title: Homing of GAD65 specific autoimmunity and development of insulitis requires expression of both DQ8 and human GAD65 in transgenic mice.
abstract: MHC-class II genes determine susceptibility in human type-1 diabetes. In their context, presentation of target antigen(s) results in autoimmunity and beta-cell destruction. An animal model, in which human beta-cell autoantigen(s) are presented to effector cells in the context of human MHC-class II diabetes-susceptibility genes, would be desirable for studying molecular mechanisms of disease and developing antigen-specific immune-interventions. We report the development of antigen-specific insulitis in double-transgenic mice carrying the HLA-DQ8 diabetes-susceptibility haplotype and expressing the human autoantigen GAD65 in pancreatic beta-cells. Immunization with human GAD65 cDNA resulted in severe insulitis and low antibody levels in double-transgenic mice while control mice were mostly insulitis free. CFA/protein immunization resulted in high antibody levels and modest insulitis. Pancreatic lymphocytic infiltration progressed through stages (exocrine pancreas followed by peri- and intra-insulitis). Adoptive transfer of splenocytes from DNA-immunized mice resulted in development of insulitis in recipient transgenics. Our results show that immunization with a clinically relevant, type-1 diabetes human autoantigen, in a humanized genetic setting, results in the development of an immune response that homes to islets of Langerhans. This animal model will facilitate studies of autoimmunity to GAD65 in the context of HLA-DQ8, and development of methods to induce tolerance and prevent insulitis.
authors.affiliation: Endocrinology, Diabetes and Metabolism Section, Department of Medicine, School of Medicine, University of Wisconsin-Madison, Madison, WI 53792-5148, USA.
authors.forename: Raya B
authors.initials: RB
authors.lastname: Elagin
authors.forename: Sadguna
authors.initials: S
authors.lastname: Balijepalli
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Diacovo
authors.forename: Steinunn
authors.initials: S
authors.lastname: Baekkeskov
authors.forename: Juan C
authors.initials: JC
authors.lastname: Jaume
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D003001:Cloning, Molecular; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D037182:T-Cell Antigen Receptor Specificity; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019076:Transgenes / Q000235:genetics / Q000276:immunology
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2