Plasmid DNAs encoding insulin and glutamic acid decarboxylase 65 have distinct effects on the progression of autoimmune diabetes in nonobese diabetic mice

J Immunol. 2001 Jul 1;167(1):586-92. doi: 10.4049/jimmunol.167.1.586.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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*

Substances

  • Epitopes, T-Lymphocyte
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Insulin
  • Isoenzymes
  • Recombinant Fusion Proteins
  • Vaccines, DNA
  • Interleukin-4
  • Glutamate Decarboxylase
  • glutamate decarboxylase 2