Antigen-specific mediated suppression of beta cell autoimmunity by plasmid DNA vaccination.
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.
Tisch
R
R
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA. rmtisch@med.unc.edu
Wang
B
B
Weaver
D J
DJ
Liu
B
B
Bui
T
T
Arthos
J
J
Serreze
D V
DV
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*
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