Immunosuppressive effect of tryptophan metabolites in composite tissue allotransplantation.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Radu
Christian A
CA
Heidelberg, Germany From the Department of Hand, Plastic, and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen; and Department of Plastic and Hand Surgery, Institute of Immunology, Department of Transplantation Immunology, and Department of Experimental Surgery, University of Heidelberg.
Bosch
Nikolaus
N
Bauer
Thomas M
TM
Kleist
Christian
C
Jiga
Lucian
L
Terness
Peter
P
Opelz
Gerhard
G
Gebhard
Martha M
MM
Germann
Guenter
G
Baumeister
Steffen
S
D015095:3-Hydroxyanthranilic Acid / Q000008:administration & dosage*; D000818:Animals; D006084:Graft Rejection / Q000517:prevention & control; D006614:Hindlimb / Q000637:transplantation*; D007108:Immune Tolerance / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007273:Injections, Intramuscular; D007737:Kynurenine / Q000008:administration & dosage*; D023421:Models, Animal; D051381:Rats; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000008:administration & dosage; D016378:Tissue Transplantation; D014364:Tryptophan / Q000378:metabolism*
D007166:Immunosuppressive Agents; D015095:3-Hydroxyanthranilic Acid; D007737:Kynurenine; D014364:Tryptophan; D016559:Tacrolimus