SYNERGISTIC INTERACTIONS OF CYCLOSPORINE AND RAPAMYCIN TO INHIBIT IMMUNE PERFORMANCES OF NORMAL HUMAN PERIPHERAL-BLOOD LYMPHOCYTES INVITRO
SYNERGISTIC INTERACTIONS OF CYCLOSPORINE AND RAPAMYCIN TO INHIBIT IMMUNE PERFORMANCES OF NORMAL HUMAN PERIPHERAL-BLOOD LYMPHOCYTES INVITRO
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DOI：
10.1097/00007890-199101000-00038
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发表时间：
1991-01-01
期刊：
影响因子：
6.2
通讯作者：
CHOU, TC
中科院分区：
文献类型：
--
作者：
KAHAN, BD;GIBBONS, S;CHOU, TC
雷帕霉素（一种放线菌大环内酯内酯，可抑制细胞因子诱导的免疫激活）和环孢菌素（一种阻止淋巴因子信使 RNA 转录的内肽）在体外和体内表现出相互协同的相互作用。 通过严格的中位效应分析来剖析免疫抑制药物相互作用的本质，雷帕霉素显着增强了环孢素和/或地塞米松对植物血凝素、抗 CD3 单克隆抗体和混合淋巴细胞反应引起的人外周血淋巴细胞活化的抑制作用。 此外，分别使用细胞介导的淋巴溶解和有限稀释分析，添加雷帕霉素增强了环孢菌素的活性，以减少体外同种异体激活期间细胞毒性细胞的产生和前体频率。 同样，环孢素增强了雷帕霉素对 IL-2 (CTLL-2) 和 IL-6 (MH60.BSF-2) 淋巴因子依赖性细胞系增殖的抑制作用。 Michaelis-Menton 方程的 Lineweaver-Burk 图表明雷帕霉素以竞争性方式抑制 IL-2 信号转导，并以非竞争性方式抑制 IL-6 信号转导，这表明了各种细胞因子受体机制的独特组成部分。 在体内，环孢素/雷帕霉素组合对大鼠异位心脏同种异体移植物的排斥反应产生协同免疫抑制作用，使用的浓度在药物单独无效的浓度下。 这些观察结果表明，环孢菌素和雷帕霉素可以以显着降低的剂量联合使用，以达到前所未有的免疫抑制功效水平。
Rapamycin, an actinomycete macrolide lactone that inhibits cytokine-induced immunoactivation, and cyclosporine, an endecapeptide that prevents transcription of lymphokine messenger RNA, display mutually synergistic interactions in vitro and in vivo. Using the rigorous median-effect analysis to dissect the nature of immunosuppressive drug interactions, rapamycin significantly augmented the inhibitory effects of cyclosporine and/or dexamethasone upon human peripheral blood lymphocyte activation by phytohemagglutinin, anti-CD3 monoclonal antibody, and mixed lymphocyte reaction. Furthermore, the addition of rapamycin potentiated the activity of cyclosporine to reduce cytotoxic cell generation and precursor frequency during in vitro alloactivation, using cell-mediated lympholysis and limiting dilution analyses, respectively. Similarly, cyclosporine potentiated the inhibitory effects of rapamycin upon proliferation of IL-2 (CTLL-2) and IL-6 (MH60.BSF-2) lymphokine-dependent cell lines. Lineweaver-Burk plots of the Michaelis-Menton equation suggested rapamycin inhibits IL-2 signal transduction in competitive, and IL-6 signal transduction in noncompetitive fashion, suggesting distinctive components of the various cytokine-receptor mechanisms. In vivo the cyclosporine/rapamycin combination exerted synergistic immunosuppression of rejection reactions in rats toward heterotopic cardiac allografts, using concentrations at which drugs were individually ineffective. These observations suggest that cyclosporine and rapamycin may be combined at significantly reduced doses to achieve unprecedented levels of immunosuppressive efficacy.