Role of platelets and/or neutrophils in the development of Type 1 diabetes
Type 1 diabetes (T1D) in humans is associated with the immune destruction of insulin-producing beta cells in the Islets of Langerhans in the pancreas. Currently there is no cure for T1D and insulin therapy leads to long-term complications. The non-obese diabetic (NOD) mouse strain is a very useful model of T1D in humans. In this project, neutrophils and platelet-neutrophil aggregates (PNAs; markers of activated neutrophils) will be examined in the peripheral blood and islet-infiltrating leukocyte populations in NOD mice at different ages during T1D development and at T1D-onset. In parallel, neutrophils, neutrophil products (e.g., neutrophil extracellular traps (NETs), myeloperoxidase, neutrophil elastase) and PNAs will be identified in pancreas sections by immunofluorescence microscopy and correlated with disease progression. Monoclonal antibody treatment to deplete neutrophils or platelets in NOD mice at different ages will be used to ascertain whether the activation of neutrophils by platelets contributes to the initiation of T1D, T1D progression and clinical disease onset. These studies will help to ascertain whether activated neutrophils damage islet beta cells early in T1D development and throughout the preclinical phase of T1D progression. Such damage may assist T cell-mediated autoimmune responses. Preventing the toxicity of platelet-activated neutrophils may therefore represent a new therapy for T1D.