Intragraft gene expression profile associated with the induction of tolerance
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE7424 | GEO | 2007/04/03
SECONDARY ACCESSION(S): PRJNA97859
REPOSITORIES: GEO
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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. Experiment Overall Design: The GalT BMT recipient is a GalT knockout mouse which recieved GalT gene transduced allo-bone marrow cells transplantation after sublethal irradiation. A heart of wild type C57BL/6 was heterotopically transplanted into the recipient after GalT BMT. Syngeneic Control recipient is a wild type C57BL/6 transplanted a heart of wild C57BL/6.
2008-06-15 | E-GEOD-7424 | 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). 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:CD4+Foxp3+ regulatory T cells (Tregs) play an essential role in suppressing transplant rejection but their role within the graft, is poorly understood. To address this, we compared phenotypic and transcriptomic characteristics of Treg populations within lymphoid-organs and grafts in an islet xenotransplant model of tolerance induced by co-stimulation blockade. In this study, Tregs were essential for tolerance induction and their numbers increased over time. Tregs demonstrated phenotypic and transcriptional heterogeneity within the graft, and lymphoid organs of tolerant mice. A sub-population of CD127highTreg with memory-like and suppressive features were present in high proportions within long surviving islet-grafts of tolerant mice and had a transcriptomic profile consistent with tissue-Tregs. Importantly these CD127highTregs were better able to prevent rejection by effector T cells, after adoptive transfer into secondary Rag-/- hosts, than naïve Tregs, or unselected Tregs isolated from tolerant mice. We propose that after initial development within the draining lymph node they undergo further genetic reprogramming within the graft towards a phenotype that has shared characteristics with other tissue or tumour Tregs. These findings provide a new focus for engineering such cells either in vivo or for adoptive transfer for inducing tolerance.
2024-03-22 | GSE220447 | GEO
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 better understand the pathophysiology of galactose-1-phosphate uridyltransferase (GALT) deficiency in humans, we studied the mechanisms by which a GALT-deficient yeast survived on galactose medium. Under normal conditions, GALT-deficient yeast cannot grow in medium that contains 0.2% galactose as the sole carbohydrate, a phenotype of Gal(-). We isolated revertants from a GALT-deficient yeast by direct selection for growth in galactose, a phenotype of Gal(+). Comparison of gene expression profiles among wild-type and revertant strains on galactose medium revealed that the revertant down-regulated genes encoding enzymes including galactokinase, galactose permease, and UDP-galactose-4-epimerase (the GAL regulon). By contrast, the revertant strain up-regulated the gene for UDP-glucose pyrophosphorylase, UGP1. There was reduced accumulation of galactose-1-phosphate in the galactose-grown revertant cells when compared to the GALT-deficient parent cells.
2008-04-10 | E-MEXP-1420 | biostudies-arrayexpress
Project description:Background Immune tolerance and persistent mixed chimerism can be achieved reproducibly after combined organ and hematopoietic cell transplantation in mice conditioned with total lymphoid irradiation plus anti-thymocyte globulin. We studied the safety and reproducibility of this approach in a cohort of kidney transplant patients, and tried to identify immune monitoring procedures that can predict tolerance and guide complete immunosuppressive drug withdrawal. Methods Ten patients conditioned with 10 doses of total lymphoid irradiation and 5 doses of anti-thymocyte globulin were given kidney transplants and an injection of CD34+ hematopoietic progenitor cells and T cells from HLA matched donors. Blood cell monitoring included changes in chimerism, balance of T cell subsets, gene expression, and responses to donor alloantigens. Results Nine of 10 patients developed multi-lineage chimerism without graft versus host disease (GVHD), and all had excellent graft function at the last observation point. Five of these with chimerism persisting for at least 12 months were completely withdrawn from immunosuppressive drugs for 6 to 35 months. Blood cells from patients off drugs showed development of specific unresponsiveness to donor alloantigens, M-bM-^@M-^\toleranceM-bM-^@M-^] profiles on gene microarrays, early high ratios of regulatory versus conventional naM-CM-/ve T cells, and early high levels of chimerism among NK cells. Conclusions Total lymphoid irradiation, and anti-thymocyte globulin promoted the development of persistent chimerism and tolerance in a cohort of patients given kidney transplants and donor cell injections. Assays were identified that can assist in the safe withdrawal of immunosuppressive drugs. 45 Agilent Microarray samples were conducted, including 16 tolerance patients, 10 chronic rejection patients, 5 healthy normal controls, and 7 paired pre and post-transplant induced tolerance patients. The aim is to see whether induced tolerance patients show operational tolerance gene expression signature and can withdraw or minimize the immunosuppression regimens.
