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Absence of significant overlap in transcriptional patterns between operationally tolerant liver and kidney recipients

ABSTRACT: Transplant recipients spontaneously accepting their grafts in the absence of immunosuppression demonstrate the feasibility of attaining allograft tolerance in humans. Previous studies have identified blood transcriptional and cell phenotypic markers specific for either liver or kidney tolerant recipients, but the two settings have not been directly compared yet employing the same platforms. To identify potential similarities in immune parameters between recipients tolerant to different organs, we analyzed blood samples from tolerant and non-tolerant liver and kidney recipients employing whole genome expression microarrays. Tolerant and non-tolerant liver and kidney recipients differed in their peripheral blood expression patterns, but no significant overlap was observed between the two datasets. This was confirmed at the functional level by employing gene set enrichment analysis.The lack of obvious similarities in immune parameters associated with liver and kidney tolerant recipients implies the involvement of different mechanisms in the two settings and argues against the existence of a common immunological constant of spontaneous operational tolerance in clinical transplantation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE22707 | GEO | 2012/01/01

SECONDARY ACCESSION(S): PRJNA128289

REPOSITORIES: GEO

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Absence of significant overlap in transcriptional patterns between operationally tolerant liver and kidney recipients

Project description:Transplant recipients spontaneously accepting their grafts in the absence of immunosuppression demonstrate the feasibility of attaining allograft tolerance in humans. Previous studies have identified blood transcriptional and cell phenotypic markers specific for either liver or kidney tolerant recipients, but the two settings have not been directly compared yet employing the same platforms. To identify potential similarities in immune parameters between recipients tolerant to different organs, we analyzed blood samples from tolerant and non-tolerant liver and kidney recipients employing whole genome expression microarrays. Tolerant and non-tolerant liver and kidney recipients differed in their peripheral blood expression patterns, but no significant overlap was observed between the two datasets. This was confirmed at the functional level by employing gene set enrichment analysis.The lack of obvious similarities in immune parameters associated with liver and kidney tolerant recipients implies the involvement of different mechanisms in the two settings and argues against the existence of a common immunological constant of spontaneous operational tolerance in clinical transplantation. The complete database comprised the expression measurements of 54,675 genes for liver and kidney trasplant inmunotolerance groups (n=12 for each group).A group of 12 samples from Healthy volunteer are included.

2012-01-01 | E-GEOD-22707 | biostudies-arrayexpress

Multiparameter Immune Profiling of Operational Tolerance in Liver Transplantation

Project description:mmunosuppressive drugs can be completely withdrawn in up to 20% of liver transplant recipients, commonly referred to as ‘operationally’ tolerant. Immune characterization of these patients, however, has not been performed in detail, and we lack tests capable of identifying tolerant patients among recipients receiving maintenance immunosuppression. In the current study we have analyzed a variety of biological traits in peripheral blood of operationally tolerant liver recipients in an attempt to define a multiparameter ‘fingerprint’ of tolerance. Thus, we have performed peripheral blood gene expression profiling and extensive blood cell immunophenotyping on 16 operationally tolerant liver recipients, 16 recipients requiring on-going immunosuppressive therapy, and 10 healthy individuals. Microarray profiling identified a gene expression signature that could discriminate tolerant recipients from immunosuppression-dependent patients with high accuracy. This signature included genes encoding for ?d T-cell and NK receptors, and for proteins involved in cell proliferation arrest. In addition, tolerant recipients exhibited significantly greater numbers of circulating potentially regulatory T-cell subsets (CD4+CD25+ T-cells and Vd1+ T cells) than either non-tolerant patients or healthy individuals. Our data provide novel mechanistic insight on liver allograft operational tolerance, and constitute a first step in the search for a non-invasive diagnostic signature capable of predicting tolerance before undergoing drug weaning.

