IGRP and insulin vaccination induce CD8+ T cell‐mediated autoimmune diabetes in the RIP‐CD80GP mouse

Summary Autoimmune diabetes is characterized by autoantigen‐specific T cell‐mediated destruction of pancreatic islet beta cells, and CD 8 + 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 CD 8 + T cell‐mediated autoimmune diabetes. Antigen‐encoding DNA , peptide‐loaded dendritic cells and antigen plus incomplete F reund'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, I a‐2, I a‐2β, glutamic acid decarboxylase 67 ( G ad67), 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. CD 8 + 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 F reund's adjuvant, which can prevent diabetes in other models, led to rapid diabetes development in the RIP ‐ CD 80 GP mouse. We conclude that RIP ‐ CD 80 GP mice are a versatile model of antigen specific autoimmune diabetes and may complement existing mouse models of autoimmune diabetes for evaluating CD 8 + T cell‐targeted prevention strategies.