Igrp and insulin vaccination induce CD8⁺ T cell mediated autoimmune diabetes in the RIP-CD80GP mouse.

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 Igrp (77%, 58 days) could induce diabetes. DNA vaccination with zinc transporter 8, Ia-2, Ia-2β, Gad67, Chromogranin A, IAPP, and Nkx2.2 induced diabetes development in 25-33% of mice, and with Gad65, Sgne1, Pdx1, Cel, glucagon, and control HBsAg 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 ELISpot assay, and diabetes could also be induced by vaccination with 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