Abstract
Local catabolism of the amino acid tryptophan (Trp) by indoleamine 2,3-dioxygenase (IDO) is considered an important mechanism of regulating T cell immunity. We show that IDO transcription was increased when myelin-specific T cells were stimulated with tolerogenic altered self-peptides. Catabolites of Trp suppressed proliferation of myelin-specific T cells and inhibited production of proinflammatory T helper-1 (T(H)1) cytokines. N-(3,4,-Dimethoxycinnamoyl) anthranilic acid (3,4-DAA), an orally active synthetic derivative of the Trp metabolite anthranilic acid, reversed paralysis in mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis (MS). Trp catabolites and their derivatives offer a new strategy for treating T(H)1-mediated autoimmune diseases such as MS.
Publication types
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Research Support, N.I.H., Extramural
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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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Adoptive Transfer
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
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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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Antigen-Presenting Cells / drug effects
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Antigen-Presenting Cells / immunology
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Brain / pathology
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Cell Line
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Cytokines / biosynthesis
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Disease Models, Animal
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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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Histocompatibility Antigens Class II / immunology
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Histocompatibility Antigens Class II / metabolism
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Immune Tolerance
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Immunosuppressive Agents / pharmacology
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Immunosuppressive Agents / therapeutic use
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Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
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Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
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Interferon-gamma / immunology
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Lymphocyte Activation
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Mice
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Mice, Transgenic
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Microglia / drug effects
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Microglia / immunology
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Multiple Sclerosis / drug therapy
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Multiple Sclerosis / immunology
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Multiple Sclerosis / pathology
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Myelin Proteins / immunology
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Signal Transduction
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Spinal Cord / pathology
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T-Lymphocytes / immunology
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Th1 Cells / immunology
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Th2 Cells / immunology
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Tryptophan / metabolism*
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ortho-Aminobenzoates / administration & dosage
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ortho-Aminobenzoates / pharmacology
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ortho-Aminobenzoates / therapeutic use*
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Cytokines
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Histocompatibility Antigens Class II
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Immunosuppressive Agents
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Indoleamine-Pyrrole 2,3,-Dioxygenase
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Myelin Proteins
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ortho-Aminobenzoates
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Interferon-gamma
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Tryptophan
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tranilast