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Influence of immunosuppressive drugs on NK cells in therapeutic drug exposure in liver transplantation

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE202224 | GEO | 2024/02/01

REPOSITORIES: GEO

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Project description:BACKGROUND: At the moment, lung transplantation remains the best therapeutic option to ensure a better survival rate of cystic fibrosis (CF) patients, but, unfortunately, immunosuppressive therapies, often employed at high dosages to avoid acute rejection and a rapid pulmonary loss, may induce severe complications. In particular, patients treated with high dose of mammalian target of rapamycin inhibitors (mTOR-Is) may experience pulmonary fibrosis-associated adverse effects (including BOOP). Although epithelial to mesenchymal transition (EMT) of airway cells has a central role in this process, the complete biological machinery involved is not completely clarified. METHODS: In order to improve our knowledge on this process, primary bronchial epithelial cell cultures carrying F508del (BE91/3) were treated with 5 and 100 nM EVE for 24 hours. Subsequently, the total RNA extracted by these cells was hybridized to the Human HT-12 v3 Expression BeadChip (Illumina). Microarray results were validated by Real-Time PCR. Transepithelial resistance was measured by Millicell-ERS ohmmeter. RESULTS: High dosage EVE induced a significant up-regulation of 42 genes and a down-regulation of 12 genes. After pathway analysis by GSEA, we found that most of them were implicated in the inflammatory and pro-fibrotic pathway. Real Time PCR confirmed that 100 nM EVE was able to up-regulate some identified genes (IL-1a, IL-8, Pim-1 Oncogene) as well as pro-fibrotic elements (such as: a-SMA, fibronectin, Transforming Growth Factor Beta 1, connective tissue growth factor and metalloproteinase 12). Additionally, high dosage of EVE was also able to reduce the transepithelial resistance. In contrast, lower level of EVE did not produce similar effects. CONCLUSIONS: These results confirmed, also in cells derived from CF patients, the pro-fibrotic inflammatory-induced activity of high dosage EVE and revealed in these cells an interesting multi-factorial biological machinery associated with the above-mentioned process. Finally, they suggest that if employed in transplanted CF patients, EVE dosage should be reduced to the lowest possible to minimize pulmonary adverse effects.

Project description:Chronic calcineurin inhibitor (CNI) nephrotoxicity is a major drawback in current immunosuppressive regimens. Pathology includes vascular and tubulointerstitial alterations. Although still commonly in use, cyclosporine A (CsA) is increasingly exchanged for tacrolimus (Tac) for a more favorable clinical outcome. Data on their differential pathogenetic effects in the kidney are, however, still scarce. We asked how CsA and Tac may affect adverse renal responses differentially. Methods- Wistar rats were divided into groups receiving cyclosporineÊ AÊ (n=4, target trough plasma level 3 mg/ml) and the respective vehicle (n=4, saline), or tacrolimus (Tac, FK506, n= 6, target trough plasma level 3.5 ng/ml) and the respective vehicle (n=6, DMSO/PEG500), via subcutaneously implanted osmotic minipumps for 28 days. Clinical parameters from plasma and urine samples were controlled. Animals were prepared for high-end morphological analysis, elective immunostaining, and high-throughput technology. Large scale electron microscopy (EM), confocal, stimulated emission-depletion (STED) and 3D-structured illumination (SIM) microscopy were used for pathology. Protein biochemistry, transcriptome, proteome, and phosphoproteome technologies were used to identify gene expressional differences. Results - In rats, CsA and Tac produced common as well as distinct alterations in glomeruli and tubulointerstitium. Both drugs caused cortical fibrotic foci with sclerotic glomeruli and damaged tubules. With CsA, glomerular damage was milder than with Tac. Proximal tubules showed widespread dysmorphic lysosomes with peripheral LAMP1 signal as well as autophagic and mitophagic vacuoles along with high apoptosis rate and diminished albumin uptake; megalin-dependent endocytosis was causally involved in the changes, and lysosomal exocytosis was sharply stimulated at the luminal cell pole. KIM1 signal was moderate. With Tac, these changes were far less pronounced, but the incidence of focal tubular necrosis along with intense KIM-1 signal was high. High throughput analysis showed differential changes between CsA and Tac with almost no overlap between the respective spectra. CsA caused upregulation of components of the unfolded protein response and apoptosis, whereas Tac resulted in RAS-associated stimulation and vascular deterioration. Conclusions- CNI nephrotoxicity presented with widely differing pathogenetic characteristics upon chronical CsA vs. Tac treatments. Beyond its known vascular effects, CsA markedly affected proximal tubular integrity, whereas Tac was primarily affecting vascular/glomerular components. Both medications produced comparable degrees of nephron loss and fibrosis. Results may serve to better adjust immunosuppressive treatment combinations in transplant patients.

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Influence of immunosuppressive drugs on NK cells in therapeutic drug exposure in liver transplantation

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