Grinyó J M, Cruzado J M
Nephrology Department, Hospital Universitari de Bellvitge, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
Transplant Proc. 2004 Mar;36(2 Suppl):240S-242S. doi: 10.1016/j.transproceed.2004.01.057.
The polypeptide immunosuppressant cyclosporine is a prodrug that binds an intracellular immunophilin. The complex cyclosporine-cyclophilin binds and inhibits the phosphatase activity of calcineurin interfering with the dephosphorilation of members of the nuclear factor of activated T cells, which is involved in the regulation of genes encoding many cytokines. However, calcineurin is not exclusive from T cells; it is also present in many organs, such as the kidney, and their inhibition accounts for both the immunosuppressive and the nephrotoxic effects of cyclosporine. In renal transplantation, it was shown that graft survival improved progressively between 1998 to 1996, mainly due to reduction of acute rejection episodes. There is no doubt that cyclosporine contributed to that success. After 20 years, cyclosporine targets for maintenance immunosuppression have not been defined and the magnitude of chronic cyclosporine nephrotoxicity in renal allografts is not known, in part by the limitations of histologic classification of chronic allograft nephropathy. In the future, the new technology based on DNA microarrays can be a valuable tool to separate chronic drug toxicity from other causes of graft deterioration. On the other hand, in the cyclosporine era, chronic renal failure has emerged as a frequent adverse event after transplantation of nonrenal organs and it is associated with increased risk of death. Although there is not yet enough evidence to support a generalization of calcineurin-free immunosuppression, we should open our minds to the upcoming new concepts on immunosuppression.
多肽免疫抑制剂环孢素是一种前体药物，它能与一种细胞内亲免素结合。环孢素 - 亲环素复合物会结合并抑制钙调神经磷酸酶的磷酸酶活性，从而干扰活化T细胞核因子成员的去磷酸化过程，该因子参与许多细胞因子编码基因的调控。然而，钙调神经磷酸酶并非T细胞所特有；它也存在于许多器官中，如肾脏，对其抑制作用既解释了环孢素的免疫抑制作用，也解释了其肾毒性作用。在肾移植中，研究表明，1998年至1996年间移植物存活率逐渐提高，这主要归因于急性排斥反应发生率的降低。毫无疑问，环孢素促成了这一成功。20年后，维持免疫抑制的环孢素靶点尚未明确，肾移植中环孢素慢性肾毒性的程度也不清楚，部分原因是慢性移植肾肾病组织学分类存在局限性。未来，基于DNA微阵列的新技术可能成为区分慢性药物毒性与移植物恶化其他原因的宝贵工具。另一方面，在环孢素时代，慢性肾衰竭已成为非肾器官移植后常见的不良事件，并且与死亡风险增加相关。尽管目前尚无足够证据支持推广无钙调神经磷酸酶免疫抑制，但我们应该对即将出现的免疫抑制新概念持开放态度。
