3,4-DAA

Local catabolism of the amino acid tryptophan by indoleamine 2,3-dioxygenase (IDO) is considered an important mechanism of regulating T-cell immunity. Inhibition of the production of T helper-1 (TH1) cytokines offers a new strategy for treating TH1 mediated autoimmune diseases such as multiple sclerosis. 3,4-DAA is an orally active synthetic derivative of the tryptophan metabolite anthranilic acid. It suppresses antigen-specific proliferation of MBP Ac1-11 TCR CD4+ T-cells. At a concentration of 200 µM, 3,4-DAA reduces IFN-y, IL-2, IL-12/23 p40, and TNFa in splenocytes from antigen-induced transgenic mice. However, at a concentration of 30 µM, IL-4, and IL-10 levels were increased. Expression of inducible nitric oxide synthase and nitric oxide release from EOC20 cells induced by IFN-y and LPS are also suppressed by 3,4-DAA at concentration of 30-200 µM. Mice with experimental autoimmune encephalomyelitis treated orally (300 mg/kg per day) with 3,4-DAA exhibited fewer and milder relapses and less severe disease compared to control animals.{13600}