title: Gene gun-mediated DNA vaccination enhances antigen-specific immunotherapy at a late preclinical stage of type 1 diabetes in nonobese diabetic mice.
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.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7290, USA.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Goudy
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Roland
authors.initials: R
authors.lastname: Tisch
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity; D019470:Biolistics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D005968:Glutamate Decarboxylase / Q000097:blood / Q000235:genetics* / Q000276:immunology; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D011993:Recombinant Fusion Proteins / Q000097:blood; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D019076:Transgenes; D014611:Vaccination; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000276:immunology
chemical_list: D001324:Autoantigens; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; D015847:Interleukin-4; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2