title: Studying the immunosuppressive role of indoleamine 2,3-dioxygenase: tryptophan metabolites suppress rat allogeneic T-cell responses in vitro and in vivo.
abstract: 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 non-effective. 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.
authors.affiliation: Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bauer
authors.forename: Lucian P
authors.initials: LP
authors.lastname: Jiga
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Chuang
authors.forename: Marco
authors.initials: M
authors.lastname: Randazzo
authors.forename: Gerhard
authors.initials: G
authors.lastname: Opelz
authors.forename: Peter
authors.initials: P
authors.lastname: Terness
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology; D014364:Tryptophan / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000494:pharmacology*
chemical_list: D007166:Immunosuppressive Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan; D014366:Tryptophan Oxygenase