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3,4-DAA, an orally active synthetic tryptophan catabolite, treats established autoimmune neuroinflammation
Depletion of the essential amino acid tryptophan (Trp) by antigen-presenting cells (APCs) is believed to suppress antigen-specific T cell responses. For instance, inhibition of indoleamine-2,3-dioxygenase (IDO) which is the rate-limiting enzyme in Trp catabolism induces the rejection of tumors and fetal allografts. Thus, IDO appears to play a central role in maintaining T cell tolerance.
Using gene microarray analyses we show that IDO transcripts were more abundant in myelin-specific T cells stimulated with tolerogenic altered self-peptide compared to myelin-specific T cells stimulated with native self-peptide. Moreover we demonstrate that Trp catabolites actively suppressed antigen-specific T cell immunity. Specifically, the Trp catabolites 3-hydroxyanthranilic acid and 3-hydroxykynurenine inhibited the proliferation of T cells reactive to myelin basic protein (MBP). Furthermore, treatment of MBP-reactive T cells with Trp catabolites decreased the production of TH1 cytokines and increased the release of TH2 cytokines.
Finally, we identify a synthetic derivative of the Trp metabolite 3-hydroxyanthranilic acid, N-(3,4,-dimethoxycinnamoyl)anthranilic acid (3,4-DAA). 3,4-DAA also inhibited myelin-specific T cell proliferation and suppressed TH1 cytokines while inducing TH2 cytokines. In addition, 3,4-DAA suppressed the activation of microglial cells by interfering with signal transducer and activator of transcription (STAT) pathways. Oral 3,4-DAA treatment of mice with experimental autoimmune encephalomyelitis (EAE) downregulated the expression of main histocompatibility complex (MHC) class II and costimulatory molecules on microglial cells. In mice with established EAE oral administration of 3,4-DAA ameliorated relapses.
In conclusion, Trp catabolites and their derivatives suppress antigen-specific TH1 cell immunity, thus representing a new approach to treat TH1-mediated autoimmune diseases, such as multiple sclerosis.