Adenovirus-mediated CTLA4-FasL gene transfer prevents autoimmune diabetes in mice induced by multiple low doses of streptozotocin  

Adenovirus-mediated CTLA4-FasL gene transfer revents autoimmune diabetes in mice induced by multiple low doses of streptozotocin

作　　者：JINYongzhu WANGGuangming LIAiling HAOJie GAOXiang XIEShusheng 

机构地区：[1]DepartmentofImmunology,PekingUniversityHealthScienceCenter,Beijing100083,China

出　　处：《Chinese Science Bulletin》2004年第5期476-481,共6页

摘　　要：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 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 CTLA4.FasL gene (AdCTLA4-FasL). A single injection of 2 × 10^8 plaque forming units OPFU) 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, signifieantly increased apoptosis of pancreatic lymphocytes, quantitatively reduced IFN-γ, and Vβ8.2 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.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 CTLA4-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 reduced IFN-γ and Vβ8.2 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.

关 键 词：腺病毒 基因转移 自身免疫性糖尿病 链脲佐菌素 

分 类 号：R587.1[医药卫生—内分泌]