【作者】 陈旭明；

【导师】 张立煌；

【作者基本信息】 浙江大学 ， 免疫学， 2005， 硕士

【摘要】 小肠移植(small bowel transplantation,SBT)是解决终末期肠功能衰竭及先天性肠畸形的最根本途径,Dettering早在1964年便开始应用于临床,但因严重的排斥反应而失败。因小肠及其系膜含有大量的淋巴组织,加之小肠移植后肠功能恢复困难,肠腔细菌易位和严重的感染等,使之成为器官移植中排斥反应发生率最高、最重的脏器,临床进展缓慢。尽管环孢素A(cyclosporine A,CsA)的应用改善了小肠移植的实验结果,并且在使用免疫抑制剂他克莫司(tacrolimus,FK506)下移植鼠可获得长期存活,但在人类移植后的三大难题——严重的排斥反应、肠功能的恢复和感染仍未得到实质性的改善。虽然如此,经过数10年的努力,小肠移植已从实验研究发展成为肠衰竭的标准治疗措施之一,技术上逐渐完善,病人的生存率也有了很大的提高。 FK506是一种新型高效的免疫抑制剂,自1990年代初应用以来,它的效用已经在实验及临床的器官移植中得到肯定。FK506通过阻断钙离子依赖的白介素2(interleukin-2,IL-2)转录的信号通道,抑制其生成而抑制T-淋巴细胞的免疫应答。但FK506的毒副作用(肾毒性、神经毒性及高甘油血症)随着剂量的增大而增大,为了降低FK506的毒副作用而又能达到相同的免疫抑制效果,人们多采用联合用药的方式,并取得了成功。 乌司他丁(ulinastatin,UTI)作为一种酶抑制剂,据报道可抑制多种蛋白酶,还可以稳定溶酶体膜,清除氧自由基,抑制炎性细胞因子的释放,在临床已经应用于急性胰腺炎的治疗,抗休克治疗,抗手术刺激等,在器官移植中亦得到了应用。目前发现UTI对多种细胞因子(IL-2、interleukin-8等)有抑制作用,且通过对多种酶的抑制具有对肾脏的保护作用。故UTI具有广泛更多还原

【Abstract】 Small bowel transplantation(SBT) is the radical way of therapy for patients with intestinal failure and congenital abnonnality. Dettering had been implied SBT in clinic since 1964, but not successful due to serious rejection. Because intestine and its mesentery contain large amount lymph tissues, and because of slow recovery of intestinal function, bacterial translocation and serious infection, Small bowel becomes the most serious organ that occurs rejection and has the highest incidence of rejection in organ transplantation. So the development of human SBT is very slow in clinic. For human being, there are still three ticklers-serious rejection, recovery of function, and infection after SBT that have not been improved in essence, although application of Cyclosporine A (CsA) has greatly improved the experimental results of SBT, and the rats can survive for long-term after transplantation under the treatment of immunosuppressant-tacrolimus(FK506). Intestinal transplantation has evolved from an experimental procedure to one of the standard therapy measures for patients with intestinal failure through endeavors for several decades , which with gradually advancing technique and with greatly improving the survival rate of recipients.FK506 is a novel efficient immunosuppressant, and its effect of immunosuppression has manifested by animal experiments and clinical organ transplantations since it was applied in early 1990s. FK506 suppress the generation of interleukin-2 via block the signal passageway of its transcription that calcium dependent, and then inhibit the immuno-response of T lymphocyte. But the adverse effects (nephrotoxicity, neurotoxicity, and hyperglycemia) of tacrolimus will become increasing company with the dose upwards. People usually adopt combination with an another immunosuppressant in order to reduce its adverse effects as to abtain the same efficiency, and have achieved some success. As a protease inhibitor, it is reported that ulinastatin (UTI) can suppress sorts of proteases ,stabilize lysosomal membranes, clear up oxygen free radicals (OFRs), and can inhibit expression of inflammatory cytokines. It has been used in treatmentof acute pancreatitis, protect against shock and operation. It is used in organ transplantation too. Presently, it is found that UTI possesses suppressive effects to some inflammatory cytokines (interleukin-2, interleukin-8, etc), and can protect kidney function via suppresses several proteases. So there are great prospective applications with UTI.We successfully established the stable heterotopic segment intestinal transplantation in rat by endeavors for several months, and have carried out a series of studies on base of the models. First, we divided recipients into 6 groups in random. In these 6 groups, FK506 and UTI are applied respectively or together so as to observe the immunosuppressive effects of FK506 and UTI in rat SBT through contrasting recipients survival and pathology of grafts after operation. In result, pathologic slices showed that rejections of grafts(donor intestine) in FK506 group and FK506+UTI group were significantly milder than that in the other groups. In survival, there were very significant differences between FK506 group, FK506+UTI group and control group, UTI group(p<0.01); Significant differences also existed between 1/2FK506 group、 1/2FK506+UTI group and control group(p<0.05), in which it showed very significant differences between 1/2FK506+UTI group and control group (p<0.01); In addition, differences between FK506 group、 FK506+UTI group andl/2FK506 group showed significantly, and in which it showed very significant differences between FK506+UTI group and 1/2FK506 group (p<0.01); Whereas there was no difference among FK506 group、 FK506+UTI group and 1/2FK506+UTI group (P>0.05); And had no difference between control group and UTI group.In every organ transplantation, the graft will be confronted to a procedure of ischemia-reperfusion(I/R) inevitably, and will be injured in a certain degree during this procedure. Because of its unique characteristic更多还原