Corticosteroids inhibit the generation of lymphokine-activated killer activity in vitro.
Corticosteroids inhibit the generation of lymphokine-activated killer activity in vitro.
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皮质类固醇在体外抑制淋巴因子激活的杀伤活性的产生。
DOI：
10.1007/bf00199998
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发表时间：
1989
期刊：
影响因子：
--
通讯作者：
Young,HF
中科院分区：
文献类型：
--
作者：
McVicar,DW;Merchant,RE;Merchant,LH;Young,HF
在采用淋巴因子激活的杀伤（LAK）细胞加重组白细胞介素-2（rIL-2）（Cetus）治疗恶性胶质瘤的过继免疫治疗的I期临床试验中，我们观察到，依赖地塞米松治疗脑水肿的患者的血液单核细胞（MNC）产生的LAK活性显著低于正常献血者或未接受类固醇治疗的胶质瘤患者的MNC。因此，我们研究了各种治疗可达到浓度的皮质类固醇对正常供体血液MNC的增殖反应、γ干扰素（IFN-γ）的产生和LAK活性的诱导的体外作用。在含有rIL-2（1000 U/ml）的培养基中与地塞米松、氢化可的松、甲泼尼龙或泼尼松龙一起孵育对所有这些参数都产生了深远的影响。首先，0.01 μg/ml的地塞米松或氢化可的松引起淋巴细胞对植物血凝素的促有丝分裂反应轻微增强，当浓度增加到10 μg/ml时，出现剂量依赖性下降。泼尼松龙和甲泼尼龙的加入引起了剂量依赖性抑制淋巴细胞增殖在整个浓度范围内测试。地塞米松、氢化可的松、甲泼尼龙和泼尼松龙在0.1 μg/ml或更高浓度时，对IFN-γ的产生有显著抑制作用（P<0.02），抑制率分别为不加激素时的18.9%、4.4%、2.2%和12.3%。所有四种皮质类固醇抑制LAK活性的诱导。与单独用1000 U/ml rIL-2孵育的MNC相比，rIL-2与10 μg/ml地塞米松或泼尼松龙共同孵育的MNC对自然杀伤细胞耐药细胞系Daudi的细胞毒性显著降低（P<0.05）。在1.0 μg/ml和10 μg/ml氢化可的松的作用下，LAK细胞的杀伤活性明显下降（P<0.01），而在0.1 μg/ml、1.0 μg/ml和10 μg/ml甲基强的松龙的作用下，LAK细胞的杀伤活性明显下降（P<0.02）。当细胞毒性表示为每百万效应物的裂解单位时，裂解活性的剂量反应性下降再次明显，氢化可的松、甲泼尼龙和泼尼松龙在1.0 μg/ml和10 μg/ml时均显示出显著抑制（P<0.05），地塞米松在10 μg/ml时显示出显著抑制（P<0.01）。这些结果表明，皮质类固醇通常用于治疗脑肿瘤和其他恶性肿瘤抑制诱导LAK活性在体外，这可能解释了为什么它往往是难以产生LAK活性从血液MNC的患者谁正在接受长期类固醇治疗。
In phase-I clinical trials of adoptive immunotherapy using lymphokine-activated killer (LAK) cells plus recombinant interleukin-2 (rIL-2) (Cetus) for the treatment of malignant glioma, we observed that blood mononuclear cells (MNC) from patients dependent on dexamethasone for management of cerebral edema produced substantially less LAK activity as compared to MNC of normal blood donors or glioma patients not receiving steroid therapy. Therefore, we examined the in vitro effects, brought about by therapeutically attainable concentrations of various corticosteroids, on the proliferative response, production of γ interferon (IFN-γ), and induction of LAK activity from blood MNC of normal donors. Incubation in media containing rIL-2 (1000 U/ml) with either dexamethasone, hydrocortisone, methylprednisolone, or prednisolone profoundly affected all of these parameters. First, while 0.01 μg/ml of either dexamethasone or hydrocortisone caused a slight enhancement of the mitogenic response of lymphocytes to phytohemagglutinin, a dose-dependent decline occurred as concentrations increased to 10 μg/ml. The addition of prednisolone and methylprednisolone elicited a dose-dependent inhibition of lymphocyte proliferation over the entire concentration range tested. At 0.1 μg/ml or higher, dexamethasone, hydrocortisone, methylprednisolone and prednisolone significantly (P<0.02) inhibited the production of IFN-γ: respectively 18.9%, 4.4%, 2.2%, and 12.3% of the IFN-γ produced by MNC in the absence of steroids. All four corticosteroids inhibited the induction of LAK activity. Compared to MNC that had been incubated with 1000 U/ml rIL-2 alone, MNC cultured with rIL-2 and 10 μg/ml either dexamethasone or prednisolone demonstrated significantly lower cytotoxicity (P<0.05) for the natural-killer-cell-resistant cell line, Daudi. Culturing MNC with hydrocortisone had a more dramatic result, causing a significant decline (P<0.01) in lytic activity at both 1.0 μg/ml and 10 μg/ml, while incubation with methylprednisolone produced a significant drop (P<0.02) in LAK-mediated cytotoxicity at 0.1 μg/ml as well as 1.0 μg/ml and 10 μg/ml. When cytotoxicity was expressed as lytic units per million effectors, a dose-response decline in lytic activity was once again apparent, with hydrocortisone, methylprednisolone and prednisolone showing significant inhibition (P<0.05) at both 1.0 μg/ml and 10 μg/ml and dexamethasone at 10 μg/ml (P<0.01). These results indicate that corticosteroids commonly used in the management of cerebral tumors and other malignancies inhibit induction of LAK activity in vitro, and this may explain why it is often difficult to generate LAK activity from blood MNC of patients who are receiving chronic steroid therapy.