMR respectively diagnosed in a future biopsy. We conclude that many kidney transplant recipients have unrecognized subthreshold TCMR or ABMR activity, with significant implications for future problems.
2024-09-04 | GSE275126 | GEO
Project description:The authors report that in INTERCOM, a prospective international study of 300 kidney transplant biopsies, a microarray-based molecular score for T cell-mediated rejection changed the assessment of 26% of all biopsies, illustrating the potential of precision diagnostics to impact practice. Microarray analysis of 300 kidney transplant biopsies (non-TCMR, TCMR) and 6 nephrectomies.
2013-09-15 | E-GEOD-48581 | biostudies-arrayexpress
Project description:Antibody-mediated rejection (AMR) accounts for >50% of kidney allograft losses. AMR is caused by donor-specific antibodies (DSA) against HLA and non-HLA antigens in the glomeruli and the tubulointerstitium, which together with high interferon gamma (IFNɣ) and tumor necrosis factor-alpha (TNFα), trigger graft injury. Unfortunately, the mechanisms governing cell-specific injury in AMR remain unclear. We studied 30 for-cause kidney biopsies with early AMR, acute cellular rejection or acute tubular necrosis (‘non-AMR’). We laser-captured microdissected glomeruli and tubulointerstitium and subjected them to unbiased proteome analysis. 120/2026 glomerular and 180/2399 tubulointerstitial proteins were significantly differentially expressed in AMR vs. non-AMR biopsies (p<0.05). Basement membrane and extracellular matrix (ECM) proteins were significantly decreased in both AMR compartments. We verified decreased glomerular and tubulointerstitial LAMC1 expression, and decreased glomerular NPHS1 and PTPRO expression in AMR. Cathepsin-V (CTSV) was predicted to cleave ECM-proteins in the AMR glomeruli, and CTSL, CTSS and LGMN in the tubulointerstitium. We identified galectin-1, an immunomodulatory protein upregulated in AMR glomeruli and linked to the ECM. Anti-HLA class-I antibodies significantly increased CTSV expression, and galectin-1 expression and secretion, in human glomerular endothelial cells. We also studied glutathione S-transferase omega-1 (GSTO1), an ECM-modifying enzyme, increased in the AMR tubulointerstitium. GSTO1 expression was significantly increased in TNFα-treated proximal tubular epithelial cells. IFNɣ and TNFα significantly increased CTSS and LGMN expression in these cells. Basement membranes are often remodeled in chronic AMR, and we demonstrated that this remodeling begins early in glomeruli and tubulointerstitium. Targeting ECM-remodeling in AMR may represent a new therapeutic opportunity.
2020-09-22 | PXD017580 | Pride
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:Glomerular and tubulointerstitial fractions were enriched from human kidneys samples. Ages of human kidney samples: 15, 29, 37, 61, 67 and 69 years of age. The glomerular and tubulointerstitial samples were processed to enrich for extracellular matrix components and the fractions analysed by mass spectrometry.
2022-02-22 | PXD022219 | Pride
Project description:Background: Acute T cell-mediated rejection (TCMR) is a common immunological feature in renal transplantation and is associated with reduced graft survival. However, the full immunological profiling of acute TCMR remains unknown. Methods: A fully mismatched acute TCMR model was induced by transplanting the left kidneys from BALB/c mice into C56BL/6J mice. Allografted kidneys were harvested on day 7 (D7) and sorted for CD45+ leukocytes for single cell RNA sequencing (scRNA-seq) . In addition, scRNA-seq data of CD45+ immune cells on day 15 (D15) containing GSE157292 dataset (samples GSM4761000 and GSM4761003) were downloaded from Gene Expression Omnibus. All data obtained from D7 and D15 were integrated and analyzed. Results: We identified 20 major immune cell types among 10921 immune cells, including macrophages, B cells, T cells, dendritic cells, natural killer cells, neutrophils, and basophils in kidney allografts. Macrophages and CD8 T cells constituted the main immune cell populations on both D7 and D15. In the process towards immune regression, the proportion of CD8 T cells dropped significantly by about 25%, mainly due to decreased proliferation and naïve CD8 T cell infiltration. The proportion of both B cells and neutrophils also decreased by about 3 folds. On the contrary, the relative proportion of macrophages and DCs increased significantly, especially by a 4 fold increase in Ly6cloMrc1+ resident macrophages A group of Ly6cloEar2+ macrophages also increased by about 3 folds. Moreover, myeloid cells harbored the richest ligand and receptor (LR) pairs with other cell types, particularly for chemokine ligands such as Cxcl9, Cxcl10, Cxcl16 and Yars. However, macrophages with weak response to interferon gamma (IFNg) contributed to rejection regression. Conclusions: There is a comprehensive single-cell landscape of the kidney allograft immune cells from rejection progression to regression in acute TCMR. Reduction in CD8 T cells, B cells, and neutrophils while increasing in Ly6clo macrophages, including Ly6cloMrc1+ resident macrophages and Ly6cloEar2+ macrophages, may contribute significantly to immune rejection regression during acute TCMR.
