DNA vaccination encoding glutamic acid decarboxylase can enhance insulitis and diabetes in correlation with a specific Th2/3 CD4 T cell response in non-obese diabetic mice.
DNA vaccination encoding beta cell autoantigens has been shown very recently to prevent type I diabetes in non-obese diabetic (NOD) mice. However, DNA vaccination encoding microbial or reporter antigens is known to induce specific long-lasting CD4 Th1 and strong cytolytic CD8 T cell responses. As this immune phenotype is associated strongly with beta cell destruction leading to diabetes, we have chosen to study the effects of plasmids encoding glutamic acid decarboxylase (GAD), a crucial beta cell autoantigen, in female NOD mice that developed a 'moderate' diabetes incidence. In the present study, 3-week-old female NOD mice were vaccinated twice in tibialis muscles with plasmid-DNA encoding 65-kDa GAD or betagalactosidase. In GAD-DNA immunized mice, diabetes cumulative incidence (P < 3.10(-3)) and insulitis (P < 7.10(-3)) increased significantly. Simultaneously, DNA immunization induced GAD-specific CD4 T cells secreting interleukin (IL)-4 (P < 0.05) and transforming growth factor (TGF)-beta (P = 0.03). These cells were detected in spleen and in pancreatic lymph nodes. Furthermore, vaccination produced high amounts of Th2 cytokine-related IgG1 (P < 3.10(-3)) and TGF-beta-related IgG2b to GAD (P = 0.015). Surprisingly, diabetes onset was correlated positively with Th2-related GAD-specific IgG1 (P < 10(-4)) and TGF-beta-related IgG2b (P < 3.10(-3)). Moreover, pancreatic lesions resembled Th2-related allergic inflammation. These results indicate, for the first time, that GAD-DNA vaccination could increase insulitis and diabetes in NOD mice. In addition, our study suggests that Th2/3 cells may have potentiated beta cell injury.
Gauvrit
A
A
Immuno-Endocrinology Unit, ENVN/INRA/University, Nantes, France.
Debailleul
M
M
Vu
A-T
AT
Sai
P
P
Bach
J-M
JM
D000818:Animals; D002455:Cell Division / Q000276:immunology; D004268:DNA-Binding Proteins / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D005260:Female; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018482:Muscle, Skeletal / Q000201:enzymology; D010957:Plasmids; D016176:T-Lymphocyte Subsets / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D019444:Vaccines, DNA / Q000276:immunology*; D001616:beta-Galactosidase / Q000378:metabolism
D004268:DNA-Binding Proteins; C078422:TH3 protein; D019444:Vaccines, DNA; D001616:beta-Galactosidase; D005968:Glutamate Decarboxylase