Transcriptional changes in kidney allografts with histology of antibody-mediated rejection
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE147089 | GEO | 2020/11/10
REPOSITORIES: GEO
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Project description:We hypothesized that T cell-mediated immune mechanisms play a role in two conditions; 1: donor-specific antibody (DSA) negative transplant glomerulopathy (TGP) and 2: interstitial fibrosis and tubular atrophy (IFTA) with inflammation (i>0). We investigated gene expression profiles of those biopsies compared to biopsies with antibody-mediated rejection(ABMR) and to biopsies with non-specific IFTA and no inflammation. DSA negative TGP and IFTA with inflammation biopsies have a unique molecular signature distinct to that seen in biopsies with ABMR and IFTA without inflammation with significant expression of cytotoxic and regulatory T cells.
2017-01-17 | GSE93658 | GEO
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 investigated the clinical and molecular significance of minimal peritubular capillary (PTC) and isolated glomerular C4d+ staining using microarrays. Immunohistochemistry for C4d was performed on paraffin-embedded sections. Of the 255 biopsies analyzed, 51% were C4d negative, 4% were minimal, 15% focal or diffuse PTC C4d+, and 31% isolated glomerular C4d+. Minimal and focal/ diffuse PTC C4d+ staining were associated with a higher frequency of donor-specific anti-HLA antibodies (DSA) (67% vs. 82% vs. 25%), antibody mediated rejection (AMR) (66% vs. 89% vs. 19%) and mean glomerulitis (0.88 vs. 0.65 vs. 0.25, p=0.003), interstitial inflammation (1.25 vs. 1.41 vs. 0.79; p=0.003) and peritubular capillaritis scores (1.5 vs. 1.5 vs. 0.34; p < 0.001), compared to the C4d negative group, respectively. There were no differences in the DSA frequency, AMR rate, and Banff scores between isolated glomerular C4d+ and negative patients. While both minimal and focal/diffuse C4d+ biopsies showed increased expression of genes related to the immune response, and interferon-gamma and rejection induced, cytotoxic T cell and constitutive macrophage-associated pathogenesis based transcripts, there was no activation of immune-response related genes in isolated glomerular C4d+ biopsies. In summary, minimal PTC C4d+ staining but not isolated glomerular C4d+ staining is associated with AMR. Total of 92 arrays included in this study. G1. Native pre-implantation biopsies (N= 10); G2. Focal or diffuse PTC C4d+ (N= 13); G3. Minimal PTC C4d+ (N=4); G4. Isolated glomerular C4d+ with glomerular disease (N= 13); G5. Isolated glomerular C4d+ staining without glomerular disease (N= 15); G6. C4d negative with glomerular disease (N= 12); G7. C4d negative biopsies without evidence of glomerular disease (N=25)
2012-05-28 | E-GEOD-38262 | biostudies-arrayexpress
Project description:We investigated the clinical and molecular significance of minimal peritubular capillary (PTC) and isolated glomerular C4d+ staining using microarrays. Immunohistochemistry for C4d was performed on paraffin-embedded sections. Of the 255 biopsies analyzed, 51% were C4d negative, 4% were minimal, 15% focal or diffuse PTC C4d+, and 31% isolated glomerular C4d+. Minimal and focal/ diffuse PTC C4d+ staining were associated with a higher frequency of donor-specific anti-HLA antibodies (DSA) (67% vs. 82% vs. 25%), antibody mediated rejection (AMR) (66% vs. 89% vs. 19%) and mean glomerulitis (0.88 vs. 0.65 vs. 0.25, p=0.003), interstitial inflammation (1.25 vs. 1.41 vs. 0.79; p=0.003) and peritubular capillaritis scores (1.5 vs. 1.5 vs. 0.34; p < 0.001), compared to the C4d negative group, respectively. There were no differences in the DSA frequency, AMR rate, and Banff scores between isolated glomerular C4d+ and negative patients. While both minimal and focal/diffuse C4d+ biopsies showed increased expression of genes related to the immune response, and interferon-gamma and rejection induced, cytotoxic T cell and constitutive macrophage-associated pathogenesis based transcripts, there was no activation of immune-response related genes in isolated glomerular C4d+ biopsies. In summary, minimal PTC C4d+ staining but not isolated glomerular C4d+ staining is associated with AMR.
