Rintala J M, Savikko J, Rintala S E, von Willebrand E
Transplantation Laboratory, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland.
Transplant Proc. 2006 Oct;38(8):2719-21. doi: 10.1016/j.transproceed.2006.08.079.
Acute rejection is the single most important risk factor for the development of subsequent chronic allograft nephropathy (CAN). Both platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) are major mitogens mediating mesenchymal cell proliferation and epithelial to mesenchymal cell transition. Early posttransplant induction of these growth factors may start molecular mechanisms leading to CAN. A new promising immunosuppressive drug, FK778, is an analogue of the active metabolite of leflunamide, which inhibits de novo pyrimidine biosynthesis. Herein we investigated the effect of FK778 on acute rejection and on the expression of PDGF and TGF-beta both alone and in combination with cyclosporine (CsA) or tacrolimus (Tac).
Kidney transplantations were performed from Dark Agouti (DA) to Wistar-Furth (WF) rats with syngeneic controls between DA rats. No immunosuppression was given to syngeneic grafts. Allografts were immunosuppressed with FK778 alone or in combination with CsA or Tac. Grafts were harvested on day 5 for histology and immunohistochemistry (PDGF-A, -B, PDGFR-alpha, -beta, TGF-beta1, and TGF-betaR1).
FK778 ameliorated the inflammatory response and reduced PDGF and TGF-beta expression in a dose-dependent manner. It also showed synergy with calcineurin inhibitors, an effect that was stronger with Tac than with CsA.
Our results indicated that FK778 decreased PDGF and TGF-beta expression early in acute rejection, suggesting it to be a promising therapy for CAN.
急性排斥反应是后续慢性移植肾肾病（CAN）发生的最重要单一危险因素。血小板衍生生长因子（PDGF）和转化生长因子-β（TGF-β）都是介导间充质细胞增殖和上皮细胞向间充质细胞转化的主要促有丝分裂原。移植后早期这些生长因子的诱导可能启动导致CAN的分子机制。一种新的有前景的免疫抑制药物FK778是来氟米特活性代谢物的类似物，它抑制从头嘧啶生物合成。在此我们研究了FK778对急性排斥反应以及单独或与环孢素（CsA）或他克莫司（Tac）联合使用时PDGF和TGF-β表达的影响。
将Dark Agouti（DA）大鼠的肾脏移植到Wistar-Furth（WF）大鼠，并在DA大鼠之间设置同基因对照。同基因移植物不给予免疫抑制。同种异体移植物单独用FK778或与CsA或Tac联合进行免疫抑制。在第5天收获移植物用于组织学和免疫组织化学检查（检测PDGF-A、-B、PDGFR-α、-β、TGF-β1和TGF-βR1）。
FK778改善了炎症反应，并以剂量依赖方式降低了PDGF和TGF-β的表达。它还显示出与钙调神经磷酸酶抑制剂具有协同作用，与Tac联合的效果比与CsA联合更强。
我们的结果表明，FK778在急性排斥反应早期降低了PDGF和TGF-β的表达，提示它可能是一种有前景的CAN治疗方法。
