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

We previously demonstrated that administration of plasmid DNAs (pDNAs) enco ding IL-4 and a fragment of glutamic acid decarboxylase 65 (GAD65) fused to IgGFc induces GAD65-specific Th2 cells and prevents insulin-dependent diab etes 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 varie ty of strategies prevents IDDM in NOD mice. Surprisingly, young NOD mice re ceiving i.m. injections of pDNA encoding insulin B chain-IgGFc with or with out IL-4 exhibited an accelerated progression of insulitis and developed ea rly diabetes. Exacerbation of IDDM correlated with an increased frequency o f WN-gamma -secreting CD4(+) and CD8(+) T cells in response to insulin B ch ain-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. V accination with pDNAs encoding GAD65-specific and IL-4, however, prevented IDDM. These results demonstrate that insulin- and GAD65-specific T cell rea ctivity induced by pDNA vaccination has distinct effects on the progression of IDDM. The Journal of Immunology, 2001.