2012-05-29 | GSE38262 | GEO
Project description:The presence of Donor-Specific anti-HLA Antibodies (DSA) is associated with an increased risk of both acute and chronic antibody-mediated rejection (AMR) in kidney allografts. AMR has remained challenging in kidney transplantation and is the major cause of late allograft loss. However, not all patients with DSA develop AMR, leading to the question of whether this represents accommodation, if other protective mechanisms exist or if this is actually a state of pre-rejection. Clinical and histological features, and gene expression profiles of kidney biopsy and blood samples of donor-specific antibody (DSA)+ patients without rejection were compared to antibody-mediated rejection (AMR) patients to elucidate the mechanisms involved in prevention of AMR. Of the 71 DSA+ patients, 46 had diagnosis of AMR and 25 did not show rejection. 50 DSA- patients without rejection were used as control. A subgroup of patients with available biopsy (n=61) and blood samples (n=54) were analyzed by microarrays. Both, DSA+/AMR+ and DSA+/AMR- biopsies showed increased expression of gene transcripts associated with cytotoxic T, natural killer cells, macrophages, interferon-gamma and rejection compared to DSA- biopsies. Regulatory T cell transcripts were up-regulated in DSA+/AMR+ and B cell transcripts in DSA+/AMR- biopsies. Whole blood gene expression analysis showed increased immune activity in only DSA+/AMR+ patients. There were no differentially expressed tolerant genes studied (n=14) in the blood or biopsy specimens of DSA+/AMR- patients. During a median 36 months follow-up, 4 DSA+/AMR- patients developed AMR, 12 continued to have DSAs but 9 lost DSAs. Gene expression profiles did not predict the development of AMR or persistence of DSAs. These results indicate increased immune activity in DSA+/AMR- biopsies despite lack of histologic findings of rejection. All clinically indicated kidney transplant biopsies performed at our institution after January 2009 were reviewed and 263 patients with anti-HLA antibody testing at the time of biopsy were identified. There were 71 DSA+ and 192 DSA- patients (Figure 1). Of the 71 DSA+ patients, 46 had biopsy diagnosis of acute AMR (n=9) or chronic AMR (n=37), and 25 had normal histopathology or minimal non-specific interstitial fibrosis/tubular atrophy (IFTA). Of the 192 DSA- patients, 50 patients with normal histology and/or mild non-specific IFTA were used as a control group. Clinical and histopathological findings of these 3 groups (DSA+/AMR+, DSA+/AMR- and DSA-) were analyzed. A subgroup of patients who were enrolled in the Institutional Review Board-approved âImmune Monitoring Studyâ who had clinically indicated biopsy (n=61) and whole blood samples (n=54) stored were used for genomic analysis. Twenty-eight biopsy and blood samples from DSA+/AMR+ patients, 13 biopsy and 14 blood samples from DSA+/AMR- patients, and 20 biopsy and 12 blood samples from DSA- patients, were available for microarray analysis.
2013-08-23 | E-GEOD-50084 | biostudies-arrayexpress
Project description:The presence of Donor-Specific anti-HLA Antibodies (DSA) is associated with an increased risk of both acute and chronic antibody-mediated rejection (AMR) in kidney allografts. AMR has remained challenging in kidney transplantation and is the major cause of late allograft loss. However, not all patients with DSA develop AMR, leading to the question of whether this represents accommodation, if other protective mechanisms exist or if this is actually a state of pre-rejection. Clinical and histological features, and gene expression profiles of kidney biopsy and blood samples of donor-specific antibody (DSA)+ patients without rejection were compared to antibody-mediated rejection (AMR) patients to elucidate the mechanisms involved in prevention of AMR. Of the 71 DSA+ patients, 46 had diagnosis of AMR and 25 did not show rejection. 50 DSA- patients without rejection were used as control. A subgroup of patients with available biopsy (n=61) and blood samples (n=54) were analyzed by microarrays. Both, DSA+/AMR+ and DSA+/AMR- biopsies showed increased expression of gene transcripts associated with cytotoxic T, natural killer cells, macrophages, interferon-gamma and rejection compared to DSA- biopsies. Regulatory T cell transcripts were up-regulated in DSA+/AMR+ and B cell transcripts in DSA+/AMR- biopsies. Whole blood gene expression analysis showed increased immune activity in only DSA+/AMR+ patients. There were no differentially expressed tolerant genes studied (n=14) in the blood or biopsy specimens of DSA+/AMR- patients. During a median 36 months follow-up, 4 DSA+/AMR- patients developed AMR, 12 continued to have DSAs but 9 lost DSAs. Gene expression profiles did not predict the development of AMR or persistence of DSAs. These results indicate increased immune activity in DSA+/AMR- biopsies despite lack of histologic findings of rejection.
