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  • Title: Simultaneous stimulation of Fas-mediated apoptosis and blockade of costimulation prevent autoimmune diabetes in mice induced by multiple low-dose streptozotocin.
    Author: Jin Y, Qu A, Wang GM, Hao J, Gao X, Xie S.
    Journal: Gene Ther; 2004 Jun; 11(12):982-91. PubMed ID: 15042121.
    Abstract:
    Type I diabetes is the result of a selective destruction of insulin-producing beta cells in pancreatic islets by autoreactive T cells. Depletion of autoreactive T cells through apoptosis may be a potential strategy for the prevention of autoimmune diabetes. Simultaneous stimulation of the Fas-mediated pathway and blockade of costimulation by a CTLA4-Fas ligand (FasL) fusion protein has been reported to lead to enhanced in vitro apoptosis of peripheral lymphocytes. To test the feasibility of CTLA4-FasL-based gene therapy to prevent autoimmune diabetes, we developed a recombinant adenovirus containing the human CTLA4-FasL gene (AdCTLA4-FasL). A single injection of 2 x 10(8) plaque-forming units of AdCTLA4-FasL via the tail vein of mice greatly reduced the incidence of autoimmune diabetes (13%, n=15) induced by multiple low-dose streptozotocin. AdCTLA4-FasL administration abrogated pancreatic insulitis, significantly increased apoptosis of pancreatic T-lymphocytes, and altered splenocyte response to mitogenic and antigenic stimulation. These results indicate the therapeutic potential of simultaneous stimulation of the Fas-mediated pathway and blockade of costimulation by adenovirus-mediated CTLA4-FasL gene transfer in the prevention of autoimmune diabetes.
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