Yoshimura N, Kahan B D
Transplantation. 1985 Dec;40(6):661-6. doi: 10.1097/00007890-198512000-00018.
There are presently no monitoring tools to assess the immunosuppressive effect of cyclosporine (CsA) in vivo, since the mode of drug action is incompletely understood in man. Experimental in vitro studies suggest that CsA causes reversible inhibition of T helper cell generation of interleukin-2 (IL-2). Therefore the present study examined the effect of CsA administered in vivo on the capacity of kidney transplant recipient lymphocytes to generate IL-2 after mitogen (phytohemagglutinin [PHA]) stimulation. IL-2 production was measured by the capacity of lymphocyte supernates to trigger proliferation of a human IL-2-dependent T cell line. Peripheral blood lymphocytes (PBL) from CsA-Pred treated recipients displayed 40.6% inhibition (1.14 +/- 0.06 U/ml, n = 117, P less than 0.001) of IL-2 production compared with normal individuals (1.93 +/- 0.04 U/ml, n = 164). Dialysis patients did not display inhibited IL-2 production. The inhibition of IL-2 generation was observed in patients treated solely with CsA without supplemental corticosteroids (1.24 +/- 0.12 U/ml, n = 25; 35.8% inhibition, P less than 0.001). CsA did not inhibit the expression of the IL-2 receptor: 4.15 +/- 11.2% and 63.1 +/- 10.3 of normal lymphocytes and 36.7 +/- 9.8% and 60.4 +/- 12.2% of CsA-treated patient lymphocytes expressed anti-IL-2 receptors after 24 or 48 hr of PHA stimulation, respectively. Serial posttransplant studies in individual patients confirmed no inhibition of IL-2 generation pretransplant (1.94 +/- 0.07 U/ml) followed by a high degree of inhibition thereafter, namely 0.87 U/ml (55.0% inhibition) at 1 week, 1.15 U/ml (40.6% inhibition) at 2 weeks, 0.42 U/ml (78.2% inhibition) at 3 weeks, and 0.99 U/ml (48.7% inhibition) at 4 weeks. There was a correlation between the occurrence of rejection episodes in the 7 patients who suffered this event, and IL-2 generation by patient PBL. Before pulse therapy there was no inhibition of IL-2 generation (2.39 U/ml; -23.8 inhibition), documenting a poor level of immunosuppression in these patients. At 1, 2, 3, or 4 days after corticosteroid pulse therapy, PBL displayed 39.4%, 57.0%, 50.0% and 49.2% inhibition, respectively. These findings suggest not only that CsA treatment impairs the generation of IL-2 by patient lymphocytes, but also that failure to display this response is associated with a poor level of immunosuppression and allograft rejection. These studies provide a foundation for serial analyses of IL-2 generation, in order to dissect its utility as a pharmacodynamic parameter to assess the level of CsA-induced immunosuppression.
目前尚无监测工具可在体内评估环孢素（CsA）的免疫抑制作用，因为在人体中药物作用方式尚未完全明确。体外实验研究表明，CsA可导致T辅助细胞产生白细胞介素-2（IL-2）受到可逆性抑制。因此，本研究检测了体内给予CsA对肾移植受者淋巴细胞在有丝分裂原（植物血凝素[PHA]）刺激后产生IL-2能力的影响。通过淋巴细胞上清液触发人IL-2依赖性T细胞系增殖的能力来测定IL-2的产生。与正常个体（1.93±0.04 U/ml，n = 164）相比，接受CsA-泼尼松治疗的受者外周血淋巴细胞（PBL）的IL-2产生受到40.6%的抑制（1.14±0.06 U/ml，n = 117，P＜0.001）。透析患者的IL-2产生未受抑制。在仅接受CsA治疗而未补充皮质类固醇的患者中也观察到IL-2产生受到抑制（1.24±0.12 U/ml，n = 25；35.8%的抑制率，P＜0.001）。CsA未抑制IL-2受体的表达：在PHA刺激24小时或48小时后，正常淋巴细胞分别有4.15±11.2%和63.1±10.3%表达抗IL-2受体，接受CsA治疗的患者淋巴细胞分别有36.7±9.8%和60.4±12.2%表达抗IL-2受体。对个体患者进行的移植后系列研究证实，移植前IL-2产生未受抑制（1.94±0.07 U/ml），但此后受到高度抑制，即1周时为0.87 U/ml（55.0%的抑制率），2周时为1.15 U/ml（40.6%的抑制率），3周时为0.42 U/ml（78.2%的抑制率），4周时为0.99 U/ml（48.7%的抑制率）。在经历排斥反应的7例患者中，排斥反应的发生与患者PBL产生IL-2之间存在相关性。在脉冲治疗前，IL-2产生未受抑制（2.39 U/ml；-23.8%的抑制率），表明这些患者的免疫抑制水平较差。在皮质类固醇脉冲治疗后1、2、3或4天，PBL的抑制率分别为39.4%、57.0%、50.0%和49.2%。这些发现不仅表明CsA治疗会损害患者淋巴细胞产生IL-2的能力，而且未能表现出这种反应与免疫抑制水平差和同种异体移植排斥反应相关。这些研究为IL-2产生的系列分析奠定了基础，以便剖析其作为评估CsA诱导的免疫抑制水平的药效学参数的效用。
