Abstract
The proinflammatory Th1 cytokine, tumor necrosis factor-alpha (TNF alpha), the cell death signaling molecule FasL, and several extracellular matrix degrading metalloproteinases have been implicated in the pathogenesis of multiple sclerosis (MS). The latter enzymes, as well as TNF alpha-converting enzyme and FasL-converting enzyme, can be blocked by matrix metalloproteinase inhibitors (MMPIs). In this study, we show that a potent MMPI was clinically effective in an animal model for MS, experimental autoimmune encephalomyelitis (EAE) in the SJL/J mouse. Efficacy was remarkable, as indicated by blocking and reversal of acute disease and reduced number of relapses and diminished mean cumulative disease score in chronic relapsing animals. Also, demyelination and glial scarring were significantly decreased in MMPI-treated mice with chronic relapsing EAE, as was central nervous system gene expression for TNF alpha and fasL. It is interesting that expression of the beneficial cytokine interleukin-4 (IL-4) was increased, and IL-4 was expressed on glial cells. The relevance of these compounds for MS was underscored by their ability to specifically inhibit TNF alpha shedding and cytotoxicity of myelin-autoreactive human cytotoxic CD4+ T-cell clones. This is the first report to show a positive effect by MMPIs on chronic relapsing EAE, its central nervous system cytokine profile, and on TNF alpha shedding by human myelin-autoreactive T cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Astrocytes / chemistry
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Autoimmune Diseases / drug therapy
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Autoimmune Diseases / pathology
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Base Sequence
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Benzyl Compounds
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Chi-Square Distribution
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Clone Cells
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Cytokines / analysis
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Cytokines / genetics
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Demyelinating Diseases / pathology
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Demyelinating Diseases / prevention & control
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Dexamethasone / pharmacology
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Dexamethasone / therapeutic use*
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Down-Regulation
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Drug Combinations
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Encephalitis / drug therapy*
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Encephalitis / pathology
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Gene Expression Regulation / drug effects
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Glial Fibrillary Acidic Protein / analysis
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Humans
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Hydroxamic Acids / therapeutic use*
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Immunohistochemistry
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Metalloendopeptidases / antagonists & inhibitors*
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Mice
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Microglia / chemistry
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Microscopy, Electron
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Multiple Sclerosis / drug therapy*
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Multiple Sclerosis / pathology
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Optic Nerve / ultrastructure
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Organic Chemicals
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Pentoxifylline / pharmacology
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Pentoxifylline / therapeutic use*
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Protease Inhibitors / pharmacology
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Protease Inhibitors / therapeutic use*
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RNA / analysis
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Recurrence
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Spinal Cord / ultrastructure
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Statistics, Nonparametric
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Succinates
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Tumor Necrosis Factor-alpha / drug effects
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Up-Regulation
Substances
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BB 1101
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BB 1268
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BB 2275
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Benzyl Compounds
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Cytokines
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Drug Combinations
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Glial Fibrillary Acidic Protein
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Hydroxamic Acids
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Organic Chemicals
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Protease Inhibitors
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Succinates
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Tumor Necrosis Factor-alpha
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RNA
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Dexamethasone
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Metalloendopeptidases
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Pentoxifylline