Abstract
Experimental allergic encephalomyelitis (EAE) is an inflammatory, CD4+ Th1-mediated autoimmune disease, which serves as a model for multiple sclerosis. We examined the effect of a novel anti-inflammatory drug, lisofylline (LSF), on EAE induced either by injection of mouse spinal cord homogenate or following transfer of myelin basic protein-reactive T cells. Orally administered LSF significantly inhibited EAE in both cases, decreasing peak clinical scores by >70% and >80%, respectively. In addition, analysis of representative spinal cord sections from LSF-treated mice showed complete lack of demyelination and lymphocyte infiltration. The reduction in EAE correlated with the inhibition of Th1 differentiation by LSF in vivo, as indicated by a reduction in T cell IFN-gamma production ex vivo after Ag restimulation. The inhibition of Th1 differentiation in vivo is consistent with a block in IL-12 receptor signaling, because LSF blocked IL-12-driven Th1 differentiation and T cell proliferation in vitro, yet had no effect on IL-12 secretion from APCs ex vivo or in vitro.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adoptive Transfer
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
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Autoimmune Diseases / drug therapy
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Autoimmune Diseases / immunology
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Autoimmune Diseases / prevention & control*
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Cell Differentiation / drug effects
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Drug Evaluation, Preclinical
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Encephalomyelitis, Autoimmune, Experimental / drug therapy
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / prevention & control*
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Female
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Gene Expression Regulation / drug effects
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Immunization
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Interferon-gamma / biosynthesis
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Interferon-gamma / genetics
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Interleukin-12 / antagonists & inhibitors
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Interleukin-12 / metabolism
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Interleukin-12 / physiology*
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Interleukin-4 / biosynthesis
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Interleukin-4 / genetics
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Lymphocyte Activation / drug effects
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Mice
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Mice, Inbred Strains
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Myelin Basic Protein / immunology
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Pentoxifylline / analogs & derivatives*
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Pentoxifylline / pharmacology
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Pentoxifylline / therapeutic use
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Recombinant Proteins / pharmacology
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Severity of Illness Index
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Signal Transduction / drug effects*
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Th1 Cells / cytology
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Th1 Cells / drug effects*
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Th1 Cells / immunology
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Th1 Cells / metabolism
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Myelin Basic Protein
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Recombinant Proteins
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Interleukin-12
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Interleukin-4
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Interferon-gamma
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lisofylline
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Pentoxifylline