Studying the immunosuppressive role of indoleamine 2,3-dioxygenase: tryptophan metabolites suppress rat allogeneic T-cell responses in vitro and in vivo
- 1 January 2005
- journal article
- Published by Frontiers Media SA in Transplant International
- Vol. 18 (1), 95-100
- https://doi.org/10.1111/j.1432-2277.2004.00031.x
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.Keywords
This publication has 13 references indexed in Scilit:
- Tolerogenic Dendritic CellsAnnual Review of Immunology, 2003
- Manipulation of Brain Kynurenines: Glial Targets, Neuronal Effects, and Clinical OpportunitiesJournal of Pharmacology and Experimental Therapeutics, 2002
- Potential Regulatory Function of Human Dendritic Cells Expressing Indoleamine 2,3-DioxygenaseScience, 2002
- Inhibition of Allogeneic T Cell Proliferation by Indoleamine 2,3-Dioxygenase–expressing Dendritic CellsThe Journal of Experimental Medicine, 2002
- Endogenous kynurenines as targets for drug discovery and developmentNature Reviews Drug Discovery, 2002
- Characterization of Murine Dendritic Cells Derived from Adherent Blood Mononuclear Cells In VitroScandinavian Journal of Immunology, 2000
- Immunology at the Maternal-Fetal Interface: Lessons for T Cell Tolerance and SuppressionAnnual Review of Immunology, 2000
- Indoleamine 2,3-Dioxygenase Production by Human Dendritic Cells Results in the Inhibition of T Cell ProliferationPublished by The American Association of Immunologists ,2000
- Redox reactions related to indoleamine 2,3-dioxygenase and tryptophan metabolism along the kynurenine pathwayRedox Report, 1999
- Antioxidant Activities and Redox Regulation of Interferon-Gamma-Induced Tryptophan Metabolism in Human Monocytes and MacrophagesAdvances in experimental medicine and biology, 1999