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3.
J Exp Med ; 194(7): 873-82, 2001 Oct 01.
Article in English | MEDLINE | ID: mdl-11581310

ABSTRACT

Experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, can be induced by immunization with a number of myelin antigens. In particular, myelin oligodendrocyte glycoprotein, a central nervous system (CNS)-specific antigen expressed on the myelin surface, is able to induce a paralytic MS-like disease with extensive CNS inflammation and demyelination in several strains of animals. Although not well understood, the egress of immune cells into the CNS in EAE is governed by a complex interplay between pro and antiinflammatory cytokines and chemokines. The hematopoietic growth factor, granulocyte macrophage colony-stimulating factor (GM-CSF), is considered to play a central role in maintaining chronic inflammation. The present study was designed to investigate the previously unexplored role of GM-CSF in autoimmune-mediated demyelination. GM-CSF(-/)- mice are resistant to EAE, display decreased antigen-specific proliferation of splenocytes, and fail to sustain immune cell infiltrates in the CNS, thus revealing key activities for GM-CSF in the development of inflammatory demyelinating lesions and control of migration and/or proliferation of leukocytes within the CNS. These results hold implications for the pathogenesis of inflammatory and demyelinating diseases and may provide the basis for more effective therapies for inflammatory diseases, and more specifically for multiple sclerosis.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/therapy , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Multiple Sclerosis/therapy , Animals , Autoantibodies/blood , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/etiology , Granulocyte-Macrophage Colony-Stimulating Factor/deficiency , Immunity, Innate , Immunotherapy , Mice , Mice, Inbred NOD , Mice, Mutant Strains , Multiple Sclerosis/etiology , Myelin Proteins , Myelin-Associated Glycoprotein/immunology , Myelin-Oligodendrocyte Glycoprotein , T-Lymphocytes/immunology
4.
Immunology ; 104(1): 92-8, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11576226

ABSTRACT

Mice lacking the suppressor of cytokine signalling-1 (SOCS1) die within weeks of birth with extensive fatty degeneration of the liver, consistent with acute hepatic toxicity to interferon-gamma (IFN-gamma), and inflammation of multiple organs. We show here that treatment for 1 week from birth with neutralizing antibody to IFN-gamma rescues SOCS1-/- mice from lethal liver disease but the mice subsequently succumb to chronic inflammatory lesions characterized by T-lymphocyte infiltration of skeletal muscle, pancreas, lung, liver and skin. Elevated blood levels of eosinophils, neutrophils and platelets were also observed and the thymic lymphocyte population was depleted of CD4+ CD8+ T cells and showed a reduced CD4 : CD8 ratio. All T-cell populations in thymus, spleen and lymph node exhibited an increased proportion of cells bearing the activation marker CD44. These data suggest an important role for SOCS1 in T-lymphocyte regulation.


Subject(s)
Carrier Proteins/immunology , Fatty Liver/prevention & control , Hepatitis, Animal/prevention & control , Inflammation/prevention & control , Interferon-gamma/antagonists & inhibitors , Animals , Animals, Newborn , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Carrier Proteins/genetics , Carrier Proteins/metabolism , Chronic Disease , Fatty Liver/immunology , Hepatitis, Animal/immunology , Inflammation/immunology , Inflammation/pathology , Interferon-gamma/immunology , Lymphocyte Count , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Repressor Proteins/genetics , Repressor Proteins/immunology , Repressor Proteins/metabolism , Suppressor of Cytokine Signaling 1 Protein , Suppressor of Cytokine Signaling Proteins , beta-Galactosidase/metabolism
5.
Cell ; 98(5): 597-608, 1999 Sep 03.
Article in English | MEDLINE | ID: mdl-10490099

ABSTRACT

Mice lacking suppressor of cytokine signaling-1 (SOCS1) develop a complex fatal neonatal disease. In this study, SOCS1-/- mice were shown to exhibit excessive responses typical of those induced by interferon gamma (IFNgamma), were hyperresponsive to viral infection, and yielded macrophages with an enhanced IFNgamma-dependent capacity to kill L. major parasites. The complex disease in SOCS1-/- mice was prevented by administration of anti-IFNgamma antibodies and did not occur in SOCS1-/- mice also lacking the IFNgamma gene. Although IFNgamma is essential for resistance to a variety of infections, the potential toxic action of IFNgamma, particularly in neonatal mice, appears to require regulation. Our data indicate that SOCS1 is a key modulator of IFNgamma action, allowing the protective effects of this cytokine to occur without the risk of associated pathological responses.


