A Humanized Mouse Model to Study Type 1 Diabetes

Key requirements in type 1 diabetes are in setting up new assays as diagnostic biomarkers that will apply to prediabetes, likely T-lymphocyte assays, and in designing antigen-specific therapies to prevent its development. New preclinical models of T1D will be required to help advancing both aims. By crossing mouse strains that lack either murine major histocompatibility complex class-I, class-II genes and insulin genes, we developed YES mice that instead expresses human HLA-A*02:01, HLA-DQ8 and insulin genes as transgenes. The metabolic and immune phenotype of YES mice is basically identical to that of the parental strains. YES mice remain insulitis- and diabetes-free up to one year of follow up, maintain normoglycemia to an intraperitoneal glucose challenge in the long-term range, have a normal β-cell mass and show normal immune responses to conventional antigens. This new model has been designed to evaluate adaptive immune responses to human insulin on a genetic background that recapitulate human high susceptibility HLA-DQ8 genetic background. Although insulitis-free, YES mice develop T1D when challenged with polyInosinic-polyCytidylic acid. They allow characterizing preproinsulin epitopes recognized by CD8 + and CD4 + T-lymphocytes upon immunization against human preproinsulin or along diabetes development.