Characterization and use of human insulin transgenic mouse models for type 1 diabetes

Abstract

Abstract Type 1 diabetes (T1D) is characterized by T cell-mediated islet-specific autoimmunity leading to β cell destruction and loss of insulin production. Insulin is the primary antigen produced by β cells and due to incomplete conservation between the mouse and human insulin genes, some of the important disease-relevant T cell epitopes can be missed in the widely studied non-obese diabetic (NOD) mouse model. Thus, considering the limitations of NOD mice, we generated a novel NOD mouse model transgenically expressing human insulin (NOD.hIns mice) under the control of the human promoter. Female NOD.hIns mice spontaneously developed autoimmune diabetes as early as 15 weeks (incidence 62% by 30 weeks of age, n=21) vs NOD mice (41%, n=24), accompanied by numerous hallmarks of human T1D (including thymic human insulin expression and variable degrees of pancreatic islet infiltration by immune cells). Next, we cultured islet-infiltrating CD8 T cells from NOD.hIns mice and tested them for recognition of peptides unique to human preproinsulin. These efforts uncovered at least three T cell epitopes, validating that human insulin is a target of the autoimmune response in NOD.hIns mice. This concept was confirmed using T cells derived from NOD.hIns mice deficient in both murine insulin genes (NOD.Ins1ko.Ins2ko.hIns mice). NOD.hIns mice expressing human class I MHC molecules associated with T1D (HLA-A*24:02 and B*39:06) are currently being studied. Such well-characterized, and highly human-relevant, T1D models can be used to develop robust immune monitoring tools and to test and refine antigen-specific therapeutic strategies for T1D.