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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使得小肠移植（SBTx）成为不可逆性肠衰竭患者的既定治疗方法。然而，为了提高 SBTx 患者的生存率和生活质量，需要进一步改进免疫抑制和移植物保存，包括防止缺血/再灌注 (IR) 损伤。在这项研究中，我们旨在建立一种基于基因疗法的 SBTx 新策略。在大鼠中，通过应用编码 CTLA4Ig 或 CD40Ig 的腺病毒载体阻断 CD80/86-CD28 和/或 CD4O-CD154 共刺激信号，可显着延长完全 MHC 错配的小肠同种异体移植物。大多数同种异体移植物存活超过 300 天，但慢性排斥反应的进展是不可避免的。尽管这种基于共刺激阻断的基因疗法在 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疗法发生了严重的副作用。这一事件促使我们重新考虑实现本研究目标的方法。我们研究了新型来氟米特衍生物 FK778/FK779 和新型 NF-kB 抑制剂 DHMEQ 在啮齿动物移植模型中的免疫抑制特性，并证明这些新开发的药物具有预防急性细胞排斥和延长同种异体移植物存活的显着能力。在这项研究中，我们还表明，器官内的脂质过氧化程度与缺血再灌注和损伤的严重程度相关，并且自由基清除剂依达拉奉和 NF-kB 抑制剂 DHMEQ 可改善狗和大鼠的 FR 损伤。尽管需要进一步研究来建立 SBTx 的新策略，但我们得出的结论是，共刺激信号阻滞剂和 NF-kB 抑制剂是预防小肠同种异体移植排斥和保留/IR 损伤的有效药物，这似乎是 SBTx 临床应用的潜在候选者。