Application of Gene Engineering in Allo and Xeno Organ Transplantation

由于免疫抑制和器官保存技术的发展，器官移植已成为治疗晚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，异种移植存在着巨大的免疫障碍，即超急性排斥反应，传统的免疫抑制疗法无法抑制这种排斥反应。为了突破常规免疫抑制和常规保存技术的局限性，我们研究了基因治疗技术在器官移植中的作用。1)采用腺病毒介导的CTLA4Ig cDNA基因转染，基因表达期维持数月，载体二次给药易感。在大鼠同种异体移植模型中，该载体通过全身途径转移可抑制移植物排斥反应，随后移植物接受。在同种异种移植模型中，该基因与fk502基因联合转染可显著延长移植体的存活时间。6.2)腺病毒介导的α (1,2) focusyltransferase (FT) cDNA基因转染可下调α(1,3)半乳糖转移酶（GT）基因的表达，抑制异种移植模型的超急性排斥反应。3)利用腺病毒介导的白细胞介素10 （il10）基因转染，抑制肝脏缺血再灌注损伤，抑制细菌性腹膜炎。4)利用腺病毒介导的il - 12 (interleukin 12, il - 12) cDNA基因转染，联合抗癌药物抑制多发性肝癌或肝转移。这些结果表明，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，我们研究了在纤维旋叶末端添加20个残基树脂的新型腺病毒载体的效果。使用该载体，我们证明了与传统载体相比，转导效率提高了20到50倍。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