DNA immunization to prevent autoimmune diabetes

Coon, Bryan; An, Ling–Ling; Whitton, J. Lindsay; Herrath, Matthias G. von

doi:10.1172/jci7209

Cited by 116 publications

(97 citation statements)

References 26 publications

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“…Our results are also consistent with a growing notion that the efficacy at which Th2 cell differentiation can be induced in an Ag-specific manner is dependent on the frequency of established Th1 effector cells and uncommitted T cell precursors. For example, Coon et al (42) showed that immunization with pDNA-encoding porcine insulin B chain elicited Th2 cell reactivity and prevented diabetes induced by lymphocytic choriomeningitis virus (LCMV) infection in BALB/c mice expressing LCMV nucleoprotein in ␤ cells (42). In contrast, when established T cell effectors already existed, i.m.…”

Section: Discussionmentioning

confidence: 99%

Antigen-Specific Mediated Suppression of β Cell Autoimmunity by Plasmid DNA Vaccination

Tisch

Wang

Weaver

et al. 2001

The Journal of Immunology

111

103

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In this study, we have investigated the use of plasmid DNA (pDNA) vaccination to elicit Th2 effector cell function in an Ag-specific manner and in turn prevent insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. pDNA recombinants were engineered encoding a secreted fusion protein consisting of a fragment of glutamic acid decarboxylase 65 (GAD65) linked to IgGFc, and IL-4. Intramuscular injection of pDNA encoding GAD65-IgGFc and IL-4 effectively prevented diabetes in NOD mice treated at early or late preclinical stages of IDDM. This protection was GAD65-specific since NOD mice immunized with pDNA encoding hen egg lysozyme-IgGFc and IL-4 continued to develop diabetes. Furthermore, disease prevention correlated with suppression of insulitis and induction of GAD65-specific regulatory Th2 cells. Importantly, GAD65-specific immune deviation was dependent on pDNA-encoded IL-4. In fact, GAD65-specific Th1 cell reactivity was significantly enhanced in animals immunized with pDNA encoding only GAD65-IgGFc. Finally, NOD.IL4null mice treated with pDNA encoding GAD65-IgGFc and IL-4 continued to develop diabetes, indicating that endogenous IL-4 was also required for disease prevention. These results demonstrate that pDNA vaccination is an effective strategy to elicit β cell-specific Th2 regulatory cell function for the purpose of preventing IDDM even at a late stage of disease development.

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Section: Discussionmentioning

confidence: 99%

Antigen-Specific Mediated Suppression of β Cell Autoimmunity by Plasmid DNA Vaccination

Tisch

Wang

Weaver

et al. 2001

The Journal of Immunology

111

103

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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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“…Antigen-specific prevention of T1DM can be achieved in several ways in animal models, (i) with DNA vaccines [5][6][7], (ii) peptide derived from islet antigens [8,9], or (iii) full-length islet proteins [10,11] (Table 1). The use of DNA vaccination to prevent T1DM was pioneered by our group, and corroborated and extended by other laboratories.…”

Section: Antigen-specific Prevention Of Type 1 Diabetesmentioning

confidence: 99%