Human insulin as both antigen and protector in type 1 diabetes

Abstract

Type 1 diabetes (T1D) is characterized by T‐cell responses to islet antigens. Investigations in humans and the nonobese diabetic (NOD) mouse model of T1D have revealed that T‐cell reactivity to insulin plays a central role in the autoimmune response. As there is no convenient NOD‐based model to study human insulin (hIns) or its T‐cell epitopes in the context of spontaneous T1D, we developed a NOD mouse strain transgenically expressing hIns in islets under the control of the human regulatory region. Female NOD.hIns mice developed T1D at approximately the same rate and overall incidence as NOD mice. Islet‐infiltrating T cells from NOD.hIns mice recognized hIns peptides; both CD8 and CD4 T‐cell epitopes were identified. We also demonstrate that islet‐infiltrating T cells from HLA‐transgenic NOD.hIns mice can be used to identify potentially patient‐relevant hIns T‐cell epitopes. Besides serving as an antigen, hIns was expressed in the thymus of NOD.hIns mice and could serve as a protector against T1D under certain circumstances, as previously suggested by genetic studies in humans. NOD.hIns mice and related strains facilitate human‐relevant epitope discovery efforts and the investigation of fundamental questions that cannot be readily addressed in humans.