Adenovirus-mediatedCTLA4-FasL gene transfer prevents autoimmune diabetes in mice induced by multiple low doses of streptozotocin

Type 1 diabetes is the result of a selective destruction of insulin-producing β cells in pancreatic islets by autoreactive T cells. Depletion of autoreactive T cell through apoptosis may be a potential strategy for the prevention of autoimmune diabetes. Simultaneous stimulation of Fas-mediated pathw...

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Bibliographic Details
Published in:Chinese science bulletin 2004-03, Vol.49 (5), p.476-481
Main Authors: Jin, Yongzhu, Wang, Guangming, Li, Ailing, Hao, Jie, Gao, Xiang, Xie, Shusheng
Format: Article
Language:English
Subjects:
Adenoviruses
Apoptosis
Autoimmune diseases
Beta cells
CTLA-4 protein
Depletion
Diabetes
Diabetes mellitus (insulin dependent)
FasL protein
Fusion protein
Gene expression
Gene therapy
Insulin
Lymphocytes
Lymphocytes T
Mixed leukocyte reaction
Pancreas
Prevention
Stimulation
Streptozocin
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Summary:Type 1 diabetes is the result of a selective destruction of insulin-producing β cells in pancreatic islets by autoreactive T cells. Depletion of autoreactive T cell through apoptosis may be a potential strategy for the prevention of autoimmune diabetes. Simultaneous stimulation of Fas-mediated pathway and blockade of costimulation by a CTLA4-FasL fusion protein has been reported to lead to substantial inhibition of mixed lymphocyte reaction and enhancedin vitro apoptosis of peripheral lymphocytes. To test the feasibility of CTLA4-FasL-based gene therapy to prevent autoimmune diabetes, we developed recombinant adenovirus containing humanCTLA4- FasL gene (Ad-CTLA4-FasL). A single injection of 2 ×108 plaque forming units (PFU) of AdCTLA4-FasL via tail vein dramatically reduced the incidence of autoimmune diabetes in mice induced by multiple low doses of streptozotocin. Ad-CTLA4-FasL administration maintained islet insulin content, significantly increased apoptosis of pancreatic lymphocytes, quantitatively reducedIFN- γ andVβ8.2 TCR chain mRNA expression in pancreatic lymphocytes. These results indicate the therapeutic potential of simultaneous stimulation of Fas-mediated pathway and blockade of costimulation by adenovirus-mediated CTLA4-FasL gene transfer in the prevention of autoimmune diabetes.
ISSN:1001-6538
2095-9273
1861-9541
2095-9281
DOI:10.1007/BF02900968