Treatment of Autoimmune Neuroinflammation with a Synthetic Tryptophan Metabolite

• DOI: 10.1126/science.1117634
• Publication Date: 2005-11-03T21:48:00Z
• Authors: Michael Platten; Peggy P. Ho; Sawsan Youssef; Paulo Fontoura; Hideki Garren; Eun Mi Hur; Rohit Gupta; Lowen Y. Lee; Brian A. Kidd; William H. Robinson; Raymond A. Sobel; Michael L. Selley; Lawrence Steinman
• Keywords: 0303 health sciences; Encephalomyelitis, Autoimmune, Experimental; Multiple Sclerosis; Anti-Inflammatory Agents, Non-Steroidal; Histocompatibility Antigens Class II; Antigen-Presenting Cells; Brain; Mice, Transgenic; Lymphocyte Activation; Adoptive Transfer; Cell Line; 3. Good health; Disease Models, Animal; Interferon-gamma; Mice; 03 medical and health sciences; Immune Tolerance; Animals; Cytokines; Indoleamine-Pyrrole 2,3,-Dioxygenase; Female; Microglia; Immunosuppressive Agents

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.