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Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599
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-
-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.
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