Malononitrilamides synergistically prevent acute and treat ongoing skin allograft rejection with cyclosporine
Malononitrilamides synergistically prevent acute and treat ongoing skin allograft rejection with cyclosporine
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丙二腈与环孢菌素协同预防急性并治疗持续的皮肤同种异体移植排斥反应
DOI：
10.1111/j.1432-2277.1998.tb01151.x
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发表时间：
1998
影响因子：
3.1
通讯作者：
R. Kurrle
中科院分区：
文献类型：
--
作者：
H. Schorlemmer;E. Ruuth;R. Kurrle
摘要低分子量丙二腈酰胺（malononnitrilamides, MNAs）是一类新型免疫抑制剂，属于来氟米特活性代谢物A771726的衍生物。它们已被证明与脱氢酸脱氢酶特异性结合，抑制新生嘧啶生物合成，从而阻断T细胞和b细胞增殖，并强烈抑制IgM和IgG抗体的产生。在这里，我们评估了它们与环孢素（CyA）在大鼠皮肤同种异体移植模型中的疗效，使用不同的菌株组合。用MNAs HMR 1279和HMR 1715对这些模型中的移植动物进行单药治疗，可显著延长移植物存活时间，且呈剂量依赖性。即使是短期应用也能有效预防急性排斥反应。当在预期的排斥危机开始治疗时，MNAs也有效，显示出强大的治疗活性，可以逆转持续的急性排斥反应，而CyA对持续的同种异体移植排斥反应发作无效。MNAs与CyA联合治疗对预防急性皮肤移植排斥反应非常有效。有趣的是，尽管单独使用CyA无法治疗持续的急性排斥反应，但MNAs和CyA的联合用药，即使在短期应用后，也能协同有效并显著抑制持续的同种异体皮肤移植排斥反应。这些结果表明，MNAs是一种有效且耐受性良好的免疫抑制剂，具有与CyA相当的潜力，但它们在逆转急性排斥发作的能力方面优于CyA。它们代表了强大的救援药物，并与CyA表现出协同活性，以预防急性和治疗持续的皮肤同种异体移植排斥反应。
Abstract The low molecular weight malononitrilamides (MNAs), a new class of immunosuppressive agents, belong to the derivatives of leflunomide's active metabolite, A771726. They have been shown to bind specifically to dehydroorotate dehydrogenase and inhibit de novo pyrimidine biosynthesis, thereby blocking T- and B-cell proliferation and strongly suppressing IgM and IgG antibody production. Here we evaluated their efficacy together with cyclosporine (CyA) in rat skin allotransplantation models, using different strain combinations. Monotherapy of transplanted animals in these models with the MNAs HMR 1279 and HMR 1715 resulted in a significant and dose-dependent prolongation of the graft survival time. Even a short-term application showed efficacy in the prevention of acute rejection. The MNAs were also effective when treatment was started at the time of expected rejection crisis, demonstrating strong therapeutic activity to reverse ongoing acute rejection, whereas CyA was ineffective for the treatment of ongoing allograft rejection episodes. Combination therapy of MNAs with CyA proved to be very effective for the prevention of acute skin graft rejection. Interestingly, whereas CyA alone was unable to treat ongoing acute rejection episodes, comedication of MNAs and CyA, even after a short-term application, was synergistically effective and significantly suppressed ongoing allogeneic skin graft rejection. These results demonstrate that MNAs are potent and well tolerated immunosuppressants with a potential comparable to that of CyA, but they are superior to CyA in their ability to reverse acute rejection episodes. They represent powerful rescue drugs and demonstrate synergistic activity with CyA to prevent acute and treat ongoing skin allograft rejection.