Abstract
The pathogenesis of type 1 diabetes (T1D) involves the immune-mediated destruction of insulin-producing beta 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 beta cells, and compromised glucose homeostasis. Macrophages from mutant mice produce increased levels of p40 after LPS stimulation, whereas concurrent ablation of interferon-gamma (IFN-gamma) 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / pharmacology
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Antigens, CD / immunology
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Antigens, Differentiation / immunology
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CTLA-4 Antigen
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Diabetes Mellitus, Experimental / genetics
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Diabetes Mellitus, Experimental / immunology*
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Diabetes Mellitus, Experimental / pathology
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Diabetes Mellitus, Type 1 / genetics
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Diabetes Mellitus, Type 1 / immunology*
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Diabetes Mellitus, Type 1 / pathology
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Granulocyte-Macrophage Colony-Stimulating Factor / deficiency*
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Granulocyte-Macrophage Colony-Stimulating Factor / immunology
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Hematopoiesis / drug effects
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Hematopoiesis / genetics
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Hematopoiesis / immunology
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Humans
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Hyperglycemia / genetics
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Hyperglycemia / immunology*
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Hyperglycemia / pathology
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Insulin-Secreting Cells / immunology*
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Insulin-Secreting Cells / pathology
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Interferon-gamma / immunology
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Interleukin-3 / deficiency*
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Interleukin-3 / immunology
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Mice
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Mice, Inbred NOD
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Mice, Knockout
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Mice, Mutant Strains
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Quantitative Trait Loci / immunology
Substances
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Antibodies, Monoclonal
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Antigens, CD
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Antigens, Differentiation
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CTLA-4 Antigen
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CTLA4 protein, human
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Ctla4 protein, mouse
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Interleukin-3
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Interferon-gamma
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Granulocyte-Macrophage Colony-Stimulating Factor