免疫抑制药物对 CD8+T 细胞介导和自然杀伤细胞介导的人肾小管上皮细胞溶解作用的疗效有限。
Limited efficacy of immunosuppressive drugs on CD8+ T cell-mediated and natural killer cell-mediated lysis of human renal tubular epithelial cells.
机构信息
1 Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, Division of Nephrology and Transplantation, University Medical Center Rotterdam, the Netherlands. 2 Address correspondence to: Martijn Demmers, M.S.c., Division of Nephrology and Transplantation, Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands; Ajda T. Rowshani, M.D., Ph.D., Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
出版信息
Transplantation. 2014 Jun 15;97(11):1110-8. doi: 10.1097/TP.0000000000000108.
BACKGROUND
Although CD8+ T cell-mediated and natural killer (NK) cell-mediated cytotoxicity against renal tubular epithelial cells (TECs) plays a crucial role during rejection, the degree of inhibition of these lytic immune responses by immunosuppressive drugs is unknown. We investigated the CD8 T-cell and NK cell responses induced by TECs in vitro and questioned how these processes are affected by immunosuppressive drugs.
METHODS
Donor-derived TECs were co-cultured with recipient peripheral blood monocyte cells. Proliferation of CD8+ T cells and NK cell subsets was assessed using PKH dilution assay. CD107a degranulation and europium release assay were performed to explore CD8+-mediated and NK cell-mediated TEC lysis. Experiments were conducted in the absence or presence of tacrolimus (10 ng/mL), everolimus (10 ng/mL), and prednisolone (200 ng/mL).
RESULTS
Tubular epithelial cells induce significant CD8+ T-cell and NK cell proliferation. All immunosuppressive drugs significantly inhibited TEC-induced CD8+ T-cell proliferation. Interestingly, prednisolone was the most powerful inhibitor of NK cell proliferation. CD8-mediated and NK cell-mediated early lytic responses were marked by strong degranulation after an encounter of unstimulated TECs, represented by a high cell surface expression of CD107a. However, with the use of interferon-γ-activated and tumor necrosis factor-α-activated TECs, the NK degranulation response was significantly reduced and CD8 degranulation response was even more enhanced (P<0.05). Tubular epithelial cell-induced CD8 degranulation and CD8-mediated TEC lysis were preferentially inhibited by tacrolimus and prednisolone, and not by everolimus. Although tacrolimus showed the most inhibitory effect on the degranulation of NK cells, NK cell-mediated TEC lysis was efficiently inhibited by prednisolone (P<0.05).
CONCLUSION
Overall, our data point to a limited efficacy of immunosuppressive drugs on CD8+ T cell-mediated and NK cell-mediated lysis of human renal TECs.
背景
尽管 CD8+T 细胞介导和自然杀伤（NK）细胞介导的针对肾小管上皮细胞（TEC）的细胞毒性在排斥反应中起着至关重要的作用，但免疫抑制药物对这些裂解免疫反应的抑制程度尚不清楚。我们研究了体外 TEC 诱导的 CD8 T 细胞和 NK 细胞反应，并质疑这些过程如何受到免疫抑制药物的影响。
方法
将供体来源的 TEC 与受者外周血单核细胞共培养。使用 PKH 稀释试验评估 CD8+T 细胞和 NK 细胞亚群的增殖。进行 CD107a 脱颗粒和 europium 释放试验以探索 CD8+介导和 NK 细胞介导的 TEC 裂解。实验在不存在或存在他克莫司（10ng/mL）、依维莫司（10ng/mL）和泼尼松龙（200ng/mL）的情况下进行。
结果
肾小管上皮细胞诱导显著的 CD8+T 细胞和 NK 细胞增殖。所有免疫抑制药物均显著抑制 TEC 诱导的 CD8+T 细胞增殖。有趣的是，泼尼松龙是 NK 细胞增殖的最强抑制剂。CD8 介导和 NK 细胞介导的早期裂解反应表现为未刺激的 TEC 接触后强烈的脱颗粒，表现为 CD107a 细胞表面表达较高。然而，使用干扰素-γ激活和肿瘤坏死因子-α激活的 TEC，NK 脱颗粒反应显著减少，CD8 脱颗粒反应甚至增强（P<0.05）。肾小管上皮细胞诱导的 CD8 脱颗粒和 CD8 介导的 TEC 裂解主要被他克莫司和泼尼松龙抑制，而不是依维莫司。虽然他克莫司对 NK 细胞脱颗粒的抑制作用最强，但泼尼松龙有效地抑制了 NK 细胞介导的 TEC 裂解（P<0.05）。
结论
总体而言，我们的数据表明免疫抑制药物对人肾 TEC 中 CD8+T 细胞介导和 NK 细胞介导的裂解作用的疗效有限。
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