Abstract
T cells play a pivotal role in the initiation and progression of multiple sclerosis. We have found that 1,4-aryl-2-mercaptoimidazole (KRM-III) inhibited T-cell antigen receptor- and phorbol myristate acetate/ionomycin-induced activation of nuclear factor of activated T cells (NFAT) and T-cell proliferation with an IC(50) of 5 microM. The KRM-III-mediated inhibitory effect was specific for NFAT activation but not for nuclear factor kappaB. Oral administration of 90 mg/kg KRM-III resulted in complete abrogation of anti-CD3 antibody-induced T-cell activation and a 45.8% reduction in footpad swelling in bovine serum albumin-induced delayed-type hypersensitivity. In the murine experimental autoimmune encephalomyelitis (EAE) model, oral administration of KRM-III significantly attenuated the severity of disease when given before or after disease onset. Draining lymph node cells from KRM-III-treated mice showed markedly reduced proliferation in response to myelin oligodendrocyte glycoprotein peptide. Histological analysis indicated that KRM-III reduced the infiltration of inflammatory cells to the white matter of spinal lumbar cords. These results demonstrate that KRM-III efficiently inhibits T-cell activation and inflammatory responses and lessens EAE clinical signs, which suggest KRM-III as a potential lead compound for the treatment of T-cell-driven autoimmune diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Cell Proliferation / drug effects*
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Encephalomyelitis, Autoimmune, Experimental / diagnosis
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Encephalomyelitis, Autoimmune, Experimental / drug therapy*
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Female
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Humans
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Hypersensitivity, Delayed / diagnosis
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Hypersensitivity, Delayed / drug therapy*
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Hypersensitivity, Delayed / immunology
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Imidazoles / administration & dosage
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Imidazoles / chemistry
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Imidazoles / pharmacokinetics
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Imidazoles / therapeutic use*
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Immunologic Factors / administration & dosage
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Immunologic Factors / chemistry
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Immunologic Factors / pharmacokinetics
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Immunologic Factors / therapeutic use*
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Interleukin-2 / immunology
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Jurkat Cells
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Lymph Nodes / immunology
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Molecular Structure
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Multiple Sclerosis / immunology
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Multiple Sclerosis / prevention & control
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NFATC Transcription Factors / immunology
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Receptors, Antigen, T-Cell / immunology
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Severity of Illness Index
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Spinal Cord / immunology
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T-Lymphocytes / drug effects*
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T-Lymphocytes / immunology
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Thiones / administration & dosage
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Thiones / chemistry
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Thiones / pharmacokinetics
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Thiones / therapeutic use*
Substances
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1,4-diphenyl-2-mercaptoimidazole
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Imidazoles
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Immunologic Factors
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Interleukin-2
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NFATC Transcription Factors
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Receptors, Antigen, T-Cell
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Thiones