Development of innovative strategies for transplant immunosuppression with brand new drugs

为了开发移植免疫抑制的创新策略，我们测试了7种全新的药物，FTY 720，KF 20444，FK 778，FK 779，SZD-RAD，A802715，和CTLA 4 Ig用于单剂量研究或用于与常规免疫抑制剂的联合剂量研究FTY 720延长ACI至LEW大鼠器官移植中心脏和肝脏同种异体移植物的存活。FTY 720对大鼠同种异体移植物有较宽的治疗窗，与CsA、FK 506有协同作用，无不良反应。FTY还表现出对犬肾和肝移植物的免疫抑制作用。KF 20444对ACI-LEW大鼠心脏移植有明显的免疫抑制作用，但在4 mg/kg/d剂量下可引起严重的胃肠道毒性。进行间歇给药，试图通过延长 关于我们 FK 778/FK 779在ACI至LEW大鼠心脏移植中显示出显著延长的存活。FK 778/FK 779和CsA或FK 506联合治疗也延长了同种异体移植物的存活。在犬肾移植中，FK 778单药治疗（4 mg/kg/天和6 mg/kg/天）和FK 506联合治疗（0.5mg/kg/天）也延长了同种异体移植物的存活时间。SDZ-RAD与CsA联合应用对ACI-LEW大鼠移植心脏和肝脏无明显的免疫抑制作用，A802715与CsA联合应用对WKAH-PVG大鼠心脏移植存活有协同作用，CTLA 4 Ig对大鼠原位心脏移植有免疫抑制作用术后连续7天腹腔内给药时行小肠移植。少

To develop innovative strategies for transplant immunosuppression, we tested 7 brand new drugs, FTY720, KF20444, FK778, FK779, SZD-RAD, A802715, and CTLA4Ig for a-single-dose study or for a combined dose study with conventional immunosuppressants(cyclosproine(CsA)or tacrolimus(FK506)).FTY720 prolonged both cardiac and liver allograft survival in ACI to LEW rat organ transplantation. FTY720 has a wide therapeutic window without an adverse effect and synergistic effect with CsA and FK506 in rat allografts. FTY also exhibited immunosuppressive effects on canine renal and hepatic allografts. The immunosuppressive potency was not as strong as CsA or FK506 in canine allografts transplantation, although the therapeutic range was also wide.KF20444 showed significant immunosuppressive effect in ACI to LEW rat cardiac transplantation, although severe gastrointestinal toxicity was observed over the dose of 4mg/kg/day. Intermittent administration was done in attempt to reduce toxicity with prolong … More ed graft survival compared to the most optimal one by daily administration.FK778/FK779 showed a significant prolonged survival in ACI to LEW rat cardiac transplantation. The combination therapy with FK778/FK779 and CsA, or FK506 also prolonged allografts survival. In canine renal transplantation, FK778 monotherapy(4mg/kg/day and 6mg/kg/day)and combination therapy with FK506(0.5mg/kg/day)also prolonged allografts survival.SDZ-RAD showed significant prolonged allografts survival in ACI to LEW rat liver transplantation. The combination therapy SDZ-RAD and CsA also showed marked immunosuppressive effect in the same model.A802715 monotherapy did not show immunosuppressive effect in ACI to LEW rat cardiac and liver transplantation, while the combination therapy with A802715 and CsA exhibited a synergic effect on prolongation of allografts survival in WKAH to PVG rat cardiac transplantation.CTLA4Ig worked as an immunosuppressive agent on rat orthotopic small intestine transplantation when it was administrated into abdominal cavity during 7 successive days after surgery. Less