Difference in cytotoxicity against hepatocellular carcinoma between liver and periphery natural killer cells in humans
Difference in cytotoxicity against hepatocellular carcinoma between liver and periphery natural killer cells in humans
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DOI：
10.1002/hep.21035
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发表时间：
2006-02-01
期刊：
影响因子：
13.5
通讯作者：
Asahara, T
中科院分区：
文献类型：
--
作者：
Ishiyama, K;Ohdan, H;Asahara, T
在啮齿类动物中，肝脏自然杀伤（NK）细胞已被证明介导比外周血（PB）NK细胞更高的抗肿瘤细胞毒活性。然而，肝脏和PB NK细胞之间的这种差异尚未在人类中广泛研究。研究了活体肝移植时从肝灌注液中提取的NK细胞的表型和功能特性。肿瘤坏死因子相关凋亡诱导配体（TRAIL）是NK细胞介导的抗肿瘤细胞杀伤的关键分子，新鲜分离的PB NK细胞或肝脏NK细胞不表达。用白细胞介素（IL）-2刺激，显著上调肝脏NK细胞上TRAIL的表达，但在PB NK细胞上几乎没有观察到这种效果。在IL-2刺激后，供体肝脏NK细胞显示出对HepG 2（一种肝细胞癌（HCC）细胞系）最强的细胞毒性（在E：T = 10：1时为90.5% +/- 2.2%），与供体和受体PB NK细胞以及受体肝脏NK细胞相比（分别为64.8% +/-8.2%、56.1% +/-8.9%和34.6% +/-7.5%）。IL-2刺激导致与TRAIL表达平行的肝脏NK细胞上的杀伤抑制性受体的表达增加。因此，IL-2刺激的供体肝脏NK细胞对自身和受体淋巴母细胞的细胞毒性可以忽略不计。总之，从供体肝移植物灌注液中提取的IL-2刺激的NK细胞的过继转移可以产生抗肿瘤反应，而不会对1-单倍型相同的受体完整组织产生毒性。这些发现提出了一个概念，以防止肝移植后肝癌复发。
In rodents, liver natural killer (NK) cells have been shown to mediate higher cytotoxic activity against tumor cells than do peripheral blood (PB) NK cells. However, such differences between liver and PB NK cells have not been extensively investigated in humans. The phenotypical and functional properties of NK cells extracted from liver perfusates at the time of living donor liver transplantation were investigated. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a critical molecule for NK cell-mediated anti-tumor cell killing, was not expressed by freshly isolated PB NK cells or by liver NK cells. Stimulation with interleukin (IL)-2, significantly up-regulated the expression of TRAIL on liver NK cells, but this effect was barely observed on PB NK cells. Donor liver NK cells showed the most vigorous cytotoxicity against HepG2, a hepatocellular carcinoma (HCC) cell line, after IL-2 stimulation (90.5% +/- 2.2% at E: T = 10:1), compared with donor and recipient PB NK cells and recipient liver NK cells (64.8% +/- 8.2%, 56.1% +/- 8.9%, and 34.6% +/- 7.5%, respectively). IL-2 stimulation resulted in an increased expression of killing inhibitory receptors on liver NK cells in parallel with TRAIL expression. Consistently, the cytotoxicities of IL-2-stimulated donor liver NK cells against self and recipient lymphoblasts were negligible. In conclusion, adoptive transfer of IL-2-stimulated NK cells extracted from donor liver graft perfusate could mount an anti-tumor response without causing toxicity against 1-haplotype identical recipient intact tissues. These findings present a concept to prevent recurrence of HCC after liver transplantation.