Intragraft molecular pathways associated with tolerance induction in renal transplantation
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ABSTRACT:
PROVIDER: PRJNA417593 | ENA |
REPOSITORIES: ENA
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Project description:Complications associated with immunosuppression, specifically nephrotoxicity and infection risk, significantly affect graft and patient survival after kidney transplantation. We previously showed that tolerance could be induced and full donor chimerism, as well as immunosuppression withdrawal, was obtained in highly mismatched allograft recipients using a bioengineered stem cell product (FCRx). Gene expression profiles in renal biopsy samples from tolerance-induced FCRx recipients, paired donor organs before implant, and subjects under standard immunosuppression (SIS) without rejection and with acute rejection were compared. This dataset is part of the TransQST collection.
2018-05-07 | E-GEOD-106675 | biostudies-arrayexpress
Project description:Complications associated with immunosuppression, specifically nephrotoxicity and infection risk, significantly affect graft and patient survival after kidney transplantation. We previously showed that tolerance could be induced and full donor chimerism, as well as immunosuppression withdrawal, was obtained in highly mismatched allograft recipients using a bioengineered stem cell product (FCRx).
2018-05-07 | GSE106675 | GEO
Project description:The modern immunosuppression regimen has greatly improved short-term allograft outcomes but not long-term allograft survival. Complications associated with immunosuppression, specifically nephrotoxicity and infection risk, significantly affect graft and patient survival. Inducing and understanding pathways underlying clinical tolerance after transplantation are, therefore, necessary. We previously showed full donor chimerism and immunosuppression withdrawal in highly mismatched allograft recipients using a bioengineered stem cell product (FCRx). Here, we evaluated the gene expression and microRNA expression profiles in renal biopsy samples from tolerance-induced FCRx recipients, paired donor organs before implant, and subjects under standard immunosuppression (SIS) without rejection and with acute rejection. Unlike allograft samples showing acute rejection, samples from FCRx recipients did not show upregulation of T cell- and B cell-mediated rejection pathways. Gene expression pathways differed slightly between FCRx samples and the paired preimplantation donor organ samples, but most of the functional gene networks overlapped. Notably, compared with SIS samples, FCRx samples showed upregulation of genes involved in pathways, like B cell receptor signaling. Additionally, prediction analysis showed inhibition of proinflammatory regulators and activation of anti-inflammatory pathways in FCRx samples. Furthermore, integrative analyses (microRNA and gene expression profiling from the same biopsy sample) identified the induction of regulators with demonstrated roles in the downregulation of inflammatory pathways and maintenance of tissue homeostasis in tolerance-induced FCRx samples compared with SIS samples. This pilot study highlights the utility of molecular intragraft evaluation of pathways related to FCRx-induced tolerance and the use of integrative analyses for identifying upstream regulators of the affected downstream molecular pathways.
| S-EPMC5791065 | biostudies-literature
Project description:To ensure safety tolerance induction protocols are accompanied by conventional immunosuppressive drugs IS. But IS such as calcineurin inhibitors CNI can interfere with tolerance induction. We investigated the effect of an additional CNI treatment on anti-CD4 mAb-induced tolerance induction upon rat kidney transplantation. Additional CNI treatment induced deteriorated graft function and chronic rejection characterised by alloantibody production, intragraft plasma cells and C3d deposition. Microarray analysis revealed enhanced intragraft expression of the B cell chemokine CXCL13 upon additional CNI treatment. In contrast PNOC, a B cell-related gene highly expressed in operational tolerant kidney transplant recipients, was decreased in grafts of anti-CD4 mAb+CsA-treated recipients suggesting an altered balance of B regulatory genes. Transient B cell depletion or transfer of Tregs three weeks after transplantation could inhibit intragraft B cell accumulation, alloantibody production and ameliorate chronic rejection. These data represent unexpected findings and should be taken into consideration when designing new clinical trials. To safe the benefit of CNI in controlling memory T cell responses we need strategies for a therapeutic optimization. We show here that early B cell depletion or transfer of Tregs may be one approach to arrest B cell accumulation, activation and graft destruction. comparative analysis of different immunosuppressive regimens on renal allograft gene expression versus untreated allografts
2013-09-01 | E-GEOD-40454 | biostudies-arrayexpress
Project description:Xenotransplantation holds the promise of providing an unlimited supply of donor organs for terminal patients with organ failure. The gal carbohydrate results in rejection of wild type pig grafts, however, chimerism established by expression of the GalT gene prior to transplantation in GalT knockout mice results in tolerance to Gal+ heart grafts. We used microarrays in order to further understand the early events that occur within grafts that demonstrate tolerance. Keywords: transplntation tolerance
2007-04-03 | GSE7424 | GEO
Project description:Immunosuppression is needed in HLA identical sibling renal transplantation. We conducted a tolerance trial in this patient cohort using Alemtuzumab induction, donor hematopoietic stem cells, tacrolimus/mycophenolate immunosuppression converted to sirolimus, planning complete drug withdrawal by 24 months post-transplantation. After an additional 12 months with no immunosuppression, normal biopsies and renal function, recipients were considered tolerant. Twenty recipients were enrolled. Of the first 10 (>36 months post-transplantation), 5 had immunosuppression successfully withdrawn for 16-36 months (tolerant), 2 had disease recurrence and 3 had subclinical rejection in protocol biopsies (non-tolerant). Microchimerism disappeared after 1 year, and CD4+CD25highCD127-FOXP3+ T cells and CD19+IgD/M+CD27- B cells increased to 5 years post-transplantation in both groups, whereas immune/inflammatory gene expression pathways in the peripheral blood and urine were differentially downregulated in tolerant compared to non-tolerant recipients. Therefore, in this HLA identical renal transplant tolerance trial, absent chimerism, Treg and Breg immunophenotypes were indistinguishable between tolerant and non-tolerant recipients, but global genomic changes indicating immunomodulation were observed only in tolerant recipients.