2021-07-21 | GSE166775 | GEO
Project description:Acute rejection of human allografts has been viewed mostly through the lens of adaptive immunity, and the intragraft landscape of innate immunity genes has not been characterized in an unbiased fashion. We did RNA sequencing of 34 kidney allograft biopsy specimens from 34 adult recipients; 16 were categorized as Banff acute T-cell mediated rejection (TCMR) and 18 as normal. Computational analysis of intragraft mRNA transcriptome identified significantly higher abundance of mRNA for pattern recognition receptors in TCMR compared to normal biopsies, as well as increased expression of mRNAs for cytokines, chemokines, interferons, and caspases. Intragraft levels of calcineurin mRNA were higher in TCMR biopsies suggesting under immunosuppression compared to normal biopsies. Cell-type enrichment analysis revealed higher abundance of dendritic cells and macrophages in TCMR biopsies. Damage associated molecular patterns, the endogenous ligands for pattern recognition receptors, as well markers of DNA damage were higher in TCMR. mRNA expression patterns supported increased calcium flux and indices of endoplasmic, cellular oxidative, and mitochondrial stress were higher in TCMR. Expression of mRNAs in major metabolic pathways were decreased in TCMR. Our global and unbiased transcriptome profiling identified heightened expression of innate immune system genes during an episode of TCMR in human kidney allografts.
2019-07-26 | GSE131179 | GEO
Project description:Chronic T-cell mediated rejection (TCMR) is characterized by the reduction of vessel lumen with marked intimal thickening, fibrous hyperplasia and a strong component of leukocyte infiltrate. Aim of our work was the study of gene expression profile in renal TCMR biopsies. We performed transcriptomics study using RNA extracted from archival formalin-fixed and paraffin-embedded (FFPE) renal biopsies obtained from patients with chronic and acute TCMR. Using a FC≥1.5 and a FDR<0.05, we identified 191 genes differentially expressed in patients with chronic and acute TCMR compared to cadaveric donor (CDs). The study of gene pathways showed the up-regulation of OX40 signaling, that is involved in the generation of memory effector T cell, and the up-regulation of KLRG-1, BLIMP-1 and CD25 that characterized CD8+ memory effector T cells. However, OX40 signaling was specific only for chronic TCMR. These results suggested the involvement of memory effector T cells in chronic TCMR. The identified genes may be used as a target for specific treatment of chronic TCMR.
2015-12-30 | GSE69677 | GEO
Project description:Background: Biopsy-based diagnosis is essential for maintaining renal allograft longevity by ensuring prompt treatment for graft complications. Although histologic assessment remains the gold standard, it carries significant limitations such as subjective interpretation, suboptimal reproducibility, and imprecise quantitation of disease burden. It is hoped that molecular diagnostics could enhance the efficiency, accuracy, and reproducibility of traditional histologic methods. Methods: Quantitative label-free mass spectrometry analysis was performed on a set of formalin-fixed, paraffin-embedded (FFPE) biopsies from renal transplant patients, comprising five biopsies with the diagnosis of T-cell-mediated rejection (TCMR), five biopsies for polyomavirus BK nephropathy (BKPyVN), and normal kidney control tissue (STA). Using the differential protein expression result as a classifier, three different machine learning algorithms were tested to build a molecular diagnostic model for TCMR. Results: The label-free proteomics method yielded 800-1350 proteins that could be quantified with high confidence per sample by single-shot measurements. Among these candidate proteins, 329 and 467 proteins were defined as differentially expressed proteins (DEPs) for TCMR in comparison with STA and BKPyVN, respectively. Comparing the FFPE quantitative proteomics data set obtained in this study using label-free method with a data set we previously reported using isobaric labeling technology, a classifier pool comprised of features from DEPs commonly quantified in both data sets, was generated for TCMR prediction. Leave-one-out cross-validation result demonstrated that the random forest (RF)-based model achieved the best predictive power. In a follow-up blind test using an independent sample set, the RF-based model yields 80% accuracy for TCMR and 100% for STA. When applying the established RF-based model to two public transcriptome datasets, 78.1%-82.9% sensitivity and 58.7%-64.4% specificity was achieved respectively. Conclusions: This proof-of-principle study demonstrates the clinical feasibility of proteomics profiling for FFPE biopsies using an accurate, efficient, and cost-effective platform integrated of quantitative label-free mass spectrometry analysis with a machine learning-derived diagnostic model. It costs less than 10 dollars per test.
2023-02-01 | PXD038601 | Pride
Project description:Expression profiling of a total of 1305 genes in 25 CA TCMR cases
2021-02-24 | GSE167361 | GEO