Genetic engineering of a suboptimal islet graft with A20 preserves β cell mass and function
Genetic engineering of a suboptimal islet graft with A20 preserves β cell mass and function
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DOI：
10.4049/jimmunol.170.12.6250
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发表时间：
2003-06-15
影响因子：
4.4
通讯作者：
Ferran, C
中科院分区：
文献类型：
--
作者：
Grey, ST;Longo, C;Ferran, C
为了恢复正常血糖，需要向I型糖尿病患者移植过多的朗格汉斯胰岛(每个受者两到四个胰腺)。低氧、营养缺乏、局部炎症和β细胞炎症反应(上调依赖于核因子-kappaB的基因，如iNOS)导致移植后早期的β细胞破坏。携带抗炎和抗凋亡基因的胰岛基因工程可以防止胰岛β细胞丢失和原发的无功能。我们在体外已经证明，A20抑制胰岛中核因子-kappaB的激活，并保护其免受细胞因子和死亡受体介导的细胞凋亡的影响。在体内，对新移植的胰岛进行保护将减少成功移植所需的胰岛数量。将500只B6/AF(1)小鼠胰岛移植到同基因糖尿病受体，5天内治愈率为100%。250个胰岛移植的治愈率仅为20%。250个高表达A20的胰岛移植的治愈率为75%，平均治愈时间为5.2天，与500个胰岛移植的结果相当。表达A20的胰岛保留了功能性的β细胞团，并免受细胞死亡的影响。这些数据表明A20是一种理想的胰岛移植细胞保护性基因治疗候选方案。
Transplantation of an excessive number of islets of Langerhans (two to four pancreata per recipient) into patients with type I diabetes is required to restore euglycemia. Hypoxia, nutrient deprivation, local inflammation, and the beta cell inflammatory response (up-regulation of NF-kappaB-dependent genes such as inos) result in beta cell destruction in the early post-transplantation period. Genetic engineering of islets with anti-inflammatory and antiapoptotic genes may prevent beta cell loss and primary, nonfunction. We have shown in vitro that A20 inhibits NF-kappaB activation in islets and protects from cytokine- and death receptor-mediated apoptosis. In vivo, protection of newly transplanted islets would reduce the number of islets required for successful transplantation. Transplantation of 500 B6/AF(1) mouse islets into syngeneic, diabetic recipients resulted in a cure rate of 100% within 5 days. Transplantation of 250 islets resulted in a cure rate of only 20%. Transplantation of 250 islets overexpressing A20 resulted in a cure rate of 75% with a mean time to cure of 5.2 days, comparable to that achieved with 500 islets. A20-expressing islets preserve functional beta cell mass and are protected from cell death. These data demonstrate that A20 is an ideal cytoprotective gene therapy candidate for islet transplantation.