Wang X, Alfrey E J, Posselt A, Tafra L, Alak A M, Dafoe D C
Department of Surgery, Stanford University Medical Center, CA 94305, USA.
Transpl Int. 1995;8(4):268-72. doi: 10.1007/BF00346879.
Local delivery of immunosuppressive agents may dampen local alloreactive events with avoidance of systemic toxicity. We investigated the innovative strategy of intraportal (IPO) delivery of three immunosuppressive agents in streptozotocin diabetic rat recipients of islet allografts (Lewis to Wistar-Furth) transplanted intrahepatically. IPO budesonide (BUD, 240 or 360 micrograms/kg per day), a potent steroid, and cyclosporin (CyA, 2 or 4 mg/kg per day) did not prolong graft mean survival time [MST +/- standard deviation (SD)] as compared to nonimmunosuppressed recipients. Fourteen days of IPO FK 506 (0.16 mg/kg per day) significantly increased MST as compared with untreated controls (49 +/- 29 vs 7 +/- 1 days, P < 0.01) and was more effective than intravenous (IV) FK 506 (17 +/- 7 days, P < 0.01). When FK 506 was given for 28 days, the benefit of IPO over IV delivery was reaffirmed (MST 81 +/- 32 vs 34 +/- 4 days, P < 0.01). The potential for toxicity was lessened by lower mean systemic levels in the IPO group as compared to the IV group (1.3 +/- 0.6 vs 3.5 +/- 0.9 ng/mg, P < 0.02). The strategy of continuous IPO FK 506 was effective in the prevention of rejection of intrahepatic islet allografts.
局部递送免疫抑制剂可抑制局部同种异体反应事件，同时避免全身毒性。我们研究了在肝内移植胰岛异体移植物（从刘易斯大鼠到威斯塔 - 富思大鼠）的链脲佐菌素诱导的糖尿病大鼠受体中门静脉内（IPO）递送三种免疫抑制剂的创新策略。与未免疫抑制的受体相比，IPO布地奈德（BUD，每天240或360微克/千克），一种强效类固醇，以及环孢素（CyA，每天2或4毫克/千克）并未延长移植物平均存活时间[MST±标准差（SD）]。与未治疗的对照组相比，IPO给予FK 506（每天0.16毫克/千克）14天显著增加了MST（49±29天对7±1天，P <0.01），并且比静脉内（IV）给予FK 506更有效（17±7天，P <0.01）。当给予FK 506 28天时，再次证实了IPO给药相对于IV给药的益处（MST 81±32天对34±4天，P <0.01）。与IV组相比，IPO组较低的平均全身水平降低了毒性可能性（1.3±0.6对3.5±0.9纳克/毫克，P <0.02）。持续IPO给予FK 506的策略在预防肝内胰岛异体移植物排斥方面是有效的。
