title: Induction of autoimmune diabetes through insulin (but not GAD65) DNA vaccination in nonobese diabetic and in RIP-B7.1 mice.
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 beta-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.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, University of Ulm, Ulm, Germany. wolfram.karges@medizin.uni.ulm.de
authors.forename: Wolfram
authors.initials: W
authors.lastname: Karges
authors.forename: Klaus
authors.initials: K
authors.lastname: Pechhold
authors.forename: Sascha
authors.initials: S
authors.lastname: Al Dahouk
authors.forename: Ines
authors.initials: I
authors.lastname: Riegger
authors.forename: Matthias
authors.initials: M
authors.lastname: Rief
authors.forename: Andrea
authors.initials: A
authors.lastname: Wissmann
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schirmbeck
authors.forename: Christoph
authors.initials: C
authors.lastname: Barth
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
mesh_terms: D000375:Aging; D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D005968:Glutamate Decarboxylase / Q000235:genetics* / Q000276:immunology; D007328:Insulin / Q000235:genetics* / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology; D007527:Isoenzymes / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D011384:Proinsulin / Q000276:immunology; D011498:Protein Precursors / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D013997:Time Factors; D019444:Vaccines, DNA
chemical_list: D018122:B7-1 Antigen; D007328:Insulin; D007527:Isoenzymes; D011498:Protein Precursors; D019444:Vaccines, DNA; C013737:preproinsulin; D011384:Proinsulin; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2