Application of Gene Engineering in Allo and Xeno Organ Transplantation

由于免疫抑制和器官保存的发展，器官移植是治疗终末期器官疾病的一种临床策略。然而，供体短缺是一个严重的问题，其次是异种移植的必要性。众所周知，异种移植在免疫学上存在很大的障碍，即超急性排斥反应，而常规的免疫抑制治疗并不能抑制这种排斥反应。为了突破传统免疫抑制技术和传统保存技术的局限性，我们研究了基因治疗技术在器官移植中的作用：1)用腺病毒介导的CTLA4Ig基因转移，基因表达可维持几个月，第二次给药敏感。在大鼠同种异体移植模型中，该载体通过全身途径转移抑制了移植物排斥反应，随后移植物被接受。在协和的Xenot…中在金黄地鼠到大鼠的再移植模型中，联合应用该基因转移和FK506.2(腺病毒介导的α(1，2)岩藻糖基转移酶(FT)基因转移)可显著延长移植物存活时间，下调α(1，3)半乳糖基转移酶(GT)基因的表达，抑制异种移植的超急性排斥反应。3)腺病毒介导的白介素10(IL10)基因转移可抑制肝脏缺血再灌注损伤，抑制细菌性腹膜炎。4)腺病毒介导的白介素12(IL12)基因转移联合抗癌药物可抑制多发性肝癌或肝转移，证明腺病毒介导的基因转移技术在器官移植中是可行的。为了构建具有器官特异性和组织特异性的基因转移载体，我们检测了含有20个树脂残基的新型腺病毒载体对纤维结节末端的影响。与常规载体相比，该载体的转导效率提高了20~50倍。较少

Organ transplantation is a clinical strategy for terminal organ diseases due to the development of both immunsuppression and organ preservation. However, the donor shortage is a serious problem, followed by the necessity of xenotransplantation. It is well known that xenotransplantation has a immunologically great obstacle, which is called hyperacute rejection, and the conventional immunosuppressive therapy can not inhibit this type of rejection. To break through the limitation of both conventional immunosuppression and conventional preservation technique, we examined the effect of gene therapy technique on organ transplantation.1) Using adenovirus-mediated gene transfer with CTLA4Ig cDNA, the gene expression period was maintained for several months, and the second administration of the vector was susceptible. In allotransplantation model of rats, the graft rejection was inhibited by this vector transfer via systemic route, which was followed by the graft acceptance. In concordant xenot … More ransplantation model of hamster-to-rat, the grafts survival was prominently prolonged in the combination with both this gene transfer and FK506.2) Using adenovirns-mediated gene transfer with alpha (1, 2) fucosyltransferase (FT) cDNA, the expression of alpha (1, 3) galactosyltransferase (GT) gene was down-regulated and the hyperacute rejection reaction was suppressed in xenotransplantation model. 3) Using adenovirus-mediated gene transfer with interleukin 1O (IL1O) , the ischemia-reperfusion injury was inhibited in the liver and the bacterial peritonitis was suppressed. 4) Using adenovirus-mediated gene transfer with interleukin 12 (IL12) cDNA, the multiple hepatic cancer or hepatic metastasis was suppressed in combination with anti-cancer drug.These results demonstrated that the adenovirus-mediated gene transfer techniques were feasible for organ transplantation. To construct the gene transfer vector with organ-specific and tissue-specific characters, we examined the effect of the novel adenoviral vector with 20 residues of resin on the end of fiber-knob. Using this vector, we demonstrated the transduction eficiency with 20 to 50 folds, compared with the conventional vector. Less