Suppression of T-cell response and prolongation of allograft survival in a rat model by tryptophan catabolites

Indoleamine 2,3-dioxygenase is a rate-limiting enzyme involved in the conversion of tryptophan to various endogenous catabolites, such as 3-hydroxyanthranilic acid, 3-hydroxykynurenine, and l-kynurenine. This study aims to provide evidence to support the hypothesis that some of the tryptophan catabolites may exert strong immunosuppression against allograft rejection by inhibiting allogeneic T-cell response. The mixed lymphocyte proliferation assay was used as an in-vitro model and the rat cardiac allograft as an in-vivo model. We found that 3-hydroxyanthranilic acid and 3-hydroxykynurenine inhibited T-cell proliferation in a concentration-dependent manner. Both dendritic cell-stimulated T-cell proliferation and baseline T-cell proliferation (in the absence of dendritic cells) were inhibited by these tryptophan catabolites. Using the rat cardiac allograft model, we showed that a single i.v. administration of 3-hydroxyanthranilic acid + allogeneic dendritic cells seven days before cardiac grafting markedly prolonged the graft survival in the recipient (from seven days to fifteen days). Additional studies showed that this single administration of 3-hydroxyanthranilic acid wiped out a majority of specific T-cell sub-populations that were activated by allogeneic dendritic cells. This strong inhibition by 3-hydroxyanthranilic acid is believed to be an important mechanism contributing to the development of immunotolerance against the allogeneic graft. These observations offer a potential strategy for using tryptophan catabolites together with allogeneic dendritic cells to induce selective immunotolerance against allogeneic grafts in the recipients.