Influence of immunosuppressive drugs on natural killer cells in therapeutic drug exposure in liver transplantation.

IF 6.1 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Hepatobiliary surgery and nutrition Pub Date : 2023-12-01 Epub Date: 2023-02-28 DOI:10.21037/hbsn-22-438
Rongrong Qin, Jiwei Qin, Xuefeng Li, Zhijun Xu, Peiqi He, Xiaodong Yuan, Cheng Sun, Björn Nashan
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引用次数: 0

Abstract

Background: Natural killer (NK) cells are enriched in the liver and are the main regulators in liver transplantation regarding rejection or tolerance, viral infection, or tumor recurrence. Immunosuppression consists of a triple drug standard regimen comprising tacrolimus (TAC) and corticosteroids (CS) with either mycophenolate mofetil (MMF) or sirolimus (SIR)/everolimus (EVE). The aim of this study was to evaluate the impact of trough levels of these regimens under clinical conditions and exposure on human NK-cell activity and function in order to better understand the antiviral and anti-tumor effects of mammalian target of rapamycin inhibitor (mTORI).

Methods: Peripheral blood mononuclear cells (PBMCs) were collected from liver transplant recipients and healthy controls. Number and phenotypes of NK cells in vivo were analyzed by flow cytometry. In this study we simulated the immunosuppressive microenvironment in vitro. PBMCs were cultured at the clinically effective plasma concentration of drugs for 3 d to detect the effect of immunosuppressants on NK cells. Drug type and concentration: single drug [EVE, 5 ng/mL; SIR, 5 ng/mL; TAC, 5 ng/mL; cyclosporine A (CSA), 125 ng/mL; MMF, 15 µg/mL; CS, 0.5 µg/mL] and combined immunosuppressants (Group 1: TAC, 5 ng/mL + MMF, 15 µg/mL + CS, 0.5 µg/mL; Group 2: TAC, 5 ng/mL + SIR, 5 ng/mL + CS, 0.5 µg/mL; Group 3: TAC, 5 ng/mL + EVE, 5 ng/mL + CS, 0.5 µg/mL). In addition, NK cells were sorted from PBMCs and treated under the above conditions to detect NK cell killing function and RNA transcription characteristics.

Results: CS significantly impaired the cytolytic activity of NK cells, followed by MMF and SIR/EVE. CS and TAC/CSA significantly decreased the secretion of IFN-γ and CD107a. NK cell function in liver transplant recipients was most pronouncedly inhibited by a triple immunosuppressive regimen, with CS playing the most prominent role compared with 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 that of the MMF group, although liver transplantation patients have lower NK cell activity and function.

Conclusions: Despite an overall comparable immunosuppressive efficiency in terms of prevention of acute rejection, a mTORIs-including regimen might be considered as having less impact on NK cell function.

肝移植治疗药物暴露中免疫抑制药物对自然杀伤细胞的影响
背景:自然杀伤(NK)细胞富集于肝脏,是肝脏移植排斥或耐受、病毒感染或肿瘤复发的主要调节因子。免疫抑制包括由他克莫司(TAC)、皮质类固醇(CS)和霉酚酸酯(MMF)或西罗莫司(SIR)/依维莫司(EVE)组成的三联药物标准方案。本研究的目的是评估这些方案在临床条件下的谷值水平和暴露对人类 NK 细胞活性和功能的影响,以便更好地了解哺乳动物雷帕霉素靶抑制剂(mTORI)的抗病毒和抗肿瘤作用:方法:收集肝移植受者和健康对照组的外周血单核细胞(PBMCs)。流式细胞术分析了体内 NK 细胞的数量和表型。在这项研究中,我们在体外模拟了免疫抑制微环境。在临床有效药物血浆浓度下培养 PBMC 3 d,以检测免疫抑制剂对 NK 细胞的影响。药物类型和浓度:单一药物[EVE,5 ng/mL;SIR,5 ng/mL;TAC,5 ng/mL;环孢素A(CSA),125 ng/mL;MMF,15 µg/mL;CS,0.5 µg/mL] 和联合免疫抑制剂(第 1 组:TAC,5 ng/mL + MMF,15 µg/mL + CS,0.5 µg/mL;第 2 组:TAC,5 ng/mL + SIR,5 ng/mL + CS,0.5 µg/mL;第 3 组:TAC,5 ng/mL + EVE,5 ng/mL + CS,0.5 µg/mL)。此外,还从 PBMCs 中分拣出 NK 细胞,并在上述条件下进行处理,以检测 NK 细胞的杀伤功能和 RNA 转录特征:结果:CS明显降低了NK细胞的细胞溶解活性,其次是MMF和SIR/EVE。CS 和 TAC/CSA 能明显降低 IFN-γ 和 CD107a 的分泌。三联免疫抑制方案对肝移植受者NK细胞功能的抑制最为明显,与其他药物相比,CS的作用最为突出。含 MMF 的方案显示抑制基因的表达显著增加,尤其是 Siglec7/9 家族。与 MMF 组相比,SIR 组的 NK 细胞活性更强,尽管肝移植患者的 NK 细胞活性和功能较低:结论:尽管在预防急性排斥反应方面的免疫抑制效率总体相当,但可以认为包括mTORI的方案对NK细胞功能的影响较小。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
自引率
10.00%
发文量
392
期刊介绍: Hepatobiliary Surgery and Nutrition (HBSN) is a bi-monthly, open-access, peer-reviewed journal (Print ISSN: 2304-3881; Online ISSN: 2304-389X) since December 2012. The journal focuses on hepatopancreatobiliary disease and nutrition, aiming to present new findings and deliver up-to-date, practical information on diagnosis, prevention, and clinical investigations. Areas of interest cover surgical techniques, clinical and basic research, transplantation, therapies, NASH, NAFLD, targeted drugs, gut microbiota, metabolism, cancer immunity, genomics, and nutrition and dietetics. HBSN serves as a valuable resource for professionals seeking insights into diverse aspects of hepatobiliary surgery and nutrition.
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