Combination of N, N′-dicyclohexyl-N-arachidonic acylurea and tacrolimus prolongs cardiac allograft survival in mice
Combination of N, N′-dicyclohexyl-N-arachidonic acylurea and tacrolimus prolongs cardiac allograft survival in mice
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DOI：
10.1111/imcb.12327
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发表时间：
2020-04-24
影响因子：
4
通讯作者：
Xia, Junjie
中科院分区：
文献类型：
--
作者：
An, Ke;Qin, Qing;Xia, Junjie
目前用于器官移植的免疫抑制剂因毒性强、副作用大而不尽人意。因此，迫切需要研发新型免疫抑制剂。化合物N, N'-二环己基-N-花生四烯酰脲（DCAAA）是从传统中药材板蓝根中提取的一种新型高度不饱和脂肪酸。在本研究中，我们系统地探究了DCAAA的毒性、免疫抑制作用及其活性的潜在机制。毒性试验表明，DCAAA处理不会导致红细胞溶血，也不影响小鼠的肝肾功能。淋巴细胞转化试验显示，DCAAA处理以剂量依赖的方式抑制淋巴细胞增殖。体内心脏同种异体移植实验表明，DCAAA处理可抑制免疫排斥反应，通过降低脾脏和移植物中CD4(+) T细胞的比例、上清液和血清中干扰素-γ的浓度以及炎症细胞向移植物的浸润，显著延长受体小鼠心脏移植物的存活时间。此外，DCAAA与他克莫司联合治疗在预防心脏移植急性排斥反应方面具有协同作用。体外分子生物学实验表明，DCAAA处理抑制T细胞受体介导的磷酸肌醇3-激酶-蛋白激酶B通路的激活，从而阻止细胞周期从G(1)期向S期转变，抑制淋巴细胞增殖。总体而言，我们的研究揭示了一种新型、低毒的免疫抑制剂，当其与现有免疫抑制剂联合使用时，有可能降低现有免疫抑制剂的毒副作用。
Current immunosuppressive agents for organ transplantation are not ideal because of their strong toxicity and adverse effects. Hence, there is an urgent need to develop novel immunosuppressive agents. The compound N, N '-dicyclohexyl-N-arachidonic acylurea (DCAAA) is a novel highly unsaturated fatty acid from the traditional Chinese medicinal plant Radix Isatidis. In this study, we systematically investigated the toxicity, immunosuppressive effect and mechanisms underlying the activity of DCAAA. The toxicity tests showed that DCAAA treatment did not lead to red blood cell hemolysis and did not affect the liver and kidney functions in mice. The lymphocyte transformation test showed that DCAAA treatment inhibited lymphocyte proliferation in a dose-dependent manner. An in vivo cardiac allotransplantation experiment showed that DCAAA treatment could suppress the immune rejection and significantly prolong the survival of cardiac allografts in recipient mice by reducing the proportion of CD4(+) T cells in the spleen and grafts, concentration of interferon-gamma in the supernatant and serum and infiltration of inflammatory cells into the grafts. Moreover, a combination treatment with DCAAA and tacrolimus had a synergistic effect in preventing acute rejection of heart transplants. In vitro molecular biology experiments showed that DCAAA treatment inhibited activation of the T-cell receptor-mediated phosphoinostide 3-kinase-protein kinase B pathway, thereby arresting cell cycle transition from the G(1) to the S phase, and inhibiting lymphocyte proliferation. Overall, our study reveals a novel, low-toxicity immunosuppressive agent that has the potential to reduce the toxic side effects of existing immunosuppressive agents when used in combination with them.