title: Antigen-specific mediated suppression of beta cell autoimmunity by plasmid DNA vaccination.
abstract: 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.IL4(null) 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 beta cell-specific Th2 regulatory cell function for the purpose of preventing IDDM even at a late stage of disease development.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA. rmtisch@med.unc.edu
authors.forename: R
authors.initials: R
authors.lastname: Tisch
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.forename: D J
authors.initials: DJ
authors.lastname: Weaver
authors.forename: B
authors.initials: B
authors.lastname: Liu
authors.forename: T
authors.initials: T
authors.lastname: Bui
authors.forename: J
authors.initials: J
authors.lastname: Arthos
authors.forename: D V
authors.initials: DV
authors.lastname: Serreze
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D002417:Cattle; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000235:genetics; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000235:genetics; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use; D007273:Injections, Intramuscular; D015847:Interleukin-4 / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D007527:Isoenzymes / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D008198:Lymph Nodes / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D010957:Plasmids / Q000008:administration & dosage / Q000276:immunology*; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D019444:Vaccines, DNA; D015847:Interleukin-4; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2