Thomas J M, Carver F M, Fahrenbruch G B, Hall W R, Deepe R M, Thomas F T
Surgery. 1983 Aug;94(2):384-91.
The mechanism responsible for the profound and enduring immunosuppressive action of antithymocyte globulin (ATG) is not well understood. In a primate model, we found that a 5-day rabbit ATG (RATG treatment course activates a prostaglandin (PG)-dependent suppressor cell mechanism that persists for several months. Groups of normal rhesus monkey skin allograft recipients, kidney allograft recipients, or nontransplant control animals received either RATG or no immunosuppression. The peripheral blood mononuclear cell (PBMC) population was longitudinally monitored for (1) percentage of total T cells, helper cells, and suppressor/cytotoxic T cell subsets with the monoclonal antibodies Leu-5, OKT4, and CKT8, respectively, and (2) phytohemagglutinin (PHA)-induced lymphocyte proliferative responses (LPR). The nonimmunosuppressed control groups showed no significant changes in any of these parameters. In contrast, PBMCs from all RATG-treated monkeys developed a persistent imbalance in the ratio of OKT4+ and OKT8+ subsets. Their PBMCs became unresponsive to PHA and remained unresponsive (less than 20% of control level) for at least 3 months, although total T cell counts recovered within 2 to 3 weeks after cessation of RATG. Addition of PG synthetase inhibitors indomethacin. RO-20-5720, and tolmetin caused a significant, dose-dependent recovery of LPR that was completely inhibited by exogenous PGE2 at 1 X 10(-8) M. PBMCs from RATG-treated monkeys caused a dose-dependent suppression of the normal PHA response, and this suppressor cell activity was blocked by indomethacin. PHA responses of nonimmunosuppressed control groups were not increased significantly in the presence of PG synthetase inhibitors, were less sensitive to suppression by PGE2, and did not exhibit suppressor cell activity. These data suggest that the prolonged depression in LPR after RATG treatment is due to an active PG-dependent suppressor cell mechanism and provide a new concept to explain the immunosuppressive action of RATG.
抗胸腺细胞球蛋白（ATG）具有深刻且持久的免疫抑制作用，但其作用机制尚不清楚。在一个灵长类动物模型中，我们发现为期5天的兔抗胸腺细胞球蛋白（RATG）治疗疗程可激活一种依赖前列腺素（PG）的抑制细胞机制，该机制可持续数月。将正常恒河猴皮肤移植受者、肾移植受者或非移植对照动物分组，分别给予RATG或不进行免疫抑制。纵向监测外周血单个核细胞（PBMC）群体：（1）分别使用单克隆抗体Leu-5、OKT4和CKT8检测总T细胞、辅助性T细胞以及抑制性/细胞毒性T细胞亚群的百分比；（2）检测植物血凝素（PHA）诱导的淋巴细胞增殖反应（LPR）。未进行免疫抑制的对照组在这些参数上均未出现显著变化。相比之下，所有接受RATG治疗的猴子的PBMC中，OKT4 +和OKT8 +亚群的比例出现持续失衡。它们的PBMC对PHA无反应，并且至少3个月内一直无反应（低于对照水平的20%），尽管在停止RATG治疗后2至3周内总T细胞计数恢复正常。添加PG合成酶抑制剂吲哚美辛、RO-20-5720和托美丁可使LPR显著且呈剂量依赖性恢复，而外源性PGE2在1×10（-8）M时可完全抑制这种恢复。来自接受RATG治疗的猴子的PBMC可对正常PHA反应产生剂量依赖性抑制，并且这种抑制细胞活性可被吲哚美辛阻断。在PG合成酶抑制剂存在的情况下，未进行免疫抑制的对照组的PHA反应未显著增加，对PGE2抑制的敏感性较低，并且未表现出抑制细胞活性。这些数据表明，RATG治疗后LPR的长期降低是由于一种活跃的依赖PG的抑制细胞机制所致，并为解释RATG的免疫抑制作用提供了一个新的概念。
