Inter-individual variability in lymphocyte stimulation and transcriptomic response predicts mycophenolic acid sensitivity in healthy volunteers
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE141026 | GEO | 2020/07/15
REPOSITORIES: GEO
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Project description:Mycophenolic Acid (MPA) is the active component of the immunosuppressant Mycophenolate Mofetil, a potent inhibitor of the inosine monophosphate dehydrogenase. Direct effects of MPA on podocytes remain largely unknown. In order to elucidate genes and pathways affected by the drug, cultured murine podocytes exposed to MPA were subjected to RNA sequencing (RNASeq) analysis. Untreated samples served as controls. The RNASeq of MPA treated podocytes identified 351 significantly affected genes (padj < 0.05; 130 downregulated / 221 upregulated). Gene Ontology-Term enrichment analysis outlined two major groups of terms of particular interest, namely actin associated terms and terms related to inflammatory cell death. In conclusion, MPA treatment has a substantial effect on the transcriptome of podocytes. Analysis of the sequencing data revealed several non-immune cell dependent areas in which MPA possibly has a favorable effect on podocytes.
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Project description:Selecting the right immunosuppressant to ensure rejection-free outcomes poses unique challenges in pediatric liver transplant (LT) recipients. A molecular predictor can comprehensively address these challenges. Although early acute cellular rejection (ACR) is mediated by cytotoxic T-cells, late rejection also includes antibody-mediated damage in addition to cell-mediated injury. Currently, there are no well-validated blood-based biomarkers for pediatric LT recipients either pre- or post- transplant. Here, we discover and validate separate pre- and post- transplant molecular signatures of LT outcome from whole blood transcriptomes. Using an integrative machine learning approach, we combine transcriptomic data with the high-quality reference human protein interactome network to identify differentially regulated functional sub-components of the network, or “network module signatures”, which drive ACR. Unlike gene signatures, our approach is inherently multivariate, more robust to replication and captures the structure of the underlying molecular network, encapsulating additive effects. We also identify, in a patient-specific manner, network module signatures that can be targeted by current anti-rejection drugs and other mechanisms that can be repurposed. Overall, our approach can enable personalized adjustment of drug regimens for the dominant targetable pathways in pre- and post- LT in children.
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Project description:We used DNA microarrays (HG-U95Av2 GeneChips) to determine gene expression profiles for kidney biopsies and peripheral blood lymphocytes (PBLs) in transplant patients. Sample classes include kidney biopsies and PBLs from patients with 1) healthy normal donor kidneys, 2) well-functioning transplants with no clinical evidence of rejection, 3) kidneys undergoing acute rejection, and 4) transplants with renal dysfunction without rejection. Nomenclature for samples is as follows: 1) all sample names include either BX or PBL to indicate that they were derived from biopsies or PBLs respectively, 2) C indicates samples from healthy normal donors, 3) TX indicates samples from patients with well-functioning transplants with no clinical evidence of rejection, 3) AR indicates samples from transplant patients with kidneys undergoing acute rejection, 4) NR indicates samples from transplant patients with renal dysfunction without rejection. Abbreviations used to describe patient samples include the following: BX - Biopsy; PBL- Peripheral Blood Lymphocytes; CsA -Cyclosporine; MMF - Mycophenolate Mofetil; P - Prednisone; FK - Tacrolimus; SRL - Sirolimus; CAD -Cadaveric; LD - Live Donor; Scr - Serum Creatinine; ATN - Acute Tubular Necrosis CNI - Calcineurin Inhibitor; FSGS - Focal Segmental Glomerulosclerosis several array data sets did not pass quality control and were not analyzed. These include AR1PBL, NR4BX, and NR6PBL Keywords = DNA microarrays, gene expression, kidney, rejection, transplant Keywords: other. This dataset is part of the TransQST collection.