2008-06-25 | GSE11881 | GEO

Transcription profiling of human liver transplant patients reveals a signature that could discriminate tolerant recipients from immunosuppression-dependent patients

Project description:mmunosuppressive drugs can be completely withdrawn in up to 20% of liver transplant recipients, commonly referred to as âoperationallyâ tolerant. Immune characterization of these patients, however, has not been performed in detail, and we lack tests capable of identifying tolerant patients among recipients receiving maintenance immunosuppression. In the current study we have analyzed a variety of biological traits in peripheral blood of operationally tolerant liver recipients in an attempt to define a multiparameter âfingerprintâ of tolerance. Thus, we have performed peripheral blood gene expression profiling and extensive blood cell immunophenotyping on 16 operationally tolerant liver recipients, 16 recipients requiring on-going immunosuppressive therapy, and 10 healthy individuals. Microarray profiling identified a gene expression signature that could discriminate tolerant recipients from immunosuppression-dependent patients with high accuracy. This signature included genes encoding for ?d T-cell and NK receptors, and for proteins involved in cell proliferation arrest. In addition, tolerant recipients exhibited significantly greater numbers of circulating potentially regulatory T-cell subsets (CD4+CD25+ T-cells and Vd1+ T cells) than either non-tolerant patients or healthy individuals. Our data provide novel mechanistic insight on liver allograft operational tolerance, and constitute a first step in the search for a non-invasive diagnostic signature capable of predicting tolerance before undergoing drug weaning. Experiment Overall Design: The complete database comprised the expression measurements of 54 675 genes for nine operationally tolerant (TOL) and eight immunosuppression-dependent (ID) samples.

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Intrahepatic immune microenvironment contributes to spontaneous tolerance in pediatric liver transplantation recipients

Project description:We carried out a cross-sectional study using clinical data and biospecimens to analyze factors that were associated with immune tolerance after pediatric liver transplantation. Multivariable analysis revealed that peripheral Treg ratio (OR=2.48 (1.55-19.8), p=0.032) and maximum blood EBV-DNA copy (OR=5.53 (1.08-5.67), p=0.008) were associated with the development of tolerance during follow-up, while serum IGM titer (OR=0.73 (0.53-0.99), p=0.046) had a negative relation with tolerance. Histological evaluation indicated no difference on hepatocyte damage, portal inflammation and fibrosis stage between tolerant and non-tolerant recipients. Meanwhile, no deterioration of hepatic pathology was found in recipients with longer follow-up time. Further allograft biopsy transcriptome analysis exhibited distinguished intrahepatic expression patterns between tolerant and non-tolerant recipients. Tolerant allografts were characterized by low expression of cytotoxic and inflammatory genes (like NDUFAF2, MAN1A2, PLEK2, NUDFB4 and FCER1G) and high levels of immune regulatory ones (like SCRIB, MAPK8IP3, TSC2, CHRNA4 and D2HGDH). Especially, immunohistology staining confirmed the upregulated expression of CD39 (ENTPD1) and CD73 (NT5E) in liver sinusoidal endothelial cells and hepatocytes from tolerant allograft, which was associated with increased CD4+ Treg ratio in portal areas.

2024-05-01 | GSE242205 | GEO

Comparison between blood myeloid-derived suppressor cells (MDSCs) extracted from syngeneic kidney transplanted recipient and tolerant kidney allografted recipient induced by anti-CD28 antibody

Project description:The goal is to identify molecules involved in the accumulation of blood MDSCs in tolerant kidney allografted recipients when compared to syngeneic grafted recipients.

2011-04-13 | GSE28545 | GEO

Comparative Transcriptional and Phenotypic Peripheral Blood Analysis of Kidney Recipients under Cyclosporin A or Sirolimus Monotherapy

Project description:Due to its low level of nephrotoxicity and capacity to harness tolerogenic pathways, sirolimus (SRL) has been proposed as an alternative to calcineurin inhibitors in transplantation. The exact mechanisms underlying its unique immunosuppressive profile in humans, however, are still not well understood. In the current study we aimed to depict the in vivo effects of SRL in comparison with cyclosporin A (CSA) by employing gene expression profiling and multiparameter flow cytometry on blood cells collected from stable kidney recipients under immunosuppressant monotherapy. SRL recipients displayed an increased frequency of CD4+CD25highFoxp3+ T cells. However, this was accompanied by an increased number of effector memory T cells and by enrichment in NFkB-related pro-inflammatory expression pathways and monocyte and NK cell lineage-specific transcripts. Furthermore, measurement of a transcriptional signature characteristic of operationally tolerant kidney recipients failed to detect differences between SRL and CSA treated recipients. In conclusion, we show here that the blood transcriptional profile induced by SRL monotherapy in vivo does not resemble that of operationally tolerant recipients and is dominated by innate immune cells and NFkB-related pro-inflammatory events. These data provide novel insights on the complex effects of SLR on the immune system in clinical transplantation. The complete database comprised the expression measurements of 54 675 genes for kidney trasplant recipient PBMC treated with SRL (n=23) and CSA (n=14) monotherapy. 9 healthy controls were also included.

