Kotasek D, Vercellotti G M, Ochoa A C, Bach F H, White J G, Jacob H S
Department of Medicine, University of Minnesota, Minneapolis 55455.
Cancer Res. 1988 Oct 1;48(19):5528-32.
A new form of therapy of experimental tumors, utilizing lymphokine-activated killer (LAK) cells and high doses of interleukin 2, has recently been applied in the treatment of human neoplasms. Severe side effects, suggestive of a diffuse vascular injury of unknown etiology, have prevented a more widespread application of this form of therapy. We have investigated the etiology of this clinical capillary leak syndrome, using an in vitro model of endothelial injury. LAK cells, but not interleukin 2 itself, are cytotoxic to cultured human endothelial cells, and this cytotoxicity is time and dose dependent. This human endothelial cell cytotoxicity can be inhibited by depletion of extracellular Ca2+, inhibition of the effector cell microtubular system, and inhibitors of serine proteases, but is not inhibited in the presence of toxic oxygen radical scavengers. LAK cell-mediated endothelial cytotoxicity is far more potent than that exhibited by maximally stimulated polymorphonucleocytes. LAK cell-mediated injury of human endothelium may possibly be responsible for the capillary leak syndrome observed in patients treated with high doses of interleukin 2 and LAK cells.
一种利用淋巴因子激活的杀伤细胞（LAK细胞）和高剂量白细胞介素2治疗实验性肿瘤的新疗法，最近已应用于人类肿瘤的治疗。严重的副作用提示存在病因不明的弥漫性血管损伤，这阻碍了这种治疗方法的更广泛应用。我们使用内皮损伤的体外模型研究了这种临床毛细血管渗漏综合征的病因。LAK细胞对培养的人内皮细胞具有细胞毒性，而白细胞介素2本身则没有，并且这种细胞毒性具有时间和剂量依赖性。这种人内皮细胞毒性可通过细胞外Ca2+耗竭、效应细胞微管系统抑制和丝氨酸蛋白酶抑制剂来抑制，但在存在有毒氧自由基清除剂的情况下不会受到抑制。LAK细胞介导的内皮细胞毒性比最大刺激的多形核细胞所表现出的毒性要强得多。LAK细胞介导的人内皮损伤可能是接受高剂量白细胞介素2和LAK细胞治疗的患者中观察到的毛细血管渗漏综合征的原因。
