MOLECULAR CHARACTERIZATION OF LIVER ALLOGRAFTS FROM OPERATIONALLY TOLERANT TRANSPLANT RECIPIENTS (Affymetrix)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE26622 | GEO | 2012/01/09
SECONDARY ACCESSION(S): PRJNA142205
REPOSITORIES: GEO
Similar Datasets
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 54,675 genes for liver inmunotolerance groups: 9 Tolerant (TOL) 10 Non Tolerant (Non TOL).A subset of 5 tolerant samples (TOL POST) were taken 1 year after inmunosuppresive therapy.
2012-01-09 | E-GEOD-26622 | biostudies-arrayexpress
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.
2012-01-09 | GSE26625 | GEO
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
Project description:Immune responses induced by ongoing and/or past infections prevent the establishment of transplantation tolerance in experimental animal models. How host-pathogen interactions influence allograft tolerance in humans has not been investigated before. The spontaneous development of operational tolerance in liver transplant recipients with chronic hepatitis C virus (HCV) infection constitutes a unique setting to address this question. We conducted a clinical trial of immunosuppression withdrawal in stable HCV-infected liver recipients to elucidate: i) the mechanisms through which allograft tolerance is established in the presence of an ongoing inflammatory response; and ii) how is influenced by anti-HCV heterologous immune responses. Enrolled patients gradually discontinued their immunosuppressive drugs over 6-9 months, and those who maintained normal allograft status 12 months after drug withdrawal were considered operationally tolerant. Successful drug withdrawal was associated with intra-hepatic over-expression of type I interferon and immune-regulatory genes, and correlated with an expansion of exhausted PD1/CTLA4/2B4-positive HCV-specific circulating CD8+ T cells. These findings were already present before immunosuppression was discontinued and were specific for HCV infection. In contrast, the magnitude of HCV-induced inflammatory gene expression and the scope of anti-HCV effector T cell responses did not influence drug withdrawal outcome. Our data indicate that in humans persistent viral infections do not necessarily preclude the development of transplantation tolerance. At least in HCV-infected liver allografts, mechanisms associated with the capacity of the virus to evade adaptive immunity could contribute to the restraining of alloimmune responses and the establishment of transplantation tolerance. Transcriptomic study from the following liver tissue samples: 12 tolerant before immunosuppression (IS), 13 non-tolerant before IS, 4 from non-tolerant at the time of rejection, 13 from tolerant patients 12 months after IS discontinuation. Additionally, 8 liver tissue samples obtained from healthy living liver donors undergoing partial hepatectomy were included as non-transplanted controls.
2014-12-23 | E-GEOD-52420 | biostudies-arrayexpress
Project description:Graft acceptance without the need for immunosuppressive drugs is the ultimate goal of transplantation therapy. In murine liver transplantation, allografts are accepted across major histocompatibility antigen complex barriers without the use of immunosuppressive drugs and constitute a suitable model for research on immunological rejection and tolerance. MicroRNA (miRNA) has been known to be involved in the immunological responses. In order to identify mRNAs in spontaneous liver allograft tolerance, miRNA expression in hepatic allografts was examined using this transplantation model. According to the graft pathological score and function, miR-146a, 15b, 223, 23a, 27a, 34a and 451 were upregulated compared with the expression observed in the syngeneic grafts. In contrast, miR-101a, 101b and 148a were downregulated. Our results demonstrated the alteration of miRNAs in the allografts and may indicate the role of miRNAs in the induction of tolerance after transplantation. Furthermore, our data suggest that monitoring the graft expression of novel miRNAs may allow clinicians to differentiate between rejection and tolerance. A better understanding of the tolerance inducing mechanism observed in murine hepatic allografts may provide a therapeutic strategy for attenuating allograft rejection. B10.BR mice were used as donors and B10.D2 mice were used as recipients. Liver allo-transplantation surgery on the mice was performed in this combination. Three mice from each group were sacrificed, and the liver grafts were removed on days 5, 8, 14 and 100 after transplantation. Total RNA, including miRNA was isolated. 100ng of total RNA was labeled by Cy3 and used as probe for hybridization to the microarray.
