title: IGRP and insulin vaccination induce CD8+ T cell-mediated autoimmune diabetes in the RIP-CD80GP mouse.
abstract: Autoimmune diabetes is characterized by autoantigen-specific T cell-mediated destruction of pancreatic islet beta cells, and CD8(+) T cells are key players during this process. We assessed whether the bitransgenic RIP-CD80 x RIP-LCMV-GP (RIP-CD80GP) mice may be a versatile antigen-specific model of inducible CD8(+) T cell-mediated autoimmune diabetes. Antigen-encoding DNA, peptide-loaded dendritic cells and antigen plus incomplete Freund's adjuvant were used for vaccination. Of 14 pancreatic proteins tested by DNA vaccination, murine pre-proinsulin 2 (100% of mice; median time after vaccination, 60 days) and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) (77%, 58 days) could induce diabetes. Vaccination with DNA encoding for zinc transporter 8, Ia-2, Ia-2β, glutamic acid decarboxylase 67 (Gad67), chromogranin A, insulinoma amyloid polypeptide and homeobox protein Nkx-2.2 induced diabetes development in 25-33% of mice. Vaccination with DNA encoding for Gad65, secretogranin 5, pancreas/duodenum homeobox protein 1 (Pdx1), carboxyl ester lipase, glucagon and control hepatitis B surface antigen (HBsAg) induced diabetes in <20% of mice. Diabetes induction efficiency could be increased by DNA vaccination with a vector encoding a ubiquitin-antigen fusion construct. Diabetic mice had florid T cell islet infiltration. CD8(+) T cell targets of IGRP were identified with a peptide library-based enzyme-linked immunospot assay, and diabetes could also be induced by vaccination with major histocompatibility complex (MHC) class I-restricted IGRP peptides loaded on mature dendritic cells. Vaccination with antigen plus incomplete Freund's adjuvant, which can prevent diabetes in other models, led to rapid diabetes development in the RIP-CD80GP mouse. We conclude that RIP-CD80GP mice are a versatile model of antigen specific autoimmune diabetes and may complement existing mouse models of autoimmune diabetes for evaluating CD8(+) T cell-targeted prevention strategies.
authors.affiliation: DFG - Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany; Paul Langerhans Institute Dresden-German Center for Diabetes Research (DZD), Dresden, Germany.
authors.forename: Y F
authors.initials: YF
authors.lastname: Fuchs
authors.forename: K
authors.initials: K
authors.lastname: Adler
authors.forename: A
authors.initials: A
authors.lastname: Lindner
authors.forename: A
authors.initials: A
authors.lastname: Karasinsky
authors.forename: C
authors.initials: C
authors.lastname: Wilhelm
authors.forename: M
authors.initials: M
authors.lastname: Weigelt
authors.forename: H
authors.initials: H
authors.lastname: Balke
authors.forename: K
authors.initials: K
authors.lastname: Förtsch
authors.forename: L F
authors.initials: LF
authors.lastname: Mortler-Hildebrandt
authors.forename: D M
authors.initials: DM
authors.lastname: Harlan
authors.forename: K
authors.initials: K
authors.lastname: Pechhold
authors.forename: A-G
authors.initials: AG
authors.lastname: Ziegler
authors.forename: E
authors.initials: E
authors.lastname: Bonifacio
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D005620:Freund's Adjuvant / Q000276:immunology; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000276:immunology*; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology; D007328:Insulin / Q000235:genetics / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology; D053208:Kaplan-Meier Estimate; D008055:Lipids / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D011498:Protein Precursors / Q000235:genetics / Q000276:immunology*; D051381:Rats; D013997:Time Factors; D014611:Vaccination / Q000009:adverse effects / Q000379:methods*; D019444:Vaccines, DNA / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D018122:B7-1 Antigen; D006023:Glycoproteins; D007328:Insulin; D008055:Lipids; D011498:Protein Precursors; D019444:Vaccines, DNA; D014764:Viral Proteins; C114843:incomplete Freund's adjuvant; C013737:preproinsulin; D004247:DNA; D005620:Freund's Adjuvant; D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse
keywords: antigens/peptides/epitopes; autoimmunity; cytotoxic T cells; diabetes