2004-07-14 | E-GEOD-1563 | biostudies-arrayexpress
Project description:We used DNA microarrays (HG-U95Av2 GeneChips) to determine gene expression profiles for kidney biopsies and peripheral blood lymphocytes (PBLs) in transplant patients. Sample classes include kidney biopsies and PBLs from patients with 1) healthy normal donor kidneys, 2) well-functioning transplants with no clinical evidence of rejection, 3) kidneys undergoing acute rejection, and 4) transplants with renal dysfunction without rejection. Nomenclature for samples is as follows: 1) all sample names include either BX or PBL to indicate that they were derived from biopsies or PBLs respectively, 2) C indicates samples from healthy normal donors, 3) TX indicates samples from patients with well-functioning transplants with no clinical evidence of rejection, 3) AR indicates samples from transplant patients with kidneys undergoing acute rejection, 4) NR indicates samples from transplant patients with renal dysfunction without rejection. Abbreviations used to describe patient samples include the following: BX - Biopsy; PBL- Peripheral Blood Lymphocytes; CsA -Cyclosporine; MMF - Mycophenolate Mofetil; P - Prednisone; FK - Tacrolimus; SRL - Sirolimus; CAD -Cadaveric; LD - Live Donor; Scr - Serum Creatinine; ATN - Acute Tubular Necrosis CNI - Calcineurin Inhibitor; FSGS - Focal Segmental Glomerulosclerosis several array data sets did not pass quality control and were not analyzed. These include AR1PBL, NR4BX, and NR6PBL Keywords = DNA microarrays, gene expression, kidney, rejection, transplant Keywords: other
2004-07-14 | GSE1563 | GEO
Project description:Primary objectives: We believe that patients who have had a liver transplant and are infected with Hepatitis C will develop less scarring (fibrosis) in their transplant liver if their anti-rejection (immunosuppressant)medication is switched from a calcineurin inhibitor (current standard therapy) to Sirolimus. This trial will test this hypothesis.
Primary endpoints: The primary endpoint is change in fibrosis stage over the study period.
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Project description:Mycophenolic acid (MPA) is a potent inhibitor of the inosine monophosphate dehydrogenase and commonly used as an immunosuppressive drug in transplantation. MPA inhibits proliferation of both T- and B-lymphocytes by guansoin depletion. Since fibroblasts rely on the de novo synthesis of guanosin nucleotides, it is assumed that MPA interacts with fibroblasts causing an increased frequency of wound healing problems. We show a downregulation of the cytoskeletal proteins actin, vinculin and tubulin in human dermal fibroblasts exposed to pharmacologic doses of MPA using microarray technology and western blot. This reduction in protein content is accompanied by a substantial derangement of the cytoskeleton in MPA-treated fibroblasts as documented by confocal microscopy. The dysfunctional fibroblast growth was validated by scratch test documenting impaired migrational capacity. The results of the cultured dermal fibroblasts were applied to skin biopsies of renal transplant recipients. Skin biopsies of patients treated with MPA expressed less tubulin and actin as compared to control biopsies which could explain potential wound healing problems post transplantation. The perspective of MPA-induced cytoskeletal dysfunction may go beyond wound healing disturbances and has potential beneficial effects on (renal) allografts with respect to scarring. Keywords: Timecourse and MPA and/or Guanosin response
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Project description:Mycophenolic acid (MPA), an immunosuppressive drug widely used in kidney transplantation, has been suggested to have anti-fibrotic effects. To analyze at a genomic level these effects, we prospectively studied a group of stable kidney transplant recipients (n=35) on cyclosporine (CyA) and azathioprine treatment. Twenty patients were converted from azathioprine to MPA (MPA group) and 15 patients continued on azathioprine (AZA group). RNA was extracted by peripheral blood mononuclear cells at baseline and 3 months thereafter. Genomic analysis, performed on 5 randomly-selected MPA patients, revealed that 17 genes discriminated the transcriptomic profile after conversion. Neutral endopeptidase (NEP), an enzyme degrading angiotensin-II, was the most significant up-regulated gene. NEP expression level was inversely correlated to proteinuria at baseline and after conversion. Immunohistochemistry on graft biopsy of 33 independent patients demonstrated higher glomerular and tubular NEP protein expression in CyA+MPA (n=13) compared to CyA+AZA (n=12) and CyA alone (n=8). Glomerular NEP levels were inversely correlated to proteinuria and glomerulosclerosis. Tubular NEP expression was inversely correlated to interstitial fibrosis. Incubation of proximal tubular cells with MPA led to a dose- and time-dependent increase of NEP gene expression. The direct influence of MPA on NEP expression may suggest a novel therapeutic effect of this drug.
