Induction of Autoimmune Diabetes Through Insulin (but Not GAD65) DNA Vaccination in Nonobese Diabetic and in RIP-B7.1 Mice

Induction of Autoimmune Diabetes Through Insulin (but Not GAD65) DNA Vaccination in Nonobese Diabetic and in RIP-B7.1 Mice Wolfram Karges 1 , Klaus Pechhold 3 , Sascha Al Dahouk 1 , Ines Riegger 1 , Matthias Rief 1 , Andrea Wissmann 1 , Reinhold Schirmbeck 2 , Christoph Barth 1 and Bernhard O. Boehm 1 1 Division of Endocrinology, Department of Internal Medicine, University of Ulm, Ulm, Germany 2 Department of Immunology and Medical Microbiology, University of Ulm, Ulm, Germany 3 National Institute of Diabetes and Digestive and Kidney Diseases–Navy Transplantation and Autoimmunity Branch, Bethesda, Maryland Abstract Insulin has been used to modify T-cell autoimmunity in experimental models of type 1 diabetes. In a large clinical trial, the effect of insulin to prevent type 1 diabetes is currently investigated. We here show that insulin can adversely trigger autoimmune diabetes in two mouse models of type 1 diabetes, using intramuscular DNA vaccination for antigen administration. In female nonobese diabetic (NOD) mice, diabetes development was enhanced after preproinsulin (ppIns) DNA treatment, and natural diabetes resistance in male NOD mice was diminished by ppIns DNA vaccination. In contrast, GAD65 DNA conferred partial diabetes protection, and empty DNA plasmid was without effect. In RIP-B7.1 C57BL/6 mice (expressing the T-cell costimulatory molecule B7.1 in pancreatic β-cells), autoimmune diabetes occurred in 70% of animals after ppIns vaccination, whereas diabetes did not develop spontaneously in RIP-B7.1 mice or after GAD65 or control DNA treatment. Diabetes was characterized by diffuse CD4 + CD8 + T-cell infiltration of pancreatic islets and severe insulin deficiency, and ppIns, proinsulin, and insulin DNA were equally effective for disease induction. Our work provides a new model of experimental autoimmune diabetes suitable to study mechanisms and outcomes of insulin-specific T-cell reactivity. In antigen-based prevention of type 1 diabetes, diabetes acceleration should be considered as a potential adverse result. Footnotes Address correspondence and reprint requests to Dr. Wolfram Karges, Division of Endocrinology, Department of Internal Medicine, University of Ulm, Robert Koch Strasse, D 89081 Ulm, Germany. E-mail: wolfram.karges{at}medizin.uni-ulm.de . Received for publication 17 October 2001 and accepted in revised form 8 August 2002. aa, amino acids; APC, antigen-presenting cell; CMV, cytomegalovirus; CTL, cytotoxic T-cell; EAD, experimental au