The primary focus of my work is the study of the mechanisms contributing to autoimmune disease development. Using the type 1 diabetes (T1D) prone NOD-mouse, we have developed multiple new pre-clinical models for several different autoimmune diseases. Project 1 centers around “HLA-humanization” of NOD mice. Using CRISPR/Cas9 technology, we have genetically ablated murine major histocompatibility genes and replaced them with various combinations of human leukocyte antigen (HLA) genes associated with T1D-development. These mice are then further engineered to express patient-derived T-cell receptor genes to create more clinically relevant systems to test potential T1D therapeutics. Project 2 & 3 centers around using two of these HLA-humanized mouse models for studying the genetics and cellular mechanisms leading to immune checkpoint inhibitor (ICI) induced T1D (Project 2) and myocarditis/myositis (Project 3). Project 4 is focused on studying T1D-associated autoimmune neuritis development. We are currently mapping NOD alleles associated with spontaneous nerve infiltration observed in NOD but not C57BL/6 mice. A second model takes advantage of a peripherin-reactive B-cell receptor transgenic mouse that develops accelerated T1D. Transfer of T-cells from these mice into NOD.scid recipient mice precipitates autoimmune neuritis development that can be studied in a synchronized manner. A new Project 5, currently in development, is understanding how genetic ablation of Bcl3 leads to robust T1D-protection and whether modulation of Bcl3 expression levels affects other autoimmune disorders in the NOD-background.
