TY - JOUR
T1 - Functional deficiencies of granulocyte-macrophage colony stimulating factor and interleukin-3 contribute to insulitis and destruction of β cells
AU - Enzler, Thomas
AU - Gillessen, Silke
AU - Dougan, Michael
AU - Allison, James P.
AU - Neuberg, Donna
AU - Oble, Darryl A.
AU - Mihm, Martin
AU - Dranoff, Glenn
PY - 2007/8/1
Y1 - 2007/8/1
N2 - The pathogenesis of type 1 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 nonobese 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-γ (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 patients with T1D and in NOD mice, indicate that functional deficiencies of these cytokines contribute to diabetes.
AB - The pathogenesis of type 1 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 nonobese 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-γ (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 patients with T1D and in NOD mice, indicate that functional deficiencies of these cytokines contribute to diabetes.
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U2 - 10.1182/blood-2006-08-043786
DO - 10.1182/blood-2006-08-043786
M3 - Article
C2 - 17483299
AN - SCOPUS:34547934288
SN - 0006-4971
VL - 110
SP - 954
EP - 961
JO - Blood
JF - Blood
IS - 3
ER -