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

手术技术和免疫抑制的进步使得小肠移植（SBTx）成为不可逆肠衰竭患者的一种确定的治疗方法。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，包括对缺血/再灌注（IR）损伤的保护。在本研究中，我们旨在建立一种基于基因治疗的SBTx新策略。在大鼠中，利用编码CTLA4Ig或CD40Ig的腺病毒载体阻断CD80/86-CD28和/或cd40 - cd154共刺激信号可显著延长完全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，然而，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治疗在SBTx中取得了成功，但腺病毒介导的基因治疗变得不切实际，因为在临床试验中这种治疗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。我们在啮齿动物移植模型中检测了新的来氟米特衍生物FK778/FK779和一种新的NF-kB抑制剂DHMEQ的免疫抑制特性，并证明这些新开发的药物具有显著的预防急性细胞排斥和延长同种异体移植物存活的能力。同样在这项研究中，我们已经表明，器官内脂质过氧化程度与I/R损伤的严重程度相关，自由基清除剂依达拉奉和NF-kB抑制剂DHMEQ可以改善狗和大鼠的FR损伤。虽然需要进一步的研究来建立SBTx的新策略，但我们得出的结论是，共刺激信号阻断剂和NF-kB抑制剂是预防小肠同种异体移植排斥反应和保存/IR损伤的有效药物，似乎是SBTx临床应用的潜在候选药物。

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.