Molecular mechanisms of immunosuppression by cyclosporine, FK506, and rapamycin.
Molecular mechanisms of immunosuppression by cyclosporine, FK506, and rapamycin.
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DOI：
10.1097/00041552-199511000-00002
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发表时间：
1995-11-01
影响因子：
3.2
通讯作者：
Heitman, J
中科院分区：
文献类型：
--
作者：
Cardenas, M E;Zhu, D;Heitman, J
免疫抑制剂环孢素A彻底改变了移植排斥的治疗方法。两种新的药物，FK 506和雷帕霉素，显示出巨大的临床潜力。这些药物通过形成蛋白质-药物复合物来抑制免疫系统，所述蛋白质-药物复合物与T细胞活化所需的信号转导途径的关键组分相互作用并抑制所述关键组分。亲环素A-环孢菌素A和FKBP 12-FK 506复合物的靶标是钙调磷酸酶，一种通过T细胞受体进行信号传导所需的蛋白磷酸酶。环孢素A和FK 506肾毒性可能反映了钙调神经磷酸酶的肾脏特异性功能。FKBP 12-雷帕霉素复合物的靶点是TOR，一种脂质和蛋白激酶同系物，可能是T细胞响应白细胞介素-2增殖所需的。环孢霉素A、FK 506和雷帕霉素靶点的鉴定揭示了许多关于T细胞信号传导的问题，并提供了设计具有降低毒性的新型免疫抑制剂的方法。
The immunosuppressant cyclosporine A revolutionized treatment of graft rejection. Two newer agents, FK506 and rapamycin, show great clinical potential. These drugs suppress the immune system by forming protein-drug complexes that interact with and inhibit key components of the signal transduction pathways required for T-cell activation. The target of the cyclophilin A-cyclosporine A and FKBP12-FK506 complexes is calcineurin, a protein phosphatase required for signaling via the T-cell receptor. Cyclosporine A and FK506 nephrotoxicity may reflect renal-specific functions of calcineurin. The target of the FKBP12-rapamycin complex is TOR, a lipid and protein kinase homolog that is likely to be required for T-cell proliferation in response to interleukin-2. The identification of cyclosporine A, FK506, and rapamycin targets reveals much concerning T-cell signaling and provides the means to design novel immunosuppressants with reduced toxicity.