Expression of IL-2 in β cells by AAV8 gene transfer in pre-diabetic NOD mice prevents diabetes through activation of FoxP3-positive regulatory T cells.
Expression of IL-2 in β cells by AAV8 gene transfer in pre-diabetic NOD mice prevents diabetes through activation of FoxP3-positive regulatory T cells.
复制标题
通过 AAV8 基因转移在糖尿病前期 NOD 小鼠中通过 AAV8 基因转移在 β 细胞中表达 IL-2，通过激活 FoxP3 阳性调节 T 细胞来预防糖尿病。
DOI：
10.1038/gt.2014.45
复制
发表时间：
2014
期刊：
影响因子：
5.1
通讯作者：
Robbins,PD
中科院分区：
文献类型：
--
作者：
Flores,RR;Zhou,L;Robbins,PD
我们先前证明了腹膜内递送腺相关病毒血清型8（AAV 8）稳定地转导胰腺，包括胰岛中的β细胞。我们进一步证明了在双链自身互补AAV载体中使用鼠胰岛素启动子在β细胞中特异性递送和表达靶基因至少6个月的能力。重组白细胞介素（IL）-2已被证明在几种自身免疫性疾病的小鼠模型中诱导CD 4 + CD 25+调节性T细胞（T细胞）。在此，我们评估了双链腺相关病毒血清型8-小鼠胰岛素启动子（dsAAV 8-mIP）介导的2向非肥胖糖尿病（NOD）小鼠中的胰腺β细胞的递送的作用。AAV 8-mIP介导的IL-2向10周龄NOD小鼠的胰腺β细胞的基因表达以剂量依赖性方式更多地防止NOD小鼠中高血糖症的发作，其中较低剂量的病毒比较高剂量的AAV-mIP-IL-2和IL-4更有效。此外，IL-2的局部β细胞表达增加了NOD和C57 BL/6小鼠中胰腺淋巴结（PLN）和SPL中的CD 4 + CD 25 + FoxP 3+细胞的数量。综上所述，这些结果表明，胰岛中mIL-2的局部低表达通过调节TGFAP阻止糖尿病的进展。
We previously demonstrated that intraperitoneal delivery of adeno-associated virus serotype 8 (AAV8) stably transduces the pancreas, including the β cells in the pancreatic islets. We further demonstrated the ability to deliver and express target genes specifically in β cells for at least 6 months using a murine insulin promoter in a double-stranded, self-complementary AAV vector. Recombinant interleukin (IL)-2 has been shown to induce CD4+ CD25+ regulatory T cells (Tregs) in several mouse models of autoimmune disease. Here we evaluated the effects of double-stranded adeno-associated virus serotype 8-mouse insulin promoter (dsAAV8-mIP)-mediated delivery of 2 to pancreatic β cells in non-obese diabetic (NOD) mice. AAV8-mIP-mediated gene expression of IL-2 to pancreatic β cells of 10-week-old NOD mice prevented the onset of hyperglycemia in NOD mice more in a dose-dependent manner with the lower dose of virus being more effective than a higher dose of AAV-mIP-IL-2 and IL-4. Moreover, the local β-cell expression of IL-2 increased the number of CD4+ CD25+ FoxP3+ cells in the pancreatic lymph node (PLN) and SPL in both NOD and C57BL/6 mice. Taken together, these results demonstrate that local, low expression of mIL-2 in islets prevents progress of diabetes through the regulation of Tregs.