2013-04-01 | GSE45593 | GEO
Project description:Intragraft transcriptional profiles were investigated in patients with tubular dysfunction to disclose subclinical mechanisms underlying graft deterioration. Moreover, we analyzed whether individualization of immunosuppression could modify this profile while improving renal function after 12 months of regimen modification.
2015-07-31 | GSE48250 | GEO
Project description:Immunosuppression is needed in HLA identical sibling renal transplantation. We conducted a tolerance trial in this patient cohort using Alemtuzumab induction, donor hematopoietic stem cells, tacrolimus/mycophenolate immunosuppression converted to sirolimus, planning complete drug withdrawal by 24 months post-transplantation. After an additional 12 months with no immunosuppression, normal biopsies and renal function, recipients were considered tolerant. Twenty recipients were enrolled. Of the first 10 (>36 months post-transplantation), 5 had immunosuppression successfully withdrawn for 16-36 months (tolerant), 2 had disease recurrence and 3 had subclinical rejection in protocol biopsies (non-tolerant). Microchimerism disappeared after 1 year, and CD4+CD25highCD127-FOXP3+ T cells and CD19+IgD/M+CD27- B cells increased to 5 years post-transplantation in both groups, whereas immune/inflammatory gene expression pathways in the peripheral blood and urine were differentially downregulated in tolerant compared to non-tolerant recipients. Therefore, in this HLA identical renal transplant tolerance trial, absent chimerism, Treg and Breg immunophenotypes were indistinguishable between tolerant and non-tolerant recipients, but global genomic changes indicating immunomodulation were observed only in tolerant recipients. A total of 46 PBMC samples representing blood draws from four time points in the first 9 recipients were processed for microarray analysis (The Scripps Research Institute, La Jolla, CA). The analyzed time points were: immediately pre-operatively in the absence of immunosuppression (n=9); post-operatively at 1 year (n=8, range 11-13 months); at 2 years (n=12, range 18-25 months); >3 years (n=17, range 32-48 months). (At year 2 and at > 3 years, repeated samples were obtained from individual subjects, and at one year, one subject had a technically unsatisfactory sample.) To discount the effects of immunosuppression on gene expression, microarray data were included on whole blood from 18 healthy human subjects (controls: GSE40586; NCBI Gene Expression Omnibus [GEO] repository).
2013-04-01 | E-GEOD-45593 | biostudies-arrayexpress
Project description:To ensure safety tolerance induction protocols are accompanied by conventional immunosuppressive drugs IS. But IS such as calcineurin inhibitors CNI can interfere with tolerance induction. We investigated the effect of an additional CNI treatment on anti-CD4 mAb-induced tolerance induction upon rat kidney transplantation. Additional CNI treatment induced deteriorated graft function and chronic rejection characterised by alloantibody production, intragraft plasma cells and C3d deposition. Microarray analysis revealed enhanced intragraft expression of the B cell chemokine CXCL13 upon additional CNI treatment. In contrast PNOC, a B cell-related gene highly expressed in operational tolerant kidney transplant recipients, was decreased in grafts of anti-CD4 mAb+CsA-treated recipients suggesting an altered balance of B regulatory genes. Transient B cell depletion or transfer of Tregs three weeks after transplantation could inhibit intragraft B cell accumulation, alloantibody production and ameliorate chronic rejection. These data represent unexpected findings and should be taken into consideration when designing new clinical trials. To safe the benefit of CNI in controlling memory T cell responses we need strategies for a therapeutic optimization. We show here that early B cell depletion or transfer of Tregs may be one approach to arrest B cell accumulation, activation and graft destruction.
2013-09-01 | GSE40454 | GEO
Project description:Intragraft transcriptional profiles were investigated in patients with tubular dysfunction to disclose subclinical mechanisms underlying graft deterioration. Moreover, we analyzed whether individualization of immunosuppression could modify this profile while improving renal function after 12 months of regimen modification. 33 renal transplant patients were enrolled in the study considering their high urinary levels of retinol binding protein, a biomarker of proximal tubular dysfunction (PTD). They were divided in two groups regarding immunosuppressive therapy. At time zero (t0), 33 patients were biopsied and 18 patients had their immunosuppression regimen modified, namely, reduction of cyclosporine dosage and introduction of mycophenolate mofetil (MYF), while 15 patients remained under azathioprine (AZA) schema. All patients were followed-up for 12 months (t12) and then re-biopsied. Microarray experiments were performed using biopsies from 17 patients. Molecular changes due to elevated uRBP levels and immunosuppressive therapies were interpreted via transcriptional network analysis. This dataset is part of the TransQST collection.
2015-07-31 | E-GEOD-48250 | biostudies-arrayexpress