Subject(s)
Carrier Proteins/physiology , Gene Expression Regulation, Developmental , Interferon-gamma/antagonists & inhibitors , Repressor Proteins , Signal Transduction , Alphavirus Infections/mortality , Alphavirus Infections/prevention & control , Animals , Disease Susceptibility , Interferon-gamma/pharmacology , Interferon-gamma/physiology , Leishmania major/immunology , Leishmaniasis/mortality , Leishmaniasis/prevention & control , Lymphopenia/mortality , Lymphopenia/prevention & control , Macrophages/drug effects , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Semliki forest virus/immunology , Semliki forest virus/metabolism , Suppressor of Cytokine Signaling 1 Protein , Suppressor of Cytokine Signaling Proteins
6.
J Immunol ; 163(3): 1562-9, 1999 Aug 01.
Article in English | MEDLINE | ID: mdl-10415060

ABSTRACT

Recent studies suggest that Fas expression on pancreatic beta cells may be important in the development of autoimmune diabetes in the nonobese diabetic (NOD) mouse. To address this, pancreatic islets from NOD mice were analyzed by flow cytometry to directly identify which cells express Fas and Fas ligand (FasL) ex vivo and after in vitro culture with cytokines. Fas expression was not detected on beta cells isolated from young (35 days) NOD mice. In vitro, incubation of NOD mouse islets with both IL-1 and IFN-gamma was required to achieve sufficient Fas expression and sensitivity for islets to be susceptible to lysis by soluble FasL. In islets isolated from older (>/=125 days) NOD mice, Fas expression was detected on a limited number of beta cells (1-5%). FasL was not detected on beta cells from either NOD or Fas-deficient MRLlpr/lpr islets. Also, both NOD and MRLlpr/lpr islets were equally susceptible to cytokine-induced cell death. This eliminates the possibility that cytokine-treated murine islet cells commit "suicide" due to simultaneous expression of Fas and FasL. Last, we show that NO is not required for cytokine-induced Fas expression and Fas-mediated apoptosis of islet cells. These findings indicate that beta cells can be killed by Fas-dependent cytotoxicity; however, our results raise further doubts about the clinical significance of Fas-mediated beta cell destruction because few Fas-positive cells were isolated immediately before the development of diabetes.


Subject(s)
Apoptosis/immunology , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/pathology , Islets of Langerhans/immunology , Islets of Langerhans/pathology , fas Receptor/physiology , Animals , Cell Death/immunology , Cells, Cultured , Cytokines/pharmacology , Diabetes Mellitus, Type 1/metabolism , Fas Ligand Protein , Female , Islets of Langerhans/chemistry , Ligands , Membrane Glycoproteins/analysis , Membrane Glycoproteins/biosynthesis , Mice , Mice, Inbred MRL lpr , Mice, Inbred NOD , Nitric Oxide/physiology , Staining and Labeling , Up-Regulation/immunology , fas Receptor/analysis , fas Receptor/biosynthesis
7.
Endocrinology ; 140(7): 3219-27, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10385418

ABSTRACT

Tumor necrosis factor-alpha (TNFalpha) is a potential mediator of beta cell destruction in insulin-dependent diabetes mellitus. We have studied TNF-responsive pathways leading to apoptosis in beta cells. Primary beta cells express low levels of the type I TNF receptor (TNFR1) but do not express the type 2 receptor (TNFR2). Evidence for TNFR1 expression on beta cells came from flow cytometry using monoclonal antibodies specific for TNFR1 and TNFR2 and from RT-PCR of beta cell RNA. NIT-1 insulinoma cells similarly expressed TNFR1 (at higher levels than primary beta cells) as detected by flow cytometry and radio-binding studies. TNF induced NF-kappaB activation in both primary islet cells and NIT-1 cells. Apoptosis in response to TNFalpha was observed in NIT-1 cells whereas apoptosis of primary beta cells required both TNFalpha and interferon-gamma (IFNgamma). Apoptosis could be prevented in NIT-1 cells by expression of dominant negative Fas-associating protein with death domain (dnFADD). Apoptosis in NIT-1 cells was increased by coincubation with IFNgamma, which also increased caspase 1 expression. These data show that TNF-activated pathways capable of inducing apoptotic cell death are present in beta cells. Caspase activation is the dominant pathway of TNF-induced cell death in NIT-1 cells and may be an important mechanism of beta cell damage in insulin-dependent diabetes mellitus.


Subject(s)
Apoptosis/drug effects , Insulinoma/pathology , Islets of Langerhans/physiology , Pancreatic Neoplasms/pathology , Tumor Necrosis Factor-alpha/pharmacology , Animals , Apoptosis/physiology , Caspase 1/metabolism , Caspase Inhibitors , Enzyme Inhibitors/pharmacology , Female , Insulinoma/metabolism , Insulinoma/physiopathology , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Male , Mice , Mice, Inbred NOD , NF-kappa B/physiology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/physiopathology , Receptors, Tumor Necrosis Factor/metabolism , Tumor Cells, Cultured/drug effects
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