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Science 310 (5749): 850-855

Copyright © 2005 by the American Association for the Advancement of Science

Treatment of Autoimmune Neuroinflammation with a Synthetic Tryptophan Metabolite

Michael Platten,1,3*{dagger} Peggy P. Ho,1* Sawsan Youssef,1 Paulo Fontoura,1,4 Hideki Garren,1,5 Eun Mi Hur,1 Rohit Gupta,1 Lowen Y. Lee,1 Brian A. Kidd,1,6 William H. Robinson,1,6 Raymond A. Sobel,2 Michael L. Selley,7 Lawrence Steinman1{dagger}

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 (TH1) 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 TH1-mediated autoimmune diseases such as MS.

1 Department of Neurology and Neurological Sciences, Beckman Center for Molecular Medicine, Stanford University, Stanford, CA 94305, USA.
2 Department of Pathology (Neuropathology), Stanford University, Stanford, CA 94305, USA.
3 Department of General Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
4 Department of Immunology, Faculty of Medical Sciences, New University of Lisbon, 1169–056 Lisbon, Portugal.
5 Bayhill Therapeutics Inc., Palo Alto, CA 94303, USA.
6 Geriatrics Research and Education Clinical Center (GRECC), Veterans Affairs Health System, Palo Alto, CA 94304, USA.
7 Angiogen Pharmaceuticals Pty. Ltd., Sydney, NSW 2000, Australia.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: steinman{at}stanford.edu (L.S.), michael.platten{at}uni-tuebingen.de (M.P.)


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