Apheresis in Thoracic Organ Transplantation

The beneficial addition of cyclosporine and tacrolimus to the immunosuppressive armamentarium have unfortunately only partially solved the problems of acute and chronic rejection in thoracic organ transplantation. Apheresis techniques offer creative avenues for modifications of allograft rejection. Plasmapheresis can be used for mechanical reduction of alloantibody burdens in highly sensitized patients and permit transplantation in an otherwise almost hopeless situation and can also be used on a short-term basis for the treatment of acute humoral rejection. Extracorporeal photochemotherapy holds promise as a possibly synergistic adjunct to conventional therapy and may even reduce the severity of graft vasculopathy. The increasing availability of highly specific column immunoadsorption techniques may further increase the applicability of apheresis in transplantation.     

Mycophenolate mofetil in pediatric renal transplantation

The use of mycophenolate mofetil (MMF) in adult renal transplantation has been associated with significantly decreased incidence of acute rejection. However, limited data are available for children after renal transplantation. A total of 67 patients undergoing renal transplantation at the University of Alabama at Birmingham, AL, USA and Children's Hospital of Boston, MA, USA were enrolled into the Cooperative Clinical Trials in Pediatric Transplantation randomized controlled trial of induction with OKT3 vs. i.v. cyclosporin A (CsA) at the time of transplantation. The first 31 patients entered were begun on azathioprine (AZA), 2 mg/kg on the first post-operative day. The subsequent 36 patients were begun on MMF, 1000 mg/m2/d. Other maintenance immunosuppression included oral CsA and Prednisone. Biopsy confirmation was obtained for all suspected rejection episodes. Glomerular filtration rate (GFR) was calculated using the Schwartz formula. Data were analyzed using Kaplan Meier survival curves and compared using log-rank tests. At the time of analysis, 52 patients (mean age 10.1 +/- 5 yr) had completed at least 12 months and 15 others had completed at least 6 months of follow-up post-transplantation. Of these, there were 39 male/28 female; 48 white/15 black/4 other; 49 living donor/18 cadaver donor. There were no significant differences in the incidence of rejection episodes, number of rejection episodes, the GFR at 6 and 12 months, allograft, or patient survival between patients receiving MMF vs. AZA. We could demonstrate no significant differences in these outcomes based on sex, race or induction therapy, leading to the conclusion that pediatric patients treated under a consistent protocol in two institutions have no improvement in short-term allograft outcome with the addition of MMF therapy.     

Comparative analysis of three genetic modifications designed to inhibit human serum‐mediated cytolysis

Hyperacute rejection (HAR) remains a critical immunologic hurdle in the development of xenogeneic organs for human transplantation. Strategies that simultaneously eliminate both natural antibody reactivity and complement activation on the xenogeneic cell surface may be the best approach to achieve clinical application of xenogeneic vascularized organ transplantation. We have developed multiple lines of genetically manipulated mice to evaluate the combination of different genetic approaches aimed at inhibiting antibody and complement-mediated cell lysis. We utilized transgenic mice expressing the human complement inhibitor, CD59, the human 1,2-fucosyltransferase (H-transferase, HT) and the α1,3-galactosyltransferase (α1,3-GT) knock-out mouse line (Gal KO). Our data show that expression of hCD59 in combination with HT expression or the null phenotype of α1,3-GT are equally effective at preventing human serum-mediated cytolysis. Interestingly, the triple combination affords no additional protective effect. Therefore, coexpression of HT and a complement inhibitor is the most immediate strategy to genetically engineer transgenic pigs to be used as xenogeneic donors.     

