Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38103-3308, USA.
Mol Pharm. 2010 Oct 4;7(5):1655-66. doi: 10.1021/mp100070j. Epub 2010 Aug 2.
Islet transplantation has the potential to treat type I diabetes, however, its clinical application is limited due to the massive apoptotic cell death and other post-transplantation challenges to islet grafts. Therefore, the objective of this study was to determine whether ex vivo transduction of rat insulin producing INS-1E cells and human islets with adenoviral vector encoding human X-linked inhibitor of apoptosis (Adv-hXIAP) can protect them from inflammatory cytokines and improve their viability and function. There was dose dependent XIAP gene expression. XIAP expression led to decrease in the activities of caspase 3/7, 8 and 9, resulting in reduced apoptotic cell death induced by a cocktail of inflammatory cytokines such as IL-1β, TNFα, and IFNγ. Prolonged normoglycemic control could be achieved by transplantation of Adv-XIAP transduced human islets under the kidney capsule of streptozotocin induced diabetic NOD-SCID mice. Immunohistological staining of the islets bearing kidney sections at day 42 after transplantation was positive for insulin. Moreover, the protective effect of XIAP was reversed by coadministration of XIAP inhibitor embelin. These results indicate that ex vivo transduction of islets with Adv-XIAP will decrease cytokine induced apoptosis and improve the outcome of islet transplantation.
胰岛移植具有治疗 1 型糖尿病的潜力，但由于胰岛移植物大量凋亡细胞死亡和其他移植后挑战，其临床应用受到限制。因此，本研究的目的是确定腺病毒载体编码人 X 连锁凋亡抑制剂（Adv-hXIAP）转导大鼠胰岛素分泌 INS-1E 细胞和人胰岛是否可以保护它们免受炎症细胞因子的影响，提高它们的活力和功能。存在剂量依赖性 XIAP 基因表达。XIAP 表达导致 caspase 3/7、8 和 9 的活性降低，导致由 IL-1β、TNFα 和 IFNγ 等炎症细胞因子鸡尾酒诱导的凋亡细胞死亡减少。通过将 Adv-XIAP 转导的人胰岛移植到链脲佐菌素诱导的糖尿病 NOD-SCID 小鼠的肾包膜下，可以实现延长的正常血糖控制。移植后 42 天，胰岛携带的肾切片的免疫组织化学染色呈胰岛素阳性。此外，XIAP 抑制剂 embelin 的共同给药逆转了 XIAP 的保护作用。这些结果表明，Adv-XIAP 转导胰岛可减少细胞因子诱导的凋亡，改善胰岛移植的效果。
