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

点击翻译按钮获取中文摘要

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.