Effects of leflunomide and other immunosuppressive agents on T cell proliferation in vitro
Effects of leflunomide and other immunosuppressive agents on T cell proliferation in vitro
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DOI：
10.1097/00007890-199601150-00026
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发表时间：
1996-01-15
期刊：
影响因子：
6.2
通讯作者：
Williams, JW
中科院分区：
文献类型：
--
作者：
Chong, ASF;Rezai, K;Williams, JW
来氟米特及其活性代谢产物A771726在结构上与目前正在研究的免疫抑制剂无关。以前的体外研究表明，来氟米特主要抑制白细胞介素-2刺激的T细胞增殖。在目前的研究中，我们已经扩展了我们以前的工作，并证明来氟米特阻止T细胞的进展诱导的植物血凝素进入细胞周期的S期。为了进一步区分来自其他免疫抑制剂的来氟米特对T细胞的作用，我们进行了动力学研究，其中在混合淋巴细胞培养物（MLC）开始后或在白细胞介素-2刺激CTLL-4细胞增殖后加入来氟米特。这些研究表明，来氟米特对雷帕霉素起作用，但在MLC中与布喹那钠不同，在MLC和CTLL-4中与环孢菌素和霉酚酸不同。虽然以前的生化研究表明，来氟米特可以抑制src家族酪氨酸激酶活性，最近的研究表明，来氟米特也可以抑制嘧啶合成。我们的数据表明来氟米特（25-100 μ M）抑制MLC和CTLL-4细胞增殖的能力被尿苷（25-100 μ M）部分拮抗，并支持来氟米特抑制T细胞中嘧啶合成的假设。免疫抑制的独特分子机制表明，药物组合可能导致协同免疫抑制。我们的体外研究显示，来氟米特与环孢霉素或雷帕霉素的组合对T细胞增殖具有协同抑制作用。我们已经将这些研究扩展到定量来氟米特和布喹那钠或麦考酚酸联合用药对MLC的抑制作用。
Leflunomide and its active metabolite, A771726, are structurally unrelated to immunosuppressive agents currently under investigation Previous in vitro studies have revealed that leflunomide primarily inhibits interleukin-2-stimulated T cell proliferation. In the current study, we have extended our previous work and demonstrate that leflunomide prevents T cell progression induced by phytohemagglutinin into the S phase of the cell cycle. To discriminate further the action on T cells of leflunomide from other immunosuppressive agents, we performed kinetic studies where leflunomide was added either after the initiation of mixed lymphocyte cultures (MLC) or after interleukin-2 stimulation of CTLL-4 cell proliferation. These studies revealed that leflunomide acted comparably to rapamycin, but was distinct from brequinar sodium in the MLC, and from cyclosporine and mycophenolic acid in both MLC and CTLL-4. Although previous biochemical studies indicated that leflunomide can inhibit src-family tyrosine kinase activity, more recent studies have suggested that leflunomide can also inhibit pyrimidine synthesis. Our data demonstrate that the ability of leflunomide (25-100 mu M) to inhibit MLC and CTLL-4 cell proliferation is partially antagonized by uridine (25-100 mu M), and support the hypothesis that leflunomide inhibits pyrimidine synthesis in T cells. Unique molecular mechanisms of immunosuppression suggest that drug combinations may result in synergistic immunosuppression. Our in vitro studies revealed synergistic inhibition of T cell proliferation with the combinations of leflunomide with cyclosporine or with rapamycin. We have extended those studies to quantitate inhibition of MLC by the combinations of leflunomide and brequinar sodium or mycophenolic acid.