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Cell Autoimmunity by Plasmid DNA Vaccination1
*
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599;
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892; and
The Jackson Laboratory, Bar Harbor, ME 04609
In this study, we have investigated the use of plasmid DNA (pDNA)
vaccination to elicit Th2 effector cell function in an Ag-specific
manner and in turn prevent insulin-dependent diabetes mellitus (IDDM)
in nonobese diabetic (NOD) mice. pDNA recombinants were engineered
encoding a secreted fusion protein consisting of a fragment of glutamic
acid decarboxylase 65 (GAD65) linked to IgGFc, and IL-4. Intramuscular
injection of pDNA encoding GAD65-IgGFc and IL-4 effectively prevented
diabetes in NOD mice treated at early or late preclinical stages of
IDDM. This protection was GAD65-specific since NOD mice immunized with
pDNA encoding hen egg lysozyme-IgGFc and IL-4 continued to develop
diabetes. Furthermore, disease prevention correlated with suppression
of insulitis and induction of GAD65-specific regulatory Th2 cells.
Importantly, GAD65-specific immune deviation was dependent on
pDNA-encoded IL-4. In fact, GAD65-specific Th1 cell reactivity was
significantly enhanced in animals immunized with pDNA encoding only
GAD65-IgGFc. Finally, NOD.IL4null mice treated with pDNA
encoding GAD65-IgGFc and IL-4 continued to develop diabetes, indicating
that endogenous IL-4 was also required for disease prevention. These
results demonstrate that pDNA vaccination is an effective strategy to
elicit 
cell-specific Th2 regulatory cell function for the purpose
of preventing IDDM even at a late stage of disease
development.
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