Simultaneous stimulation of Fas-mediated apoptosis and blockade of costimulation prevent autoimmune diabetes in mice induced by multiple low-dose streptozotocin.
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.
Jin
Y
Y
Department of Immunology, Peking University Health Science Center, Beijing, People's Republic of China.
Qu
A
A
Wang
G M
GM
Hao
J
J
Gao
X
X
Xie
S
S
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D017209:Apoptosis; D060908:CTLA-4 Antigen; D002455:Cell Division; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D053222:Fas Ligand Protein; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D007515:Islets of Langerhans / Q000276:immunology*; D008099:Liver / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D014158:Transcription, Genetic
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins