title: Plasmid DNAs encoding insulin and glutamic acid decarboxylase 65 have distinct effects on the progression of autoimmune diabetes in nonobese diabetic mice.
abstract: 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.
authors: Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: D J
authors: DJ
authors: Weaver
authors: B
authors: B
authors: Liu
authors: R
authors: R
authors: Tisch
mesh_terms: D000375:Aging / Q000276:immunology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D018450:Disease Progression; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005968:Glutamate Decarboxylase / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000235:genetics; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000235:genetics; D007273:Injections, Intramuscular; D007328:Insulin / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D015847:Interleukin-4 / Q000008:administration & dosage / Q000235:genetics; D007527:Isoenzymes / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D018655:Lymphocyte Count; D051379:Mice; D016688:Mice, Inbred NOD; D010957:Plasmids / Q000008:administration & dosage / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology; D018417:Th1 Cells / Q000473:pathology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007328:Insulin; D007527:Isoenzymes; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; D015847:Interleukin-4; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2