Abstract
Subsidence of inflammation and clinical recovery in experimental autoimmune encephalomyelitis (EAE) is postulated to involve apoptosis of inflammatory cells. To test this concept, we examined the effects of overexpressing the long form of human FLICE-inhibitory protein, a potent inhibitor of death receptor-mediated apoptosis, in myelin oligodendrocyte glycoprotein-induced EAE in DBA/1 mice. We found that overexpression of the long form of human FLICE-inhibitory protein by retroviral gene transfer of hemopoietic stem cells led to a clinically more severe EAE in these mice compared with control mice receiving the retroviral vector alone. The exacerbated disease was evident by an enhanced and prolonged inflammatory reaction in the CNS of these animals compared with control mice. The acute phase of EAE was characterized by a massive infiltration of macrophages and granulocytes and a simultaneous increase in TNF-alpha production in the CNS. In the chronic phase of the disease, there was a prolonged inflammatory response in the form of persistent CD4(+) T and B cells in the CNS and a peripheral Th1 cytokine bias caused by elevated levels of IFN-gamma and reduced levels of IL-4 in the spleen. Our findings demonstrate that death receptor-mediated apoptosis can be important in the pathogenesis of EAE and further emphasize the need for effective apoptotic elimination of inflammatory cells to achieve disease remission.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Disease
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Adjuvants, Immunologic / genetics
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Adjuvants, Immunologic / toxicity
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Animals
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Apoptosis / genetics
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Apoptosis / immunology
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Bone Marrow Cells / immunology
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Carrier Proteins / biosynthesis*
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Carrier Proteins / genetics*
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Carrier Proteins / toxicity
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Cells, Cultured
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Central Nervous System / immunology
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Central Nervous System / metabolism
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Central Nervous System / pathology
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Chronic Disease
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Cytokines / biosynthesis
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Female
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Genetic Vectors
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Growth Inhibitors / genetics
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Growth Inhibitors / physiology
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Hematopoietic Stem Cell Transplantation / adverse effects
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Hematopoietic Stem Cell Transplantation / methods*
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Humans
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Inflammation / genetics
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Inflammation / immunology
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Intracellular Signaling Peptides and Proteins*
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Lymphocyte Activation / genetics
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Mice
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Mice, Inbred DBA
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Myelin Proteins
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Myelin-Associated Glycoprotein / administration & dosage
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Myelin-Associated Glycoprotein / immunology
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Myelin-Oligodendrocyte Glycoprotein
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Protein Isoforms / biosynthesis
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Protein Isoforms / genetics
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Protein Isoforms / toxicity
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Retroviridae / genetics*
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Retroviridae / immunology*
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Stem Cells / immunology
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Transduction, Genetic*
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Tumor Necrosis Factor-alpha / biosynthesis
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fas Receptor / physiology
Substances
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Adjuvants, Immunologic
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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Carrier Proteins
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Cflar protein, mouse
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Cytokines
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Growth Inhibitors
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Intracellular Signaling Peptides and Proteins
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MOG protein, human
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Mog protein, mouse
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Myelin Proteins
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Myelin-Associated Glycoprotein
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Myelin-Oligodendrocyte Glycoprotein
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Protein Isoforms
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Tumor Necrosis Factor-alpha
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fas Receptor