Compstatin, a peptide inhibitor of C3, prolongs survival of ex vivo perfused pig xenografts

Fiane AE, Mollnes TE, Videm V, Hovig T, Høgåsen K, Mellbye OJ, Spruce L, Moore WT, Sahu A, Lambris JD. Compstatin, a peptide inhibitor of C3, prolongs survival of ex vivo perfused xenografts. Xenotransplantation 1999; 6: 000-000 ©Munksgaard, Copenhagen Compstatin, a newly described C3-binding peptide, inhibits complement activation by blocking C3 convertase-mediated cleavage of C3. As the complement activation is an essential part of the rejection reaction, we evaluated the ability of Compstatin to delay or prevent hyperacute rejection in an ex vivo xenograft model. Porcine kidneys were perfused with fresh human blood containing either Compstatin (n=6) or a control agent (n=6). Graft survival and activation of complement, leukocytes and platelets both in the fluid phase and in the tissue were examined. The survival of the Compstatin-perfused kidneys (median, 380 min) was significantly (P=0.0036) longer than that of the controls (median, 90 min). The classical complement pathway (C1rs-C1inhibitor and C4bc) was significantly and equally activated in both groups during the first 60 min. C3 activation products increased fivefold and terminal complement complex eightfold in the control group, but no increase occurred in the Compstatin group during this period. Immunohistochemistry showed less C3 and fibrin deposition and immuno-electron microscopy showed less terminal SC5b-9 complement complex deposition in the Compstatin group. A significant change in total white cells, neutrophils, myeloperoxidase, and expression of the surface activation markers CD11b (CR3) and CD35 (CR1) and CD62 L ( l -selectin) was observed in both groups. Leukocyte activation was lower in the Compstatin group but the difference was not statistically significant. There were no differences in platelet counts, thrombospondin, soluble P-selectin or β-thromboglobulin between the groups. We conclude that Compstatin prolongs graft survival and suggest that it may be a useful agent for attenuating hyperacute rejection by inhibiting C3 and thus terminal complement pathway activation.     

Delayed graft function: risk factors and the relative effects of early function and acute rejection on long-term survival in cadaveric renal transplantation

Delayed graft function (DGF) and acute rejection have both been associated with reduced renal allograft survival. In some studies, they have been shown to have an interactive effect. We studied the risk factors for DGF and the relative impact of DGF and rejection on both short- and long-term survival in recipients of cadaveric renal transplants. Data from the Oxford Transplant Centre Database were assessed on 710 cadaver allografts over a 10-yr period, during which time all recipients received cyclosporin-based immunosuppressive protocols. The interaction between DGF and acute rejection was examined using logistic and Cox multivariate regression. Long cold ischaemia time (CIT), sensitisation and older donor age were found to be independent predictors of DGF. The occurrence of DGF resulted in a reduced 5-yr survival (56 vs. 75%). However, the effect of DGF was confined to the first year post-transplant, as there was no significant difference in survival, as measured by half-life (t1/2) of grafts functioning at 1 yr, with DGF alone and a group with good early function (t1/2 = 21.3 vs. 20.0 yr). There was no increase in acute rejection in grafts with DGF. However, the combination of DGF and acute rejection resulted in the worst short-term graft survival (68% at 1 yr, compared to 92.3% in those grafts with no DGF or acute rejection) and this continued over the long term (t1/2 = 10.5 yr). These data suggest that early function is critical to the success of renal transplantation. The effects of DGF are limited to the first year post-transplant. Long-term graft survival may be improved by efforts to limit CITs, particularly for grafts from older donors and sensitised recipients.     

