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ABSTRACT:
PROVIDER: PRJNA780385 | ENA |
REPOSITORIES: ENA
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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: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:Antimicrobial resistance (AMR) is one of the major challenges that humans are facing this century. Understanding the mechanisms behind the rise of AMR is crucial to tackle this global threat. Among the triggers of phenotypic antimicrobial resistance, the contribution of transition metals has been understudied in Mycobacterium abscessus (Mabs), a fast-growing non-tuberculous mycobacterium known for its extreme AMR levels. Deeper understanding of the effects of transition metal ions will be beneficial for our knowledge in AMR and the discovery of potential therapeutic targets. Here, we investigated the impact of transition metal ions, nickel, cobalt and copper on the physiology and drug susceptibility of Mabs.
2024-09-13 | GSE243031 | GEO
Project description:Cardiotoxicity remains a major cause of drug withdrawal, partially due to lacking predictability of animal models. Additionally, risk of cardiotoxicity following treatment of cancer patients is treatment limiting. It is unclear which patients will develop heart failure following therapy. Human pluripotent stem cell (hPSC)-derived cardiomyocytes present an unlimited cell source and may offer individualized solutions to this problem. We developed a platform to predict molecular and functional aspects of cardiotoxicity. Our platform can discriminate between the different cardiotoxic mechanisms of existing and novel anthracyclines Doxorubicin (DOXO), Aclarubicin (ACLA) and Amrubicin (AMR). DOXO and ACLA unlike AMR substantially affected the transcriptome, mitochondrial membrane integrity, contractile force and transcription factor availability. Cardiomyocytes recovered fully within two or three weeks, corresponding to the intermittent clinical treatment regimen. Our system permits the study of hPSC-cardiomyocyte recovery and the effects of accumulated dose after multiple dosing, allowing individualized cardiotoxicity evaluation, which effects millions of cancer patients treated with anthracyclines annually.
2023-10-01 | GSE232331 | 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:<p>The study of antimicrobial resistance (AMR) in infectious diarrhea has generally been limited to cultivation, antimicrobial susceptibility testing and targeted PCR assays. When individual strains of significance are identified, whole genome shotgun (WGS) sequencing of important clones and clades is performed. Genes that encode resistance to antibiotics have been detected in environmental, insect, human and animal metagenomes and are known as "resistomes". While metagenomic datasets have been mined to characterize the healthy human gut resistome in the Human Microbiome Project and MetaHIT and in a Yanomani Amerindian cohort, directed metagenomic sequencing has not been used to examine the epidemiology of AMR. Especially in developing countries where sanitation is poor, diarrhea and enteric pathogens likely serve to disseminate antibiotic resistance elements of clinical significance. Unregulated use of antibiotics further exacerbates the problem by selection for acquisition of resistance. This is exemplified by recent reports of multiple antibiotic resistance in Shigella strains in India, in Escherichia coli in India and Pakistan, and in nontyphoidal Salmonella (NTS) in South-East Asia. We propose to use deep metagenomic sequencing and genome level assembly to study the epidemiology of AMR in stools of children suffering from diarrhea. Here the epidemiology component will be surveillance and analysis of the microbial composition (to the bacterial species/strain level where possible) and its constituent antimicrobial resistance genetic elements (such as plasmids, integrons, transposons and other mobile genetic elements, or MGEs) in samples from a cohort where diarrhea is prevalent and antibiotic exposure is endemic. The goal will be to assess whether consortia of specific mobile antimicrobial resistance elements associate with species/strains and whether their presence is enhanced or amplified in diarrheal microbiomes and in the presence of antibiotic exposure. This work could potentially identify clonal complexes of organisms and MGEs with enhanced resistance and the potential to transfer this resistance to other enteric pathogens.</p> <p>We have performed WGS, metagenomic assembly and gene/protein mapping to examine and characterize the types of AMR genes and transfer elements (transposons, integrons, bacteriophage, plasmids) and their distribution in bacterial species and strains assembled from DNA isolated from diarrheal and non-diarrheal stools. The samples were acquired from a cohort of pediatric patients and controls from Colombia, South America where antibiotic use is prevalent. As a control, the distribution and abundance of AMR genes can be compared to published studies where resistome gene lists from healthy cohort sequences were compiled. Our approach is more epidemiologic in nature, as we plan to identify and catalogue antimicrobial elements on MGEs capable of spread through a local population and further we will, where possible, link mobile antimicrobial resistance elements with specific strains within the population.</p>
| phs001260 | dbGaP
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:Background: Plasmapheresis/rituximab-based desensitization therapy has successfully reduced anti-ABO antibody levels and suppressed antibody-mediated rejection (AMR) in ABO-incompatible (ABOi) kidney transplantation (KT). However, high titers of anti-ABO antibodies in some patients are refractory to standard desensitization, leading to loss of KT opportunities or AMR. Methods: Eculizumab-based desensitization was used to rescue high-titer ABOi KT patients refractory to plasmapheresis/rituximab-based desensitization. Results: The initial titers of anti-ABO IgG antibodies in the two patients were 1:512 and >1:1024; the final pre-transplant titers after desensitization were 1:128 and 1:64. Both patients received eculizumab from the day of KT to two or four weeks post-KT and maintained stable renal function up to one-year post-transplantation without overt infectious complications, despite early episodes of suspicious AMR or borderline T cell-mediated rejection. Molecular phenotype analysis of allograft biopsies using the Banff Human Organ Transplant gene panel revealed that gene expression patterns in the ABOi KT with eculizumab group overlapped with those in the ABOi KT with AMR group more than in the ABOi KT without AMR group, except for complement pathway-related gene expression. Anti-ABO antibody titers decreased to low levels 1–3 months post-transplant in the eculizumab group in parallel with decreasing anti-B-specific B cells at this time point. Conclusions: Short-term eculizumab-based desensitization therapy is promising for rescuing ABOi KT recipients with unacceptably high anti-ABO antibody titers refractory to plasmapheresis-based desensitization therapy.
2024-10-15 | GSE274052 | GEO
Project description:Investigation whether PBMCs miRNAs could be a predictable biomarker for chronic AMR (CAMR). A validation study (Study I) based on microarray profiling of total 435 mature human miRNAs using pooled samples of Group I-1 (Stable: n=11), Group I-2 (DSA: n=11) and Group I-3 (clinical CAMR: n=6)
2014-08-31 | GSE59014 | GEO