Influence of immunosuppressive drugs on NK cells in therapeutic drug exposure in liver transplantation
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ABSTRACT:
PROVIDER: PRJNA835087 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19084400_1.fastq.gz | Fastqsanger.gz | |||
| SRR19084400_2.fastq.gz | Fastqsanger.gz | |||
| SRR19084401_1.fastq.gz | Fastqsanger.gz | |||
| SRR19084401_2.fastq.gz | Fastqsanger.gz | |||
| SRR19084402_1.fastq.gz | Fastqsanger.gz |
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Project description:Natural killer (NK) cells are enriched in the liver and are main regulators in liver transplantation (LT) regarding rejection or tolerance, viral infection or tumor recurrence. Immunosuppression (IS) consists of a triple drug standard regimen, including Tacrolimus (TAC) and Corticosteroids (CS) with either Mycophenolate Mofetil (MMF) or Sirolimus (SIR)/Everolimus (EVE). In this study we simulated the immunosuppressive microenvironment in vitro. Peripheral blood mononuclear cells (PBMC) were cultured at the clinically effective plasma concentration of each drug for 3 days. CS seriously impaired the killing function of NK cells, followed by MMF and SIR/EVE. CS and TAC/CSA significantly decreased the secretion of IFN-γ. NK cell function in liver transplant (LT) recipients was most pronouncedly inhibited by a triple immunosuppressive regimen, CS playing the most prominent role compared to the other drugs. The MMF containing regimen demonstrated a significant increase in the expression of suppressive genes, especially of the Siglec7/9 family. The SIR group had stronger NK cell activity compared with the MMF group, although liver transplantation patients have lower NK cell activity and function. In conclusion, despite an overall comparable immunosuppressive efficiency in terms of prevention of acute rejection, a mTORI including regimen might be considered as having less impact on NK cell function and thus retaining their function.
2024-02-01 | GSE202224 | GEO
Project description:Cancer-induced tolerance mostly involves myeloid suppressor cells, regulatory T cells and immunosuppressive cytokines, which all subvert adaptive immune responses against tumor cells. Here, we show that a subset of innate effectors, c-kit expressing NK cells (Kit+ NK), can participate in tumor-induced tolerance by compromising the NK cell arm of tumor immunosurveillance. IL-18 produced by tumor cells can convert Kit- into Kit+ NK cells that overexpress B7-H1/PD-L1 molecules. Upon tumor inoculation, Kit+ NK cells rapidly develop in lymphoid organs in a IL-18R/MyD88 dependent manner and directly kill Kit- NK cells in a B7-H1/PD-1-dependent manner, thereby promoting the progression of NK-controlled cancers. Our data suggest that, in a tumoral context, IL-18 subverts antitumor NK cell functions. Systemic neutralization of IL-18 by IL-18-binding protein may improve the NK-mediated immunosurveillance. Keywords: cell type comparison
2009-03-01 | GSE9431 | GEO
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:Liver transplantation (LT) is a definitive treatment for end-stage liver disease and hepatocellular cancer. As donor-recipient HLA matching is not employed, there is potential for natural killer (NK) cell-mediated alloreactivity. Here we report that recipient NK cells exhibit a downregulated phenotype with reduced expression of activating receptors NKp30 and NKp46. We found associated hypofunctionality, with impaired NK cell cytotoxicity, degranulation and IFN-gamma production. Gene expression analysis using microarray and quantitative PCR identified significant downregulation of STAT-4 in LT with associated reduction in miR-155, a microRNA target of STAT-4 and a key regulator of NK differentiation. These data indicate that LT induces recipient NK cell tolerance through altered peripheral maturation at a step prior to the acquisition of inhibitory receptors for HLA class I.
2014-02-01 | E-MTAB-2132 | biostudies-arrayexpress
Project description:NK cells were first isolated from PBMCs using EasySep⢠Human NK cell enrichment kit (STEMCELL biotechnology). The magnetically isolated NK cells were stained with anti-CD3 FITC, anti-CD56 Pe-Cy7 and LIVE/DEAD® red stain for a further enrichment, whereby the CD3 negative and CD56 positive live cells were sorted with MoFlo⢠cell sorter (Beckman Coulter). The sorted NK cell populations were sent to AROS Applied Biotechnology A/S (Aarhus N, Denmark) to be analysed using GeneChip® Human Transcriptome Array 2.0 (Affymetrix, USA). The transcription profile of NK cells from day 14 post stem cell transplantation was compared with those from healthy donors.
2018-10-31 | E-MTAB-5474 | 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, “tolerance” profiles on gene microarrays, early high ratios of regulatory versus conventional naïve 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.
2012-12-15 | GSE17068 | GEO
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:Autologous hematopoietic stem cell transplantation (autoHSCT) is a treatment option for hematological disorders and pediatric solid tumors. Natural killer (NK) cells are the first lymphocyte subset returning to normal levels. To uncover global changes during NK cell reconstitution after autoHSCT, we performed for the first time RNA-sequencing on NK cells before and after autoHSCT. Results showed profound changes in gene expression profile of NK cells immediately after autoHSCT. Several biological processes including cell cycle, DNA replication and the mevalonate pathway were enriched. Significantly, we observed that following autoHSCT, NK cells acquired a decidual-like gene expression profile. By using multiparametric flow cytometry, we confirmed the expansion of NK cells expressing CD9 immediately after autoHSCT, and we observed that these decidual-like NK cells exhibited lower degranulation besides higher granzyme B and perforin expression than CD9- NK cells. These results provide new insights on the physiopathology of NK cells during their reconstitution after autoHSCT.
2022-10-26 | GSE199608 | GEO
Project description:Kidney transplantation remains the optimal therapeutical option for end stage kidney disease. Current immunosuppressive regimens are efficient in combating acute kidney rejection. However, the insight in chronic kidney allograft injury remains limited. Simultaneously, pregnancy in kidney recipients appears more prevalent than during dialysis treatment. Due to ethical issues comprehensive studies on the impact of current immunosuppressive regimens on pregnancy are challenging. Omics- technology enables the systemic insight into biology both of immunity and pregnancy beyond up-to-date collected knowledge. The aim of the study was to investigate the proteomic status of lymphocytes obtained from pregnant female rats under immunosuppressive treatment. The group of 10 pregnant Wistar rat females, 5 of which treated with tacrolimus, mofetil mycophenolate and glicocorticosteroids, 5 used as control. The lymphocytes were obtained and analyzed with mass-spectrometry. The outcomes were verified statistically in terms of proteins up- and down regulation.
2023-03-11 | PXD035571 | Pride
Project description:Solid organ transplantation in the mouse is a powerful research tool that has provided a pathway to find important mechanistic insights into the regulation of allograft injury, allograft immunopathology, and transplant rejection/tolerance, and that has unique advantages over transplantation in larger species, due to the well characterization of mouse genome and availability of genetically modified animals. However, setup of mouse liver, heart and kidney transplantation is a technically demanding surgical procedure, especially the orthotopic liver transplantation in mouse. Here, we performed Microwell-based single cell RNA-seq of three mouse organ transplantation models (liver, heart and kidney). Comparison of lymphocytes, parenchyma cells and peripheral blood mononuclear cells in liver, heart and kidney revealed distinct immune microenvironment at acute rejection and tolerance state respectively. Single-cell transcriptome analysis of mouse allograft without immunosuppressive drugs provided rich resources to help understand functioning solid-organ transplantation in human.
2022-11-18 | GSE189069 | GEO