Functional deficiencies of granulocyte-macrophage colony stimulating factor and interleukin-3 contribute to insulitis and destruction of β cells Journal Article


Authors: Enzler, T.; Gillessen, S.; Dougan, M.; Allison, J. P.; Neuberg, D.; Oble, D. A.; Mihm, M.; Dranoff, G.
Article Title: Functional deficiencies of granulocyte-macrophage colony stimulating factor and interleukin-3 contribute to insulitis and destruction of β cells
Abstract: 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. © 2007 by The American Society of Hematology.
Keywords: controlled study; nonhuman; mouse; mouse mutant; animals; mice; mice, knockout; animal tissue; granulocyte macrophage colony stimulating factor; animal experiment; animal model; mice, mutant strains; hyperglycemia; antibodies, monoclonal; gamma interferon; lipopolysaccharide; hematopoiesis; glucose homeostasis; antigens, cd; cytotoxic t lymphocyte antigen 4; macrophage; insulin dependent diabetes mellitus; diabetes mellitus, type 1; mice, inbred nod; nonobese diabetic mouse; pancreas islet beta cell; insulin-secreting cells; antibody; quantitative trait loci; antigens, differentiation; immunopathogenesis; protein p40; granulocyte-macrophage colony-stimulating factor; insulitis; interferon type ii; interleukin 3; interleukin-3; diabetes mellitus, experimental
Journal Title: Blood
Volume: 110
Issue: 3
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2007-08-01
Start Page: 954
End Page: 961
Language: English
DOI: 10.1182/blood-2006-08-043786
PUBMED: 17483299
PROVIDER: scopus
PMCID: PMC1924767
DOI/URL:
Notes: --- - "Cited By (since 1996): 7" - "Export Date: 17 November 2011" - "CODEN: BLOOA" - "Source: Scopus"
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  1. James P Allison
    129 Allison