Gruber S A, Hughes S E, Xiao S, Perera S, Jayasankar V, Rosario A D, Singh J
The Departments of Surgery and Pathology, Albany Medical College, Albany, New York 12208, USA.
J Surg Res. 1997 Aug;71(2):137-44. doi: 10.1006/jsre.1997.5156.
Local immunosuppression is based on the rationale that one can simultaneously prevent rejection and reduce systemic side effects by administering appropriately chosen immunosuppressive agents directly into the allograft. We utilized a mongrel canine renal transplant model with a programmable, implantable pump/catheter system to estimate the first-pass extraction of 15-deoxyspergualin (DSG) during renal artery infusion and to compare the efficacy and toxicity of continuous intraarterial (ia) versus intravenous (iv) DSG delivery. Six autotransplanted dogs were given DSG by both iv bolus (1 mg/kg) and ia infusion (1.0 mg/kg/d). DSG was administered to allograft recipients by continuous ia infusion at 0.5 (n = 11) and 0.75 (n = 8) mg/kg/day and by continuous iv infusion at 0.5 (n = 12) and 0.75 (n = 6) mg/kg/day. Mean +/- SD elimination half-life was 0.6 +/- 0.1 hr, and the transplanted kidney removed as much as 55-88% (mean 66%) of locally infused DSG. When compared with untreated controls [mean survival time (MST) = 8 days], low-dose (0. 5 mg/kg/day) DSG produced a significant antirejection effect when given ia (MST = 12 days; P = 0.04) but not iv (MST = 9 days; P = 0. 09), with equivalent overall mean drug levels during normal renal function. However, two of the four longest-surviving animals in the ia group died from severe systemic toxicity, manifested by anorexia, diarrhea, leukopenia, and sepsis. High-dose (0.75 mg/kg/day) DSG significantly prolonged survival via both local (MST = 12 days; P = 0.04) and systemic (MST = 11 days; P = 0.02) routes, but half of the iv-treated dogs died from, and four of the longer-surviving ia-treated animals manifested signs of, systemic toxicity, with significantly higher mean drug levels in the iv group. DSG significantly suppressed vascular rejection at both doses when administered locally and systemically, dose-dependently affected the severity of tubulointerstitial rejection and graft edema, and was not nephrotoxic. Our autotransplant pharmacokinetic data overestimated the allografted kidney's ability to extract DSG during local infusion of slightly lower, but immunosuppressive, doses, so that death from systemic toxicity was not prevented and a direct survival benefit of ia vs iv therapy was not realized. Local DSG administration might be combined with other immunosuppressants to therapeutic advantage.
局部免疫抑制的理论依据是，通过将适当选择的免疫抑制剂直接注入同种异体移植物中，可以同时预防排斥反应并减少全身副作用。我们利用一种带有可编程、可植入泵/导管系统的杂种犬肾移植模型，来估计肾动脉灌注期间15-去氧精胍菌素（DSG）的首过提取率，并比较持续动脉内（ia）与静脉内（iv）给予DSG的疗效和毒性。六只自体移植犬通过静脉推注（1mg/kg）和动脉内输注（1.0mg/kg/d）给予DSG。将DSG以0.5（n = 11）和0.75（n = 8）mg/kg/天的剂量通过持续动脉内输注给予同种异体移植受体，并以0.5（n = 12）和0.75（n = 6）mg/kg/天的剂量通过持续静脉输注给予。平均±标准差消除半衰期为0.6±0.1小时，移植肾清除了高达55 - 88%（平均66%）的局部注入的DSG。与未治疗的对照组[平均存活时间（MST）= 8天]相比，低剂量（0.5mg/kg/天）DSG通过动脉内给予时产生了显著的抗排斥作用（MST = 12天；P = 0.04），但静脉内给予时未产生（MST = 9天；P = 0.09），在肾功能正常期间总体平均药物水平相当。然而，动脉内给药组中存活时间最长的四只动物中有两只死于严重的全身毒性，表现为厌食、腹泻、白细胞减少和败血症。高剂量（0.75mg/kg/天）DSG通过局部（MST = 12天；P = 0.04）和全身（MST = 11天；P = 0.02）途径均显著延长了存活时间，但静脉内治疗的犬中有一半死于全身毒性，动脉内治疗的存活时间较长的动物中有四只出现全身毒性迹象，静脉内组的平均药物水平显著更高。DSG在局部和全身给药时，两种剂量均显著抑制血管排斥反应，剂量依赖性地影响肾小管间质排斥反应的严重程度和移植物水肿，并且无肾毒性。我们的自体移植药代动力学数据高估了同种异体移植肾在局部输注略低但具有免疫抑制作用剂量的DSG期间提取DSG的能力，因此未能预防全身毒性导致的死亡，也未实现动脉内与静脉内治疗的直接生存获益。局部给予DSG可能与其他免疫抑制剂联合使用以获得治疗优势。
