Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite.
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.
Platten
Michael
M
Department of Neurology and Neurological Sciences, Beckman Center for Molecular Medicine, Stanford University, Stanford, CA 94305, USA. michael.platten@uni-tuebingen.de
Ho
Peggy P
PP
Youssef
Sawsan
S
Fontoura
Paulo
P
Garren
Hideki
H
Hur
Eun Mi
EM
Gupta
Rohit
R
Lee
Lowen Y
LY
Kidd
Brian A
BA
Robinson
William H
WH
Sobel
Raymond A
RA
Selley
Michael L
ML
Steinman
Lawrence
L
D019264:Adoptive Transfer; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D001921:Brain / Q000473:pathology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000276:immunology; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D009185:Myelin Proteins / Q000276:immunology; D015398:Signal Transduction; D013116:Spinal Cord / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014364:Tryptophan / Q000378:metabolism*; D062367:ortho-Aminobenzoates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D009185:Myelin Proteins; D062367:ortho-Aminobenzoates; D007371:Interferon-gamma; D014364:Tryptophan; C012293:tranilast