肾移植术后应用FK506抗排斥治疗的临床研究

目的　观察ＦＫ５０６ 在肾移植术后抗排斥治疗的效果及副作用。　方法　对肾移植术后单独应用环孢素Ａ（ＣｓＡ）５０ 例和术后应用ＦＫ５０６ ５０ 例（ 术后２４ 小时应用ＦＫ５０６ ４０ 例,ＣｓＡ 中毒后改ＦＫ５０６ １０ 例）患者进行比较。　结果　ＣｓＡ 组发生急性排斥反应（ＡＲ）９ 例,发生率为１８ ％ ,逆转８ 例（８８ ％） ,肾功能在２ ～２６ 天恢复正常３８ 例（７６ ％） ,肺部感染２ 例,泌尿系感染１ 例,肾中毒２例,肝中毒３ 例,高血糖２ 例,腹泻１ 例,摘肾１ 例。ＦＫ５０６ 组ＡＲ４ 例均逆转,肾功能２～１３ 天恢复正常４０ 例（８０％ ）,高血糖１４ 例（２８％ ）,肾中毒２ 例,肝中毒１ 例,腹泻２２ 例（４４％ ）,１ 例因肺部感染、高血糖难以控制仍改用ＣｓＡ。应用ＣｓＡ 肝中毒的１０ 例患者改用ＦＫ５０６ 后肝功能７ ～１６ 天全部恢复正常。　结论　肾移植术后应用ＦＫ５０６ 安全有效,排斥率明显降低,副作用小,但对长期存活的影响及并发症还需进一步观察。     

移植肝的急性排斥反应

目的 分析供、受者年龄,受者性别,术前原发疾病,肝,肾功能以及免疫抑制剂的使用对移植肝的急性排斥反应产生的影响。方法 对玛丽医院从１９９１年１０月至１９９８年９月发生移植急性排斥反应的所有病例进行回顾性分析。结果 ８１例患者做了８３例次肝移植,共发生急性排斥反应７０例次,发生率为５３％。经过统计学分析,发现使用普乐可复（ＦＫ５０６）的受者,急性排斥反应的发生率较使用环孢素Ａ和硫唑嘌呤组为低,供,受     

脂肪源性干细胞输注剂量对抑制大鼠心脏移植急性排斥反应的影响

目的 观察供体同系脂肪源性干细胞（ADSCs）对大鼠心脏移植急性排斥反应的抑制作用,并探讨其输注剂量对其抑制作用的影响。方法 以Wistar、SD大鼠为供受体建立心脏颈部异位移植模型,术毕静脉输注不同剂量ADSCs。实验分组：①对照组,注射等体积3ml 0.9% NaCl;②输注ADSCs,0.1×10⁶/只组;③输注ADSCs,1×10⁶/只组;④输注ADSCs,10×10⁶/只组;每组12只。比较各组移植心脏存活时间和组织病理学改变,及检测血清中IL-2和IL-10的表达。结果 对照组移植心脏平均存活6.2±1.2天,输注不同剂量ADSCs （0.1×10⁶/只,1×10⁶/只,10×10⁶/只）各组移植心脏平均存活分别为10.0±1.3天,13.3±2.2天,21.0±4.9天。与对照组比较,输注各组移植心脏存活均得到显著延长（P<0.05）。病理学检查发现ADSCs输注组淋巴细胞浸润、心肌间质水肿、心肌细胞损害均较对照组减轻。与对照组比较,ADSCs输注组大鼠血清中IL-2浓度随着ADSCs浓度增加而逐步降低,且ADSCs 10×10⁶/只组差异有统计学意义（P=0.021）;IL-10浓度呈剂量相关性逐渐增高,各组间比较差异有统计学意义（P<0.05）。结论 静脉输注供体同系ADSCs,可以延长大鼠颈部移植心脏的存活时间,减轻急性排斥反应的程度,并具有一定剂量依懒性;其中以10×10⁶/只剂量的抗排斥作用最显著。     

再次背驮式肝移植并肾移植治疗肝移植术后慢性排斥并肾功能不全(附一例报告)

目的 探讨用原位背驮式肝移植并肾移植术治疗先天性多囊病肝移植术后慢性排斥并肾功能不全。方法 供肝取自同血型脑死亡供体;顺利切除原病肝,行原位再次背驮式新肝植入及右髂窝肾移植。结果 再次背驮式肝移植并肾移植手术成功,供肝,供肾功能良好,术后１８ｄ死于曲霉菌性腹膜炎所致的多器官功能衰竭。结论 背驮式技术适用于再次肝移植;肝移植术后慢性排斥反应并肾功能不全是联合肝肾移植的适应证。