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种全新药物，FTY720、KF20444、FK778、FK779、SZD-RAD、A802715和CTLA4Ig，用于单剂量研究或与常规免疫抑制剂(环丙氨酸(CsA)或他克莫司(FK506))的联合剂量研究。FTY720延长了ACI-Lew大鼠器官移植中心脏和肝脏移植的存活时间。FTY720在大鼠同种异体移植中无不良反应，与CsA、FK506有协同作用，治疗窗宽。FTY对犬同种异体肾和肝移植物也有免疫抑制作用。KF20444在犬同种异体心脏移植中的免疫抑制作用不如CsA或FK506强，但治疗范围也较广。KF20444在ACI-Lew大鼠心脏移植中有明显的免疫抑制作用，但4 mg/kg/d以上剂量出现严重的胃肠道毒性。间歇性给药试图通过延长…来减少毒性FK778/FK779在ACI-LOW大鼠心脏移植中显示出显著的延长存活时间。FK778/FK779联合CsA或FK506也可延长移植物存活时间。在犬肾移植中，FK778单独用药(4 mg/kg/d和6 mg/kg/d)以及FK506与FK506(0.5 mg/kg/d)合用也能延长移植肾存活时间。SDZ-RAD能显著延长ACI-Lew大鼠肝移植的存活时间。在同一模型中，SDZ-RAD和CsA联用也表现出明显的免疫抑制作用。A802715单药对大鼠ACI-LEW大鼠心脏和肝脏移植无免疫抑制作用，而A802715和CsA联用对延长WKAH-PVG大鼠心脏移植存活有协同作用。术后连续7d腹腔注射CTLA4Ig对大鼠原位小肠移植具有免疫抑制作用。较少

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