2013-08-23 | GSE50084 | GEO
Project description:We compared the transcriptomic profile between patients without donor-specific HLA antibodies (DSA-), patients with donor-specific HLA antibodies without antibody-mediated rejection (DSA+ ABMR-) and patients with donor-specific HLA antibodies and antibody-mediated rejection (DSA+ ABMR+). We found that patient with DSA+ ABMR+ had a distinct transcriptomic profile compared to DSA- and DSA+ ABMR-, characterized by upregulation of genes encoding for germinal center T follicular helper cells function, T-B cell interaction and costimulatory molecules.
2021-07-01 | GSE134477 | GEO
Project description:We compared the transcriptomic profile between patients without donor-specific HLA antibodies (DSA-), patients with donor-specific HLA antibodies without antibody-mediated rejection (DSA+ ABMR-) and patients with donor-specific HLA antibodies and antibody-mediated rejection (DSA+ ABMR+). We found that patient with DSA+ ABMR+ had a distinct transcriptomic profile compared to DSA- and DSA+ ABMR-, characterized by upregulation of genes encoding for germinal center T follicular helper cells function, T-B cell interaction and costimulatory molecules.
2020-11-09 | GSE145503 | GEO
Project description:Kidney transplant biopsies showing transplant glomerulopathy (cg > 0) and microvascular inflammation (MVI) in the absence of C4d staining and DSAs do not fulfill the criteria for chronic active antibody-mediated rejection (CA-AMR) diagnosis or any other Banff category. In this multicenter intercontinental study including 36 cases, we compared, among other types of data, the transcriptomic profiles of 14 KTx biopsies classified as cg+MVI DSA-/C4d- with 22 classified as CA-AMR DSA+/C4d+ through novel transcriptomic analysis using the NanoString B-HOT panel. Due to lack of tissue, one sample was excluded from the transcriptomic analysis. In our analysis, nineteen genes were differentially expressed between the two study groups. Samples diagnosed with CA-AMR DSA+/C4d+ showed a higher transcriptomic cell type scores for macrophages in an environment characterized by increased expression of complement-related genes (i.e., C5AR1) and higher activity of angiogenesis, IFTA, CA-AMR, and DSA-related pathways when compared to samples diagnosed with cg+MVI DSA-/C4d-. Samples diagnosed with cg+MVI DSA-/C4d- displayed a higher activity of the T-cell receptor and B-cell associated transcripts. These results were coherent with those from our 5-plex immunofluorescence orthogonal analyses showing higher abundance of innate immune cells in the interstitium of CA-AMR DSA+/C4d+ samples when compared to cg+MVI DSA-/C4d- samples and a higher glomerular abundance of pan-T-cells in cg+MVI DSA-/C4d- samples when compared to CA-AMR DSA+/C4d+ samples. Here we show that using novel multiomic techniques, KTx biopsies with cg+MVI DSA-/C4d- have a prominent T-cell presence and activity, putting forward the possibility that these represent a more T-cell-dominant phenotype.
2023-10-09 | GSE242984 | GEO
Project description:Histologic findings on 1-year biopsies such as inflammation with fibrosis and transplant glomerulopathy predict renal allograft loss by 5 years. However, almost half of the patients with graft loss have a 1-year biopsy that is either normal or has only interstitial fibrosis. The goal of this study was to determine if there was a gene expression profile in these relatively normal 1-year biopsies that predicted subsequent decline in renal function. Using transcriptome microarrays we measured intragraft mRNA levels in a retrospective Discovery cohort (170 patients with a normal/minimal fibrosis 1-year biopsy, 54 with progressive decline in function/graft loss and 116 with stable function) and developed a nested 10-fold cross-validated gene classifier that predicted progressive decline in renal function (positive predictive value=38±34%%; negative predictive value=73±30%, c-statistic=0.59). In a prospective, multicenter Validation cohort (270 patients with Normal/Interstitial Fibrosis [IF]), the classifier had a 20% positive predictive value, 85% negative predictive value and 0.58 c-statistic. Importantly, the majority of patients with graft loss in the prospective study had 1-year biopsies scored as Normal or IF. We conclude predicting graft loss in many renal allograft recipients (i.e. those with a relatively normal 1-year biopsy and eGFR >40) remains difficult.
2021-08-31 | GSE181757 | GEO