Antigen-specific mediated suppression of beta cell autoimmunity by plasmidDNA vaccination

In this study, we have investigated the use of plasmid DNA (pDNA) vaccinati on to elicit Th2 effector cell function in an Ag-specific manner and in tur n prevent insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic ( NOD) mice. pDNA recombinants were engineered encoding a secreted fusion pro tein consisting of a fragment of glutamic acid decarboxylase 65 (GAD65) lin ked to IgGFc, and IL-4, Intramuscular injection of pDNA encoding GAD65-IgGF c and IL-4 effectively prevented diabetes in NOD mice treated at early or l ate preclinical stages of IDDM, This protection was GAD65-specific since NO D mice immunized with pDNA encoding hen egg lysozyme-IgGFc and IL-4 continu ed to develop diabetes. Furthermore, disease prevention correlated with sup pression 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 enhanc ed in animals immunized with pDNA encoding only GAD65-IgGFc, Finally, NOD.I L4(null) mice treated with pDNA encoding GAD65-IgGFc and IL-4 continued to develop diabetes, indicating that endogenous IL-4 was also required for dis ease prevention. These results demonstrate that pDNA vaccination is an effe ctive strategy to elicit beta cell-specific Th2 regulatory cell function fu r the purpose of preventing IDDM even at a late stage of disease developmen t.