2012-12-15 | E-GEOD-17068 | biostudies-arrayexpress
Project description:Although pig-to-nonhuman primate (NHP) corneal xenotransplantation has shown long-term graft survival, xenogeneic antigenrelated immune responses are still stronger than allogenic antigen-associated responses. Therefore, there is an unmet need to investigate major rejection pathways in corneal xenotransplantation, even with immunosuppression. This study aimed to identify biomarkers in aqueous humor for predicting rejection and to investigate rejection-related pathways in grafts from NHPs transplanted with porcine corneas following administration of steroids combined with tacrolimus/rituximab. NHPs who had received corneas from wild‐type (WT) or α‐1,3‐galactosyltransferase gene‐knockout (GTKO) pigs were divided into groups with or without rejection according to clinical examinations. Liquid chromatography-mass spectrometry (LC-MS) was used to analyze the proteomes of corneal tissues or aqueous humor. The biological functions of differentially expressed proteins (DEPs) were assessed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for pathways and protein–protein interaction network analysis. Among the 66 DEPs in aqueous humor, complement proteins (C3, C5, and C9) and cholesterol metabolic proteins (APOA1 and APOA2) were related to xenogeneic rejection as biomarkers, and alternative pathways of the complement system seemed to be important in xenogeneic graft rejection. Among 416 DEPs of the cornea, NF‐κB1 and proteosomes (PSMD7, PSMA5, and PSMD3) seemed to be related with xenogeneic graft rejection. Additionally, oxidative phosphorylation and leukocyte activation‐related pathways are involved in rejection. Overall, our proteomic approach highlights the important role of NF‐κB1, proteosomes, oxidative phosphorylation, and leukocyte activation-related inflammation in the cornea, and the relevance of complement pathways of the aqueous humor as a predictive biomarker of xenogeneic rejection.
2022-05-20 | PXD031320 | Pride
Project description:The site of transition between tissue resident memory (TRM) and circulating phenotypes of T cells is unknown. We integrated clonotype, alloreactivity and gene expression profiles of graft-repopulating recipient T cells in the intestinal mucosa at the single cell level after human intestinal transplantation. Host-versus-graft (HvG)-reactive T cells mainly distributed to TRM, Teff/TRM and T follicular helper compartments. RNA velocity analysis demonstrated a trajectory from TRM to effector T (Teff)/TRM clusters in association with rejection. By integrating pre- and post-Tx mixed lymphocyte reaction-determined alloreactive repertoires, we observed that pre-existing HvG-reactive T cells that demonstrated tolerance in the circulation were dominated by TRM profiles in quiescent allografts. Putative de novo HvG-reactive clones showed a transcriptional profile skewed to cytotoxic effectors in rejecting grafts. Inferred protein regulon network analysis revealed upstream regulators that accounted for the effector and tolerant T cell states. We demonstrate Teff/TRM interchangeability for individual T cell clones with known (allo)recognition in human gut, providing novel insight into TRM biology.
2024-01-11 | GSE252994 | 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. 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:When hyperacute rejection is avoided by deletion of Gal expression in the pig, delayed xenograft rejection (DXR) becomes a major immunologic barrier to successful xenotransplantation. This study was to investigate potential antigens involved in DXR. We isolated primary renal microvascular endothelial cells (RMEC) and aortic endothelial cells (AEC) from GGTA1/CMAH double-knockout (DKO) pig and immunized monkeys with both of these cells. After sensitization, monkey serum antibody binding and cytotoxicity to RMEC was significantlyhigher than to AEC,suggesting that RMEC are more immunogenic than AEC. Transcriptome sequencing of DKO pigs indicated that the expression of 1,500 genes was higher in RMEC than in AEC, while 896 genes was lower. The differentially-expressed genes were mainly related to cell and biological adhesion.
2019-07-07 | GSE99914 | GEO