Development of a gene therapy based new strategy in small bowel transplantation

开发基于基因治疗的小肠移植新策略

基本信息

批准号：
16390368
负责人：
FURUKAWA Hiroyuki
金额：
$ 9.09万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390368/
关键词：
Small bowel transplantation Gene therapy Costimulatory signals Immunosuppression Ischemia reperfusion NF-kB Adeno virus DHMEQ 拒絶反応マウス小腸虚血再灌流障害ラット CTLA4Ig CD40Ig

项目摘要

Advances in both surgical techniques and immunosuppression have made small bowel transplantation (SBTx) as an established treatment for patients with irreversible intestinal failure. However, further refinements in immunosuppression and graft preservation including protection against ischemia/reperfusion (IR) injury are necessary to improve SBTx patient survival and their quality of life. In this study, we aimed to establish a new strategy for SBTx based on a gene therapy. In rats, blockade of CD80/86-CD28 and/or CD4O-CD154 costimulatory signals by applying the adenoviral vector coding CTLA4Ig or CD40Ig markedly prolonged a fully MHC mismatched small intestinal allograft. Most of these allografts survived for over 300 days, however, progression of chronic rejection was inevitable. Despite the success of this gene therapy based costimulation blockade in SBTx, adeno-virus mediated gene therapy became unpractical because serious side-effects occurred following such therapy during its clinical trials. The event has led us to reconsider the approaches to accomplish our aim of this study. We have examined the immunosuppressive properties of new Leflunomide derivatives, FK778/FK779 and a novel NF-kB inhibitor, DHMEQ in rodent transplantation models, and demonstrated that these newly developed agents have a significant ability to prevent acute cellular rejection and to prolong allograft survival. Also in this study, we have shown that a degree of lipid peroxidation within the organ correlates with severity of I/R, injury, and that the free radical scavenging agent, Edaravone and NF-kB inhibitor DHMEQ ameliorate FR injury in dogs and rats. Although further studies are warranted to establish a new strategy in SBTx, we conclude that especially, costimulatory signal blockers and NF-kB inhibitor are effective agents for preventing small bowel allograft rejection and preservation/IR injuries that seems to be potential candidates for clinical use in SBTx.

手术技术和免疫抑制的进步都使小肠移植（SBTX）成为针对不可逆肠道衰竭患者的既定治疗方法。但是，对于改善SBTX患者生存及其生活质量，必要进行免疫抑制和移植物保存的进一步改进，包括防止缺血/再灌注（IR）损伤。在这项研究中，我们旨在建立基于基因疗法的SBTX的新策略。在大鼠中，通过应用腺病毒矢量编码CTLA4IG或CD40IG的封闭CD80/86-CD28和/或CD4O-CD154 cost刺激信号明显延长了完全MHC不匹配的小肠道同种异体移植物。这些同种异体移植物中的大多数存活了300天，但是，慢性排斥的进展是不可避免的。尽管这种基于基因疗法的COTAIMATION BLOKADE在SBTX中取得了成功，但腺病毒介导的基因疗法变得不切实际，因为在临床试验期间这种治疗后发生了严重的副作用。该活动使我们重新考虑了实现这项研究目标的方法。我们已经检查了新的Leflunomide衍生物FK778/FK779和一种新型的NF-KB抑制剂，啮齿动物移植模型中的DHMEQ的免疫抑制特性，并证明这些新发达的药物具有防止急性细胞抑制和延长Allogrogn Allograft Argaft Surverival的重要能力。同样在这项研究中，我们已经表明，器官内的一定程度的脂质过氧化与I/R，损伤的严重程度相关，并且自由基清除剂，Edaravone和NF-KB抑制剂DHMEQ在狗和大鼠中会改善FR损伤。尽管有必要进一步的研究在SBTX中建立新的策略，但我们得出的结论是，尤其是，Costimulation Signerative Blostance阻滞剂和NF-KB抑制剂是防止小肠同种异体移植和保存/IR伤害的有效药物，这似乎是SBTX临床使用的潜在候选者。