2010-12-22 | GSE14630 | GEO
Project description:We performed RNA sequencing (RNAseq) on peripheral blood mononuclear cells (PBMCs) to identify differentially expressed gene transcripts (DEGs) after kidney transplantation and after the start of immunosuppressive drugs. RNAseq is superior to microarray to determine DEGs because it’s not limited to available probes, has increased sensitivity, and detects alternative and previously unknown transcripts. DEGs were determined in adult kidney recipients, without clinical acute rejection (AR), treated with antibody induction, calcineurin inhibitor, mycophenolate, with and without steroids. Blood was obtained pre-transplant (baseline), week 1, months 3 and 6 post-transplant. PBMCs were isolated, RNA extracted and gene expression measured using RNAseq. Principal components (PCs) were computed using a surrogate variable approach. DEGs post-transplant were identified by controlling false discovery rate (FDR) at < 0.01 with at least a 2 fold change in expression from pre-transplant. The top 5 DEGs with higher levels of transcripts in blood at week 1 were TOMM40L, TMEM205, OLFM4, MMP8, and OSBPL9 compared to baseline. The top 5 DEGs with lower levels at week 1 post-transplant were IL7R, KLRC3, CD3E, CD3D, and KLRC2(Striking Image) compared to baseline. The top pathways from genes with lower levels at 1 week post-transplant compared to baseline, were T cell receptor signaling and iCOS-iCOSL signaling while the top pathways from genes with higher levels than baseline were axonal guidance signaling and LXR/RXR activation. Gene expression signatures at month 3 were similar to week 1. DEGs at 6 months post-transplant create a different gene signature than week 1 or month 3 post-transplant. RNAseq analysis identified more DEGs with lower than higher levels in blood compared to baseline at week 1 and month 3. The number of DEGs decreased with time post-transplant. Further investigations to determine the specific lymphocyte(s) responsible for differential gene expression may be important in selecting and personalizing immune suppressant drugs and may lead to targeted therapies.
2016-09-13 | GSE86884 | GEO
Project description:Acute cellular rejection occurs frequently during the first few weeks following liver transplantation. During this period its molecular phenotype is confounded by pro-inflammatory events elicited by surgery, ischemia-reperfusion injury and early post-transplant complications. To unambiguously define the molecular profile associated with rejection we collected sequential biological specimens from liver transplant patients at least 3 years after transplantation who developed rejection while enrolled in trials of intentional immunosuppression withdrawal
2016-06-01 | GSE70305 | GEO
Project description:Tacrolimus (Tac) is an effective anti-rejection agent in kidney transplantation, but its off-target effects make withdrawal desirable. While studies indicate that Tac can be safely withdrawn in a subset of kidney transplant recipients, immune mechanisms that underlie successful vs. unsuccessful Tac removal are unknown. We performed microarray analyses of PBMC RNA from subjects enrolled in the Clinical Trials in Organ Transplantation-09 study in which stable kidney transplant recipients were randomized to Tac withdrawal or maintenance of standard immunosuppression beginning 6-mo post-transplant. Eight of 14 subjects attempted but failed withdrawal, while six developed stable graft function for ≥2 years on mycophenolate mofetil plus prednisone. Whereas failed withdrawal upregulated immune activation genes, successful Tac withdrawal was associated with a distinct, T cell-specific, downregulatory, and pro-apoptotic gene program. Functional analyses suggested stronger donor-reactive immunity in subjects who failed withdrawal without evidence of regulatory T cell dysfunction. Together, our data suggest that successful Tac withdrawal can unleash an active, protective pro-apoptotic T cell program, and provide the foundation for developing strategies to promote this protective immunological phenotype in kidney transplant recipients.
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