Immunosuppressive Effect of Tryptophan Metabolites in Composite Tissue Allotransplantation

Hand transplantations have intensified immunological research into composite tissue allotransplantation to induce tolerance. Pregnancy is a successful, natural model of immunological tolerance. The enzyme indoleamine 2,3-deoxygenase plays an important role by catabolizing the amino acid tryptophan. The resulting metabolites have been shown to be immunosuppressive. The effect of tryptophan metabolites has not been investigated in vascularized organ transplantation before. In this study, the authors applied to composite tissue allotransplantation what nature has developed for pregnancy, and examined the immunosuppressive effect of tryptophan metabolites in a model of hind limb transplantation. Thirty-three allogeneic hind limb transplantations in the rat (Lewis --> Brown-Norway) were performed in three groups. Group A (n = 12) received no immunosuppression, group B (n = 13) received tryptophan metabolites (kynurenine and 3-hydroxyanthranilic acid) locally and systemically, and group C (n = 8) served as a control group receiving FK506. The timing of rejection was assessed by clinical observation. Rejection of the allogeneic hind limb occurred on average 6.58 days after transplantation in group A (no immunosuppression) and after 8.15 days in group B (tryptophan metabolites). Rejection was significantly delayed (log-rank test, p < 0.01). No rejection was seen with application of FK506 during the follow-up period of 21 days. For the first time, tryptophan metabolites have been applied in vascularized composite tissue allotransplantation and showed a significant immunosuppressive effect. These promising first results need further dose-effect and toxicological studies to increase the still limited immunosuppressive effect and define the clinical role these metabolites may play in the future.