Functional deficiencies of granulocyte-macrophage colony stimulating factor and interleukin-3 contribute to insulitis and destruction of beta cells.
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.
Enzler
Thomas
T
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Gillessen
Silke
S
Dougan
Michael
M
Allison
James P
JP
Neuberg
Donna
D
Oble
Darryl A
DA
Mihm
Martin
M
Dranoff
Glenn
G
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology; D060908:CTLA-4 Antigen; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency* / Q000276:immunology; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000473:pathology; D007371:Interferon-gamma / Q000276:immunology; D007377:Interleukin-3 / Q000172:deficiency* / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D040641:Quantitative Trait Loci / Q000276:immunology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D007377:Interleukin-3; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor