CD1d-mediated stimulation of natural killer T cells selectively activates hepatic natural killer cells to eliminate experimentally disseminated hepatoma cells in murine liver
CD1d-mediated stimulation of natural killer T cells selectively activates hepatic natural killer cells to eliminate experimentally disseminated hepatoma cells in murine liver
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DOI：
10.1002/ijc.11163
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发表时间：
2003-08-10
影响因子：
6.4
通讯作者：
Hayashi, N
中科院分区：
文献类型：
--
作者：
Miyagi, T;Takehara, T;Hayashi, N
由于肝细胞癌（HCC）由转化的肝细胞发展而来，有时以多中心的方式发展，因此免疫删除这些小的肝内区域应该是预防HCC发展的重要策略。肝脏含有丰富的先天细胞系，包括自然杀伤细胞（NK）和自然杀伤T细胞（NKT），后者被α -半乳糖神经酰胺（α - galcer）以cd1限制的方式激活。在我们的研究中，我们研究了α - galcer给药对肝脏移植肝癌细胞的抗肿瘤作用，并与肝外部位的抗肿瘤作用进行了比较。α - galcer完全抑制了BNL 1MEA.7R.1的生长（BNL）肝癌细胞在同基因BALB/c小鼠肝脏内播散，但对皮下植入的BNL细胞无抗肿瘤作用。与脾NKT细胞相比，给药后肝NKT细胞迅速激活，然后消失。肝脏NK细胞的数量大幅增加，对BNL细胞的细胞毒活性也大幅上调，但脾脏、血液和淋巴结等其他组织中的NK细胞则没有这种变化。抗亚洲草甘膦GM1抗体在体内消耗NK细胞，导致α - galcer处理小鼠的肝脏肿瘤形成，表明NK细胞在α - galcer诱导的肝脏抗肿瘤作用中起关键作用。总之，我们的研究表明，通过α - galcer刺激肝脏和肝外组织的NKT细胞，NK细胞的活化和抗肿瘤作用存在明显差异。这些先天细胞系的顺序激活可能是控制肝脏微播散性肝癌细胞的一种有吸引力的策略。(C) 2003 Wiley-Liss, Inc。
Since hepatocellular carcinomas (HCCs) develop from transformed hepatocytes, sometimes in a multicentrical manner, immunological deletion of such small intrahepatic regions should be an important strategy to prevent HCC development. The liver contains abundant innate cell lineages including natural killer (NK) cells and natural killer T (NKT) cells, the latter of which become activated in a CD1d-restricted manner by alpha-galactosylceramide (alpha-GalCer). In our study, we investigated the anti-tumor effect elicited by alpha-GalCer administration against transplanted hepatoma cells in the liver, in comparison with that in extrahepatic sites. alpha-GalCer administration completely suppressed the growth of BNL 1MEA.7R.1 (BNL) hepatoma cells disseminated in the liver of syngeneic BALB/c mouse but had no anti-tumor effect on subcutaneously implanted BNL cells. Hepatic NKT cells became rapidly activated after alpha-GalCer administration compared to splenic NKT cells and then disappeared. Hepatic NK cells substantially increased their population as well as up-regulated their cytotoxic activity against BNL cells, but NK cells in other tissues, including the spleen, blood and lymph node, did not. Anti-asialo GM1 antibody treatment, which depleted NK cells in vivo, resulted in hepatic tumor formation in alpha-GalCer-treated mice, indicating the critical involvement of NK cells in the alpha-GalCer-induced anti-tumor effect in the liver. In conclusion, our study demonstrates clear differences in NK cell activation and antitumor effect through stimulation of NKT cells by alpha-GalCer between the liver and extrahepatic tissues. Sequential activation of these innate cell lineages may be an attractive strategy for controlling micro-disseminated hepatoma cells in the liver. (C) 2003 Wiley-Liss, Inc.