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.
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.
Department of Metabolism and Aging, The Scripps Research Institute-Florida, Jupiter, FL, USA.
R R
RR
Flores
Department of Metabolism and Aging, The Scripps Research Institute-Florida, Jupiter, FL, USA.
L
L
Zhou
Department of Metabolism and Aging, The Scripps Research Institute-Florida, Jupiter, FL, USA.
P D
PD
Robbins
D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000517:prevention & control; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D015847:Interleukin-4