Functional deficiencies of granulocyte-macrophage colony stimulating factor and interleukin-3 contribute to insulitis and destruction of beta cells.
نویسندگان
چکیده
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.
منابع مشابه
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. He...
متن کاملFunctional deficiencies of granulocyte-macrophage colony stimulating factor and interleukin-3 contribute to insulitis and destruction of cells
1Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA; 2Howard Hughes Medical Institute and Program in Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY; 3Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and...
متن کاملIMMUNOBIOLOGY Functional deficiencies of granulocyte-macrophage colony stimulating factor and interleukin-3 contribute to insulitis and destruction of cells
1Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA; 2Howard Hughes Medical Institute and Program in Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY; 3Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and...
متن کاملComparison of T7- and Lac-Based Systems for the Periplasmic Expression of Human Granulocyte Macrophage Colony Stimulating Factor in Escherichia coli
متن کامل
Expression and Secretion of Human Granulocyte Macrophage-Colony Stimulating Factor Using Escherichia coli Enterotoxin I Signal Sequence
With the aim of the secretion of human granulocyte macrophage-colony stimulating factor (hGM-CSF) in Escherichia coli, hGM-CSF cDNA was fused in-frame next to the signal sequence of ST toxin (ST-I) of exteroxigenic E. coli, containing 53 or 19 amino acids of signal peptide. The fused STsig::hGM-CSF coding fragments were inserted into a T7-based expression plasmid. The recombinant plasmids were ...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Blood
دوره 110 3 شماره
صفحات -
تاریخ انتشار 2007