Plasmid DNAs Encoding Insulin and Glutamic Acid Decarboxylase 65 Have Distinct Effects on the Progression of Autoimmune Diabetes in Nonobese Diabetic Mice

• Published in: The Journal of immunology (1950) 2001-07, Vol.167 (1), p.586-592
• Main Authors: Weaver, Donald J., Jr, Liu, Bo, Tisch, Roland
• Format: Article
• Language: English
• Subjects: Aging - immunology; Animals; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Diabetes Mellitus, Type 1 - etiology; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - pathology; Diabetes Mellitus, Type 1 - prevention & control; Disease Progression; Epitopes, T-Lymphocyte - immunology; Female; Glutamate Decarboxylase - administration & dosage; Glutamate Decarboxylase - genetics; Glutamate Decarboxylase - immunology; Immunoglobulin Fc Fragments - administration & dosage; Immunoglobulin Fc Fragments - genetics; Immunoglobulin G - administration & dosage; Immunoglobulin G - genetics; Injections, Intramuscular; Insulin - administration & dosage; Insulin - genetics; Insulin - immunology; Interleukin-4 - administration & dosage; Interleukin-4 - genetics; Isoenzymes - administration & dosage; Isoenzymes - genetics; Isoenzymes - immunology; Lymphocyte Activation - genetics; Lymphocyte Count; Mice; Mice, Inbred NOD; Plasmids - administration & dosage; Plasmids - immunology; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - immunology; Th1 Cells - pathology; Vaccines, DNA - administration & dosage; Vaccines, DNA - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.167.1.586

We previously demonstrated that administration of plasmid DNAs (pDNAs) encoding IL-4 and a fragment of glutamic acid decarboxylase 65 (GAD65) fused to IgGFc induces GAD65-specific Th2 cells and prevents insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. To assess the general applicability of pDNA vaccination to mediate Ag-specific immune deviation, we examined the immunotherapeutic efficacy of recombinants encoding murine insulin A and B chains fused to IgGFc. Insulin was chosen based on studies demonstrating that administration of insulin or insulin B chain by a variety of strategies prevents IDDM in NOD mice. Surprisingly, young NOD mice receiving i.m. injections of pDNA encoding insulin B chain-IgGFc with or without IL-4 exhibited an accelerated progression of insulitis and developed early diabetes. Exacerbation of IDDM correlated with an increased frequency of IFN-gamma-secreting CD4(+) and CD8(+) T cells in response to insulin B chain-specific peptides compared with untreated mice. In contrast, treatment with pDNAs encoding insulin A chain-IgGFc and IL-4 elicited a low frequency of IL-4-secreting Th cells and had no effect on the progression of IDDM. Vaccination with pDNAs encoding GAD65-IgGFc and IL-4, however, prevented IDDM. These results demonstrate that insulin- and GAD65-specific T cell reactivity induced by pDNA vaccination has distinct effects on the progression of IDDM.