Sutherland F, Borkenhagen K, Temple L, Bryant L D, Lafreniere R
University of Calgary, Health Sciences Center, Canada.
Cancer Immunol Immunother. 1990;31(5):312-20. doi: 10.1007/BF01740940.
Lymphokine-activated killer cells appear to arise from precursor cells bearing natural killer (NK) cell antigens. Cyclosporin (CsA) is a well-known immunosuppressive agent that can down-regulate NK cell cytotoxicity. Studies were initiated to evaluate the effects of CsA on splenocytes before and after exposure to recombinant interleukin-2 (rIL-2). Normal C57BL/6 mice receiving CsA at a dose of 100 mg/kg demonstrated a decrease in NK cell lysis against the YAC-1 lymphoma target in a 4-h chromium-release assay. When splenocytes obtained from CsA-treated mice were cultured for 3 days in complete medium containing 1000 U rIL-2/ml, they demonstrated a return of NK cell lysis to normal (mean cytotoxicity = 65 LU versus 60 LU for control and CsA-exposed splenocytes respectively; P, NS, five consecutive experiments) but revealed a decrease in the lysis of a NK-resistant target: the MCA-102 sarcoma (mean cytotoxicity = 20 LU vs 12 LU for control and CsA-exposed splenocytes respectively; P less than 0.02, five consecutive experiments). Fresh splenocytes cultured in media containing rIL-2 and CsA demonstrated a decrease in proliferation, cell-cycle S-phase fraction and cell yields compared to splenocytes cultured in media containing rIL-2 alone. In addition, a decrease in tumor cell lysis for NK-cell sensitive (mean percentage lysis = 98% vs 60%, rIL-2 vs rIL-2 + CsA; effector-to-target ratio 100: 1) and resistant targets (mean percentage lysis = 68% vs 28%, rIL-2 vs rIL-2 + CsA; effector-to-target ratio 100: 1) was also seen. CsA had no effects on the phenotypic antigenic expression of splenocytes cultured with high-dose rIL-2 although activated T cell antigens were down-regulated when fresh splenocytes were evaluated after in vivo exposure to CsA. These studies support the down-regulating effects of CsA on NK cell lysis and suggest that the rIL-2-activated cell population is heterogeneous as demonstrated by the differential down-regulation and recovery of NK-resistant cell lysis versus NK-sensitive cell lysis.
淋巴因子激活的杀伤细胞似乎起源于带有自然杀伤（NK）细胞抗原的前体细胞。环孢素（CsA）是一种著名的免疫抑制剂，可下调NK细胞的细胞毒性。本研究旨在评估CsA对暴露于重组白细胞介素-2（rIL-2）前后脾细胞的影响。在4小时的铬释放试验中，接受100mg/kg剂量CsA的正常C57BL/6小鼠对YAC-1淋巴瘤靶标的NK细胞裂解作用降低。当从经CsA处理的小鼠获得的脾细胞在含有1000U rIL-2/ml的完全培养基中培养3天时，它们的NK细胞裂解作用恢复正常（平均细胞毒性分别为65LU和60LU，对照组和经CsA处理的脾细胞；P，无显著性差异，连续五次实验），但对NK抗性靶标MCA-102肉瘤的裂解作用降低（平均细胞毒性分别为20LU和control和经CsA处理的脾细胞分别为12LU；P小于0.02，连续五次实验）。与仅在含有rIL-2的培养基中培养的脾细胞相比，在含有rIL-2和CsA的培养基中培养的新鲜脾细胞增殖、细胞周期S期比例和细胞产量均降低。此外，对于NK细胞敏感靶标（平均裂解百分比=98%对60%，rIL-2对rIL-2+CsA；效应细胞与靶细胞比例100:1）和抗性靶标（平均裂解百分比=68%对28%，rIL-2对rIL-2+CsA；效应细胞与靶细胞比例100:1），肿瘤细胞裂解也有所降低。CsA对用高剂量rIL-2培养的脾细胞的表型抗原表达没有影响，尽管在体内暴露于CsA后评估新鲜脾细胞时，活化T细胞抗原被下调。这些研究支持了CsA对NK细胞裂解的下调作用，并表明rIL-2激活的细胞群体是异质性的，这通过NK抗性细胞裂解与NK敏感细胞裂解的差异下调和恢复得到证明。