2010-10-01 | E-GEOD-22224 | biostudies-arrayexpress

MOLECULAR CHARACTERIZATION OF LIVER ALLOGRAFTS FROM OPERATIONALLY TOLERANT TRANSPLANT RECIPIENTS (Affymetrix)

2012-01-09 | E-GEOD-26622 | biostudies-arrayexpress

MOLECULAR CHARACTERIZATION OF LIVER ALLOGRAFTS FROM OPERATIONALLY TOLERANT TRANSPLANT RECIPIENTS (Illumina)

Project description:In clinical organ transplantation complete cessation of immunosuppressive therapy can be successfully accomplished in selected recipients providing a proof-of-principle that allograft tolerance is attainable in humans. The intra-graft molecular pathways associated with human allograft tolerance, however, have not been comprehensively studied before. In this study we analyzed sequential liver tissue samples collected from liver recipients enrolled in a prospective multicenter immunosuppressive withdrawal clinical trial. Tolerant and non-tolerant recipients differed in the intra-graft expression of genes involved in the regulation of iron homeostasis.These results point to a critical role of iron homeostasis in the regulation of intra-graft alloimmune responses in humans and provide a set of novel biomarkers to conduct drug-weaning trials in liver transplantation. The complete database comprised the expression measurements of 48766 probes in liver biopsies. The liver biopsy specimens available for the study were obtained: a) before immunosuppressive drugs were discontinued from tolerant (TOL, n=24) and non-tolerant (Non-TOL, n=29) recipients; b) at the time of rejection from non-tolerant recipients (Non TOL REJ, n=18); In addition, liver tissue samples were also collected from the following control patient groups: a) liver transplant recipients with chronic hepatitis due to recurrent hepatitis C virus infection (HEPC, n=12); b) liver transplant recipients with typical acute cellular rejection taking place during the immediate post-transplant period (REJ, n=9); c) liver transplant recipients under maintenance immunosuppression with normal liver function and normal liver histology 1 year after transplantation (CONT-Tx, n=8); and d) non-transplanted patients undergoing surgery for colorectal liver metastases (CONT, n=10).

2012-01-09 | E-GEOD-26625 | biostudies-arrayexpress

Comparative Transcriptional and Phenotypic Peripheral Blood Analysis of Kidney Recipients under Cyclosporin A or Sirolimus Monotherapy

2010-10-01 | GSE22224 | GEO

Indices of Tolerance (IOT): Cross-platform biomarkers that identify kidney transplant tolerance

Project description:Being able to identify patients in whom immunological tolerance has been established or is developing would allow an individually tailored approach to post-transplant management of kidney allograft recipients. Ex vivo immunological monitoring was performed on samples from five groups of European renal transplant recipients (“IOT samples”): ten drug-free tolerant recipients who were functionally stable despite remaining immunosuppression-free for more than one year (Tol-DF); also functionally stable patients on minimal immunosuppression (<10 mg/day prednisone, s-LP); stable patients maintained with calcineurin inhibitors (s-CNI); stable patients maintained on CNI-free immunosuppression regimen (s-nCNI); patients showing signs of chronic rejection (CR) and healthy controls (HC). Among the investigation of other biomarkers and bioassays, gene expression profiles were generated on custom Agilent 8x15K 60mer oligonucleotide microarrays (“RISET 2.0”) on the IOT cohort (training set) and on an independent cohort of patients from the ITN (USA) that contained similar groups of patients and included 23 tolerant recipients (“ITN samples”, test set). Set of genes were identified, whose expression on whole blood allowed the identification of 100% of the tolerant recipients in the training set and 84% in the test set. Keywords: classification of clinical samples, tolerance prediction

2010-05-25 | GSE14655 | GEO

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