Abstract
Type 1 diabetes (T1D) is characterized by the T cell mediated destruction of the insulin-producing beta cells. Antigen-specific immunotherapies are used to selectively tolerize beta cell-specific pathogenic T cells either directly, or indirectly through the induction of immunoregulatory T cells. A key concern of antigen-specific immunotherapy is exacerbating autoimmunity. We compared the T cell reactivity and efficacy induced by plasmid DNA (pDNA) encoding glutamic acid decarboxylase 65 (GAD65) administered via intramuscular versus gene gun vaccination in NOD mice at a late preclinical stage of T1D. Whereas intramuscular injection of pGAD65 promoted a predominant type 1 CD4(+) T cell response and failed to suppress ongoing beta cell autoimmunity, gene gun vaccination preferentially induced IL-4 secreting CD4(+) T cells and significantly delayed the onset of diabetes. These findings demonstrate that gene gun delivery of autoantigen-encoding pDNA preferentially elicits immunoregulatory T cells and offers a safe, effective mode of pDNA vaccination for the treatment of T1D and other autoimmune diseases.