Gruessner R W, Fryer J P, Fasola C, Nakhleh R E, Gruessner A C, Kim S, Dunn D L, Pirenne J, Bekersky I, Benedetti E
Department of Surgery, University of Minnesota, Minneapolis.
Transplantation. 1995 Jan 27;59(2):164-71.
Rejection remains a major barrier to successful bowel transplantation, and immunosuppressive protocols are far from standardized. In 88 nonrelated outbred pigs, we compared the effects of two immunosuppressive regimens--one with FK506, the other with cyclosporine (CsA) and pig antithymocyte globulin (ATG)--on incidence and severity of rejection in the early, critical posttransplant period. Group A (n = 14) was nonimmunosuppressed (controls). Group B (n = 17) received pig ATG (10 mg/kg/day x 10 days), CsA (3 mg/kg/day), prednisolone (2 mg/kg/day), and azathioprine (2.5 mg/kg/day); prednisolone and azathioprine were each reduced by 50% at 8 and 15 days posttransplant. Trough CsA whole-blood concentrations were > or = 400 ng/ml for the first 7 days, > or = 200 ng/ml thereafter. Group C (n = 13) received FK506 (0.2 mg/kg/day) and prednisolone (2 mg/kg/day); prednisolone was reduced by 50% at 8 and 15 days. FK506 whole-blood concentrations were > or = 20 ng/ml. All immunosuppression in groups B and C was given intravenously. We performed orthotopic small bowel transplants with systemic venous drainage. Recipient bowel was resected distal to the second portion of the duodenum and proximal to the rectum at transplant; bowel continuity was restored by duodenojejunostomy; ileostomy was created distally to allow access for daily biopsies. We graded interstitial and vascular rejection separately, according to a scoring system (no, mild, moderate, and severe rejection). Rejection-free graft survivals at 7, 14, and 21 days posttransplant were 38%, 19%, and 0% in group A; 93%, 93%, and 62% in group B; and 100%, 91%, and 82% in group C (P < 0.001). Comparing rejection in the immunosuppressed groups, group C (FK506) had a stronger tendency toward rejection than group B (CsA-ATG); significant differences between groups B and C were, however, noted only on individual days posttransplant, not over time. The death rate due to irreversible rejection was not significantly different in groups B and C (P = 0.8), but was significantly better in both of these immunosuppressed groups than in group A (P < 0.001). Pig survival was significantly longer in group C than in B (P = 0.001) due to a lower infection rate in group C. Posttransplant serum interleukin 2 and 7 levels did not correlate with rejection grades. Graft-versus-host reaction was noted only in the skin in 29% of group A, 73% of group B, and 77% of group C pigs; liver and native bowel were not involved.(ABSTRACT TRUNCATED AT 400 WORDS)
排斥反应仍然是肠道移植成功的主要障碍，免疫抑制方案远未标准化。在88只非亲缘远交猪中，我们比较了两种免疫抑制方案（一种使用FK506，另一种使用环孢素（CsA）和猪抗胸腺细胞球蛋白（ATG））对移植后早期关键阶段排斥反应的发生率和严重程度的影响。A组（n = 14）未进行免疫抑制（对照组）。B组（n = 17）接受猪ATG（10 mg/kg/天，共10天）、CsA（3 mg/kg/天）、泼尼松龙（2 mg/kg/天）和硫唑嘌呤（2.5 mg/kg/天）；移植后第8天和第15天，泼尼松龙和硫唑嘌呤的剂量均减少50%。移植后前7天，CsA全血谷浓度≥400 ng/ml，此后≥200 ng/ml。C组（n = 13）接受FK506（0.2 mg/kg/天）和泼尼松龙（2 mg/kg/天）；移植后第8天和第15天，泼尼松龙剂量减少50%。FK506全血浓度≥20 ng/ml。B组和C组的所有免疫抑制药物均通过静脉给药。我们进行了原位小肠移植并采用全身静脉引流。移植时，在十二指肠第二部远端和直肠近端切除受体肠段；通过十二指肠空肠吻合术恢复肠道连续性；在远端行回肠造口术以便每日进行活检。我们根据评分系统（无、轻度、中度和重度排斥反应）分别对间质排斥和血管排斥进行分级。移植后7天、14天和21天无排斥反应的移植物存活率在A组分别为38%、19%和0%；在B组分别为93%、93%和62%；在C组分别为100%、91%和82%（P < 0.001）。比较免疫抑制组的排斥反应，C组（FK506）比B组（CsA - ATG）有更强的排斥倾向；然而，B组和C组之间的显著差异仅在移植后的个别天数出现，而非随时间变化。B组和C组因不可逆排斥导致的死亡率无显著差异（P = 0.8），但这两个免疫抑制组均显著优于A组（P < 0.001）。由于C组感染率较低，C组猪的存活时间显著长于B组（P = 0.001）。移植后血清白细胞介素2和7水平与排斥反应分级无关。仅在29%的A组、73%的B组和77%的C组猪的皮肤中观察到移植物抗宿主反应；肝脏和自身肠道未受累。（摘要截选至400字）
