Weil-Hillman G, Hank J A, Rosenthal N S, Sondel P M
Department of Human Oncology, University of Wisconsin, Madison.
J Biol Response Mod. 1988 Oct;7(5):424-37.
Cancer patients were treated with recombinant interleukin-2 (IL-2) in a Phase I clinical trial. Patients were given four repetitive weekly cycles of four days of continuous i.v. IL-2 infusions followed by 3 days of observation. A transient 80% decrease in the number of circulating peripheral blood lymphocytes (PBLs) was noted 24 h after initiation of the IL-2 infusion. The in vitro IL-2 induced proliferative response, and natural killer (NK) activity of the PBLs recovered at this time was only 10-20% of that by the same number of PBLs obtained prior to IL-2 therapy. This effect was transient and rebound increases in circulating lymphocytes expressing high NK and lymphokine-activated killer functions were demonstrated at the end of a 4 day IL-2 infusion. To study further whether the drop in lymphocyte activity observed at initiation of IL-2 therapy was due to activation of a suppressor mechanism, patient PBLs isolated 24 h into the IL-2 infusion were mixed with their pre-IL-2 therapy PBLs at different ratios and assayed in NK and proliferation assays. These mixing experiments did not prove suppression to be the mechanism for the decreased response; rather, the PBLs obtained 24 h into IL-2 therapy merely diluted out the in vitro response of PBLs obtained prior to therapy. Although there was a considerable drop in circulating PBLs 24 h after initiation of each of three subsequent weekly IL-2 treatment cycles, these remaining lymphocytes in the peripheral blood were functional in both NK and IL-2 proliferative assays. These PBLs obtained 24 h into each of the subsequent three cycles showed a progressive increase in their in vitro NK and IL-2-induced proliferative activity, reaching levels two to three times higher than that of pretherapy PBLs by the fourth cycle. Thus, IL-2 caused a transient disappearance of lymphocytes from the circulation at the initiation of each cycle, but lymphocyte function was impaired only in the first IL-2 cycle. These data suggest that resting IL-2 responsive cells initially leave the circulation upon exposure to IL-2, but that such cells become activated and some remain detectable in the circulation when subsequent weekly cycles of IL-2 are given.
在一项I期临床试验中，癌症患者接受了重组白细胞介素-2（IL-2）治疗。患者接受四个为期四天的连续静脉注射IL-2的重复每周周期，随后进行三天观察。在开始IL-2输注后24小时，观察到循环外周血淋巴细胞（PBL）数量短暂下降80%。此时，IL-2体外诱导的PBL增殖反应以及自然杀伤（NK）活性仅为IL-2治疗前相同数量PBL的10%-20%。这种效应是短暂的，在4天的IL-2输注结束时，观察到表达高NK和淋巴因子激活杀伤功能的循环淋巴细胞出现反弹增加。为了进一步研究在开始IL-2治疗时观察到的淋巴细胞活性下降是否是由于抑制机制的激活，将在IL-2输注24小时时分离的患者PBL与治疗前的PBL以不同比例混合，并进行NK和增殖试验。这些混合实验并未证明抑制是反应降低的机制；相反，在IL-2治疗24小时时获得的PBL仅仅稀释了治疗前获得的PBL的体外反应。尽管在随后三个每周一次的IL-2治疗周期中的每一个开始后24小时，循环中的PBL都有相当大的下降，但外周血中剩余的这些淋巴细胞在NK和IL-2增殖试验中均有功能。在随后三个周期的每一个周期24小时时获得的这些PBL在体外NK和IL-2诱导的增殖活性方面显示出逐渐增加，到第四个周期时达到比治疗前PBL高两到三倍的水平。因此，IL-2在每个周期开始时导致淋巴细胞从循环中短暂消失，但淋巴细胞功能仅在第一个IL-2周期中受损。这些数据表明，静止的IL-2反应性细胞在接触IL-2后最初离开循环，但当随后每周给予IL-2周期时，这些细胞会被激活，并且一些细胞仍可在循环中检测到。
