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Studying the immunosuppressive role of indoleamine 2,3‐dioxygenase: tryptophan metabolites suppress rat allogeneic T‐cell responses in vitro and in vivo

Pregnancy is a natural model of successful tolerance induction against allogeneic tissues. Recent studies pointed to a role of indoleamine 2,3‐dioxygenase (IDO), a tryptophan‐degrading enzyme expressed in the placenta, in mediation of T‐cell suppression. We want to apply to organ transplantation what nature has developed for suppression of fetal rejection during pregnancy. Here we analyze whether IDO‐induced tryptophan metabolites are able to suppress the allogeneic T‐cell response and allograft rejection in rats. Rat lymphocytes were stimulated with allogeneic dendritic cells in vitro in the presence of increasing amounts of tryptophan metabolites (kynurenine, 3‐hydroxykynurenine, anthranilic acid, 3‐hydroxyanthranilic acid and quinolinic acid) and T‐cell proliferation was determined. The findings showed that kynurenine, 3‐hydroxykynurenine and 3‐hydroxyanthranilic acid strongly suppress the T‐cell response, whereas anthranilic and quinolinic acid are noneffective. Vital staining of cells with subsequent fluorescence‐activated cell sorter analyses demonstrated that suppression is mediated by T‐cell death. Thereafter, the action of metabolites was analyzed in a skin allograft model (BN→LEW). Lewis recipients received daily s.c. injections of tryptophan metabolite mixture (kynurenine + 3‐hydroxyanthranilic acid), cyclosporin A (positive control), or no treatment (negative control). The metabolites induced a significant prolongation (P = 0.0018) of graft survival. We conclude that IDO‐induced tryptophan metabolites suppress the T‐cell response and prolong allograft survival in rats.