Functional Deficiencies of Granulocyte-Macrophage Colony Stimulating Factor and Interleukin-3 Contribute to Insulitis and Destruction of β-Cells Short title: GM-CSF, IL-3 and Diabetes

The pathogenesis of type I diabetes (T1D) involves the immune-mediated destruction of insulin producing β-cells in the pancreatic islets of Langerhans. Genetic analysis of families with a high incidence of T1D and non-obese diabetic (NOD) mice, a prototypical model of the disorder, uncovered multiple susceptibility loci, although most of the underlying immune defects remain to be delineated. Here we report that aged mice doubly deficient in granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-3 (IL-3) manifest insulitis, destruction of insulin producing β-cells, and compromised glucose homeostasis. Macrophages from mutant mice produce increased levels of p40 after LPS stimulation, whereas concurrent ablation of interferon-gamma (IFN-γ) ameliorates the disease. The administration of antibodies that block cytotoxic T lymphocyte associated antigen-4 (CTLA-4) to young mutant mice precipitates the onset of insulitis and hyperglycemia. These results, together with previous reports of impaired hematopoietic responses to GM-CSF and IL-3 in T1D patients and NOD mice, indicate that functional deficiencies of these cytokines contribute to diabetes. For personal use only. on December 30, 2017. by guest www.bloodjournal.org From