Intragraft molecular pathways associated with tolerance induction in renal transplantation
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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: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: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: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 molecular pathways associated with tolerance induction in renal transplantation
2020-06-22 | E-GEOD-106675 | ExpressionAtlas
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: Not available
| S-EPMC5791065 | biostudies-literature
Project description:The development of reliable biomarkers of transplant tolerance would enhance the safety and feasibility of clinical trials and potentially also facilitate management of patients on standard immunosuppressive therapies. To this end, we examined peripheral blood samples of spontaneously tolerant renal transplant recipients, as well as patients enrolled in two interventional tolerance trials, using multiparameter flow cytometry and gene expression analysis. Repeat analysis of samples from a previously reported tolerant cohort, as well as newly identified tolerant patients, confirmed that tolerance was associated with increased expression of B cell-associated genes relative to immunosuppressed patients with stable renal function. This was not accounted for merely by an increase in total B cell numbers, but appeared to be the result of increased frequencies of transitional and naïve B cells. Moreover, serial measurements demonstrated that this pattern persisted over several years. Importantly, patients rendered tolerant via induction of transient mixed chimerism, and those weaned to low levels of immunosuppression, showed similar increases in the expression of selected B cell genes as did spontaneously tolerant individuals. Collectively, these findings support the notion that alterations in B cells may be a common theme for tolerant kidney transplant recipients, and a useful immune monitoring tool in prospective trials. The MassARRAY QGE (Sequenom) multiplexed primer and competitive template designs and analysis were reported previously.
2015-09-30 | GSE66612 | GEO
Project description:Histological analysis of biopsy is the gold standard to assess renal allograft status. Furthermore, 1-year protocol biopsy is often performed to evaluated graft outcome. However, since biopsy cannot be performed in a time serial basis, we decided to investigate whether blood can be a good compartment to predict allograft outcome. Gene expression microarrays and a large phenotype have been performed in peripheral blood mononuclear cells from 79 renal transplanted patients taken 3 months after transplantation. We evaluated the association of biological parameters with 4 histological groups defined on renal biopsy taken at 1-year post-transplantation: patients which display normal biopsy (n=45), patients with signs of tubular atrophy and interstitial fibrosis (IFTA) (n=14), with IFTA with inflammation (i-IFTA) (n=14) and patients with alloimmune lesions (n=6) Transcriptomic profile using PBMC from patients showing normal biopsy (n=45), patients with signs of tubular atrophy and interstitial fibrosis (IFTA) (n=14), with IFTA with inflammation (i-IFTA) (n=14) and patients with alloimmune lesions (n=6).
2015-12-24 | E-GEOD-57731 | biostudies-arrayexpress