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Tolerance induction by gene therapy in organ transplantation

器官移植中基因治疗的耐受诱导

基本信息

批准号：
13854019
负责人：
TODO Satoru
金额：
$ 78.62万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (S)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2005
项目状态：
已结题

项目摘要

In this project, we aimed to develop a strategy to achieve potent immunosuppression and to induce tolerance in organ transplantation by applying a gene therapy. We examined the effect of B7-CD28 and CD40-CD154 costimulatory signaling blockades by using adenoviral vectors coding such as CTLA4Ig and CD40Ig genes, and found that a single gene therapy is potent enough to induce antigen specific tolerance in liver transplantation using a rat model. Although such gene therapies also allowed long-term acceptance of heart and small intestinal allografts in rats, progression of chronic rejection was not fully abrogated in these transplants. The mechanism of tolerance induction by CD40Ig gene therapy was exploited, and we found that CD40Ig enhances IL-2 production in CD4^+ T cells and generates CD4^+CD25^+ regulatory T cells. Concomitant use of calcineurin inhibitors did not abolish tolerance induction by the CD40Ig gene therapy, while some treatment strategy together with calcineurin inhibition … More have accelerated chronic allograft rejection in rodent heart transplantation models. To develop a suitable adjunct therapy for the gene therapy, effects of SDF-1/CXCR4 signaling blockade, a new pirimidine synthesis inhibitor Malononitrilamides and NF-κB inhibitor DHMEQ was further examined in this study. Due to the severe side-effects of viral mediated gene therapy noted in clinical trials, we developed several ways to reduce the amount of viral vector use and also applied cre/loxP system. We also tried non-viral gene transduction by utilizing an electroporation method; however, we found that it is not practical. We therefore examined the effect of a new human CD40 monoclonal antibody, 4D11 in sub-human primate kidney transplantation. Treatment with 4D11 (10-40 mg/kg) for one or 2.5 months allowed long-term renal allograft survival, without showing adverse effects such as thromboembolism or infection, which indicating 4D11 as a promising candidate for clinical use to block CD40-CD154 interactions. Less

在这个项目中，我们的目的是开发一种策略，以实现有效的免疫抑制和诱导耐受的器官移植，通过应用基因治疗。我们通过使用编码CTLA 4 Ig和CD 40 Ig基因的腺病毒载体检测了B7-CD 28和CD 40-CD 154共刺激信号传导阻断剂的作用，并发现使用大鼠模型的单基因治疗足以诱导抗原特异性耐受。虽然这种基因疗法也允许长期接受大鼠心脏和小肠同种异体移植，慢性排斥反应的进展并没有完全消除这些移植。CD 40 Ig基因治疗诱导免疫耐受的机制已被探索，我们发现CD 40 Ig可增强CD 4 ^+ T细胞产生IL-2，并产生CD 4 ^+ CD 25 ^+调节性T细胞。同时使用钙调神经磷酸酶抑制剂并不能消除CD 40 Ig基因治疗诱导的耐受，而一些治疗策略与钙调神经磷酸酶抑制剂一起使用， ...更多信息在啮齿动物心脏移植模型中加速了慢性同种异体移植排斥反应。本研究进一步研究了SDF-1/CXCR 4信号通路阻断剂、新的嘧啶合成抑制剂丙二腈酰胺类和NF-κB抑制剂DHMEQ对基因治疗的作用，以期为基因治疗提供合适的辅助治疗。由于病毒介导的基因治疗在临床试验中注意到的严重副作用，我们开发了几种方法来减少病毒载体的使用量，并且还应用了cre/loxP系统。我们还尝试了通过利用电穿孔方法进行非病毒基因转导;然而，我们发现这是不实用的。因此，我们研究了新型人CD 40单克隆抗体4D 11在亚人灵长类动物肾移植中的作用。用4D 11（10-40 mg/kg）治疗1个月或2.5个月允许长期肾移植物存活，而没有显示出诸如血栓栓塞或感染的不良反应，这表明4D 11是用于阻断CD 40-CD 154相互作用的临床用途的有希望的候选物。少