Generating new mouse models for the study and treatment of type 1 diabetes

Abstract

Type 1 diabetes (T1D) is an autoimmune disease resulting from the T cell-mediated destruction of pancreatic beta cells. Many genetic susceptibility factors associated with T1D development have also been found in the non-obese diabetic (NOD) mouse, the currently widely accepted model of this disease. However, the disease pathogenesis in humans appears more complex than in NOD mice and remains less understood and successful NOD treatments have not yet translated to humans. Humanized mouse models would help provide a better platform for understanding T1D pathogenesis and evaluating antigen-specific therapies.;We generated NOD mice with reduced thymic insulin expression that express the human MHC I molecule HLA-A2. These mice developed diabetes faster and appear to have a greater frequency of insulin-reactive islet infiltrating T cells than Ins2WT mice. This new model more closely represents T1D than the NOD mouse and could be used to evaluate insulin-specific therapies.;The therapeutic potential of an antigen-specific therapy wherein antigens are coupled to an antibody against the DC-specific endocytic receptor DEC-205 has been demonstrated. In the absence of immune stimulus, steady-state dendritic cells present epitopes on MHC class I and II in a tolerogenic manner. We generated anti-DEC-205 antibody linked to murine proinsulin and hypothesized that this therapy could cause the deletion of insulin-specific T cells and the induction of insulin-specific regulatory T cells. We verified that epitopes from anti-DEC-205/Ins2 were processed and presented by dendritic cells on both MHC class I and class II molecules.;The NOD-scid.IL2r&ggr;null .HLA-A2 (NSG-A2) mouse strain engrafts with human cells and enables the study of human autoimmunity in a mouse model. Human CD8 T cells can be "reprogrammed" into islet-specific T cells by lentiviral transduction. We compared three human TCRs specific for IGRP265-273 presented by HLA-A2 and found variations in both affinity and functional response. TCR-transduced cells were transferred to NSG-A2 mice and remained functionally active for at least five weeks. This is the first demonstration of long-term engraftment of TCR-transduced human cells in mice and provides a new system for the study of human autoreactive T cells.