2014-10-21 | E-GEOD-52164 | 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. comparative analysis of different immunosuppressive regimens on renal allograft gene expression versus untreated allografts
2013-09-01 | E-GEOD-40454 | biostudies-arrayexpress
Project description:Complications due to long-term administration of immunosuppressive therapy increase the morbidity and mortality of liver transplant recipients. Discontinuation of immunosuppressive drugs in recipients spontaneously developing operational tolerance could substantially lessen this burden. However, this strategy results in the development of rejection in a high proportion of recipients who require lifelong immunosuppression. Thus, there is a need to identify predictive factors of successful drug withdrawal and to define the clinical and histological outcomes of operationally tolerant liver recipients. Methods. We enrolled 102 stable liver transplant recipients in an immunosuppression withdrawal trial in which drugs were gradually discontinued over a 6-9 month period. Patients with stable graft function and no signs of rejection in a liver biopsy conducted 12 months after cessation of immunosuppressive therapy were considered operationally tolerant. Results. Out of the 98 recipients who completed the study, immunosuppression discontinuation was successful in 41 recipients and rejection occurred in 57. Rejection episodes were mild and were resolved in all cases. Development of tolerance was independently associated with time elapsed since transplantation, recipient age, and male gender. No histological damage was apparent in protocol biopsies performed after successful drug withdrawal.
2012-01-09 | GSE28842 | GEO
Project description:Immune responses induced by ongoing and/or past infections prevent the establishment of transplantation tolerance in experimental animal models. How host-pathogen interactions influence allograft tolerance in humans has not been investigated before. The spontaneous development of operational tolerance in liver transplant recipients with chronic hepatitis C virus (HCV) infection constitutes a unique setting to address this question. We conducted a clinical trial of immunosuppression withdrawal in stable HCV-infected liver recipients to elucidate: i) the mechanisms through which allograft tolerance is established in the presence of an ongoing inflammatory response; and ii) how is influenced by anti-HCV heterologous immune responses. Enrolled patients gradually discontinued their immunosuppressive drugs over 6-9 months, and those who maintained normal allograft status 12 months after drug withdrawal were considered operationally tolerant. Successful drug withdrawal was associated with intra-hepatic over-expression of type I interferon and immune-regulatory genes, and correlated with an expansion of exhausted PD1/CTLA4/2B4-positive HCV-specific circulating CD8+ T cells. These findings were already present before immunosuppression was discontinued and were specific for HCV infection. In contrast, the magnitude of HCV-induced inflammatory gene expression and the scope of anti-HCV effector T cell responses did not influence drug withdrawal outcome. Our data indicate that in humans persistent viral infections do not necessarily preclude the development of transplantation tolerance. At least in HCV-infected liver allografts, mechanisms associated with the capacity of the virus to evade adaptive immunity could contribute to the restraining of alloimmune responses and the establishment of transplantation tolerance.
2014-12-23 | GSE52420 | GEO
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.
2012-01-01 | GSE22707 | GEO
Project description:Graft acceptance without the need for immunosuppressive drugs is the ultimate goal of transplantation therapy. In murine liver transplantation, allografts are accepted across major histocompatibility antigen complex barriers without the use of immunosuppressive drugs and constitute a suitable model for research on immunological rejection and tolerance. MicroRNA (miRNA) has been known to be involved in the immunological responses. In order to identify mRNAs in spontaneous liver allograft tolerance, miRNA expression in hepatic allografts was examined using this transplantation model. According to the graft pathological score and function, miR-146a, 15b, 223, 23a, 27a, 34a and 451 were upregulated compared with the expression observed in the syngeneic grafts. In contrast, miR-101a, 101b and 148a were downregulated. Our results demonstrated the alteration of miRNAs in the allografts and may indicate the role of miRNAs in the induction of tolerance after transplantation. Furthermore, our data suggest that monitoring the graft expression of novel miRNAs may allow clinicians to differentiate between rejection and tolerance. A better understanding of the tolerance inducing mechanism observed in murine hepatic allografts may provide a therapeutic strategy for attenuating allograft rejection.
2014-10-21 | GSE52164 | GEO