DNA Vaccination with Glutamic Acid Decarboxylase (GAD) Generates a Strong Humoral Immune Response in BALB/c, C57BL/6, and in Diabetes-Prone NOD Mice

Wiest-Ladenburger, Uta; Fortnagel, Anja; Richter, W; Reimann, Joerg; Bo, Boehm

doi:10.1055/s-2007-978942

Cited by 15 publications

(9 citation statements)

References 9 publications

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“…Several investigators have reported protection against autoimmune diabetes by DNA vaccination against isletcell antigens (insulin, GAD65 or other) in NOD mice or other diabetes models (Table 3). [50][51][52][53][54][55][56][57][58][59][60][61] In the vast majority of cases, DNA was delivered i.m. without electroporation.…”

Section: Dna Vaccination Against T1dmentioning

confidence: 99%

Plasmid-based gene therapy of diabetes mellitus

Prud’homme

Draghia-Akli²,

Wang

2007

Gene Ther

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Type I diabetes mellitus (T1D) is due to a loss of immune tolerance to islet antigen and thus, there is intense interest in developing therapies that can re-establish it. Tolerance is maintained by complex mechanisms that include inhibitory molecules and several types of regulatory T cells (Tr). A major historical question is whether gene therapy can be employed to generate Tr cells. This review shows that gene transfer of immunoregulatory molecules can prevent T1D and other autoimmune diseases. In our studies, non-viral gene transfer is enhanced by in vivo electroporation (EP). This technique can be used to perform DNA vaccination against islet cell antigens and when combined with appropriate immune ligands results in the generation of Tr cells and protection against T1D. In vivo EP can also be applied for non-immune therapy of diabetes. It can be used to deliver protein drugs such as glucagon-like peptide 1 (GLP-1), leptin or transforming growth factor beta (TGF-b). These act in T1D or type II diabetes (T2D) by restoring glucose homeostasis, promoting islet cell survival and growth or improving wound healing and other complications. Furthermore, we show that in large animals EP can deliver peptide hormones, such as growth hormone releasing hormone (GHRH). We conclude that the non-viral gene therapy and EP represent a safe and efficacious approach with clinical potential.

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Section: Dna Vaccination Against T1dmentioning

confidence: 99%

Plasmid-based gene therapy of diabetes mellitus

Prud’homme

Draghia-Akli²,

Wang

2007

Gene Ther

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“…Other studies have investigated effects of GAD‐DNA vaccination in NOD mice which develop a high diabetes incidence [17,18,20,22,31]. In another study [30], a single immunization of 6‐week‐old mice with GAD plasmid provided a low diabetes enhancement during the first stage after DNA vaccination but was not durable, possibly because of the lack of a second DNA injection.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast with our study and those of Wiest Ladenburger et al . [30] and Balasa et al . [17], other studies [20,31] did not include pretreatment with cardiotoxin, which leads to muscle regeneration and improves DNA immunization efficiency [33].…”

Section: Discussionmentioning

confidence: 99%

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

Gauvrit

Debailleul

et al. 2004

Clinical and Experimental Immunology

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SUMMARYDNA vaccination encoding b 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 b cell destruction leading to diabetes, we have chosen to study the effects of plasmids encoding glutamic acid decarboxylase (GAD), a crucial b 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 b galactosidase. In GAD-DNA immunized mice, diabetes cumulative incidence ( P < 3·10 -3 ) and insulitis ( P < 7·10 -3 ) increased significantly. Simultaneously, DNA immunization induced GADspecific CD4 T cells secreting interleukin (IL)-4 ( P < 0·05) and transforming growth factor (TGF)-b ( 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-b -related IgG2b to GAD ( P = 0·015). Surprisingly, diabetes onset was correlated positively with Th2-related GAD-specific IgG1 ( P < 10 -4 ) and TGF-b -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 b cell injury.

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“…injection of plasmid DNA encoding different forms of GAD to prevent diabetes in NOD mice. In many cases, delivery of a cDNA coding for intracellular GAD65 not only does not appear to be effective (Wiest-Ladenburger et al, 1998;Filippova et al, 2001), but can even be pro-inflammatory (Bot et al, 2001;Tisch et al, 2001;Wolfe et al, 2002). In contrast, injection of DNA coding for a secreted polypeptide derived from GAD65 is more likely to suppress the disease, although the effects are dependent on DNA dosage or codelivery of a cytokine (Filip-…”

Section: Discussionmentioning

confidence: 99%

Intradermal or Oral Delivery of GAD-Encoding Genetic Vaccines Suppresses Type 1 Diabetes

Escher²

2003

DNA and Cell Biology

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Genetic vaccines are promising candidates for prevention of type 1 diabetes, an autoimmune disease resulting from cell-mediated destruction of pancreatic beta cells. It is known that the prophylactic effect and immune responses induced by administration of a genetic vaccine can depend on site of delivery. In the work presented here, we used the NOD mouse model for type 1 diabetes to evaluate different routes of delivery for DNA vaccines coding for the beta-cell antigen glutamic acid decarboxylase (GAD). Plasmid DNA coding for intracellular or secreted GAD was given via either the intramuscular (i.m.), intradermal (i.d.), or oral route, using, respectively, 300, 100, or 300 micro g DNA per mouse. Results indicated that both i.d. and oral delivery of GAD-encoding DNA were more effective than i.m. delivery for disease suppression. In addition, cytokine-specific ELISpot analysis indicated that immune responses induced by the different immunization protocols were more dependent on the cellular localization of GAD antigen than on the delivery route, while ELISA of anti-GAD serum antibody isotypes indicated that i.d. delivery of DNA was most likely to induce a Th2-like response. Our results suggest that i.d. or oral delivery of a genetic vaccine for type 1 diabetes might be preferable over the i.m. route in a future clinical setting.

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DNA Vaccination with Glutamic Acid Decarboxylase (GAD) Generates a Strong Humoral Immune Response in BALB/c, C57BL/6, and in Diabetes-Prone NOD Mice

Cited by 15 publications

References 9 publications

Plasmid-based gene therapy of diabetes mellitus

Plasmid-based gene therapy of diabetes mellitus

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

Intradermal or Oral Delivery of GAD-Encoding Genetic Vaccines Suppresses Type 1 Diabetes

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