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Prevention of autoimmune diabetes and islet allograft rejection by beta cell expression of XIAP: Insight into possible mechanisms of local immunomodulation

机译:预防自身免疫性糖尿病和胰岛异种移植物排斥β细胞表达:洞察局部免疫调节机制

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Overexpression of the X-linked inhibitor of apoptosis (XIAP) prevents islet allograft rejection. We constructed an adeno-associated virus expressing XIAP driven by the rat insulin promoter (dsAAV8-RIP-XIAP) for long-term beta-cell gene expression in vivo. Pancreatic delivery of dsAAV8-RIP-XIAP prevented autoimmune diabetes in 70% of non-obese diabetic (NOD) mice, associated with decreased insulitis. Islets from Balb/c mice transduced with dsAAV8-RIP-XIAP were protected following transplantation into streptozotocin (STZ)-diabetic Bl/6 recipients, associated with decreased graft infiltration. Interestingly, dsAAV8-RIP-XIAP transduction induced expression of lactate dehydrogenase (LDHA) and monocarboxylate transporter 1 (MCT1), two genes normally suppressed in beta cells and involved in production and release of lactate, a metabolite known to suppress local immune responses. Transduction of Balb/c islets with AAV8-RIP-LDHA-MCT1 tended to prolong allograft survival following transplant into STZ-diabetic Bl/6 recipients. These findings suggest that XIAP has therapeutic potential in autoimmune diabetes and raise the possibility that local lactate production may play a role in XIAP-mediated immunomodulation.
机译:细胞凋亡抑制剂的过表达(XIAP)可防止胰岛同种异体移植物排斥。我们构建了一种表达由大鼠胰岛素启动子(DSAAV8-RIP-XIAP)驱动的XIAP的腺相关病毒,用于体内长期β细胞基因表达。 DSAAV8-RIP-XIAP的胰腺递送阻止了70%的非肥胖糖尿病(NOD)小鼠的自身免疫糖尿病,与ultulitis降低相关。通过将DSAAV8-RIP-XIAP转导的BALB / C小鼠的胰岛受到在移植到链脲佐菌素(STZ)-Diabetic BL / 6受体后进行保护,与降低的接枝浸润相关。有趣的是,Dsaav8-RIP-XIAP转导诱导乳酸脱氢酶(LDHA)和单羧酸盐转运蛋白1(MCT1)的表达,两种基因通常在β细胞中抑制并参与乳酸的生产和释放,已知抑制局部免疫应答的代谢物。使用AAV8-RIP-LDHA-MCT1转导BALB / C胰岛,倾向于在移植到STZ-糖尿病BL / 6受体后延长同种异体移植物存活。这些研究结果表明,XIAP在自身免疫性糖尿病中具有治疗潜力,并提高局部乳酸产生可能在XIAP介导的免疫调节中发挥作用的可能性。

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