Adenovirus-Mediated Ctla4-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 P 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 enhanced in vitro apoptosis of peripheral lymphocytes. To test the feasibility of CTLA4-FasL- based gene therapy to prevent autoimmune diabetes, we developed recombinant adenovirus containing human C7LA4-FasL gene (Ad-CTLA4-FasL). A single injection of 2X10(8) 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. AdCTLA4-FasL administration maintained islet insulin content, significantly increased apoptosis of pancreatic lymphocytes, quantitatively reduced IFN-gamma and Vbeta8.2 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.