Suppression of T-cell response and prolongation of allograft survival in a rat model by tryptophan catabolites.
Indoleamine 2,3-dioxygenase is a rate-limiting enzyme involved in the conversion of tryptophan to various endogenous catabolites, such as 3-hydroxyanthranilic acid, 3-hydroxykynurenine, and L-kynurenine. This study aims to provide evidence to support the hypothesis that some of the tryptophan catabolites may exert strong immunosuppression against allograft rejection by inhibiting allogeneic T-cell response. The mixed lymphocyte proliferation assay was used as an in-vitro model and the rat cardiac allograft as an in-vivo model. We found that 3-hydroxyanthranilic acid and 3-hydroxykynurenine inhibited T-cell proliferation in a concentration-dependent manner. Both dendritic cell-stimulated T-cell proliferation and baseline T-cell proliferation (in the absence of dendritic cells) were inhibited by these tryptophan catabolites. Using the rat cardiac allograft model, we showed that a single i.v. administration of 3-hydroxyanthranilic acid+allogeneic dendritic cells seven days before cardiac grafting markedly prolonged the graft survival in the recipient (from seven days to fifteen days). Additional studies showed that this single administration of 3-hydroxyanthranilic acid wiped out a majority of specific T-cell sub-populations that were activated by allogeneic dendritic cells. This strong inhibition by 3-hydroxyanthranilic acid is believed to be an important mechanism contributing to the development of immunotolerance against the allogeneic graft. These observations offer a potential strategy for using tryptophan catabolites together with allogeneic dendritic cells to induce selective immunotolerance against allogeneic grafts in the recipients.
Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Xiangchen
X
Dai
Bao Ting
BT
Zhu
D015095:3-Hydroxyanthranilic Acid / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001853:Bone Marrow / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051381:Rats; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D023001:Transplantation Tolerance / Q000187:drug effects* / Q000276:immunology; D014364:Tryptophan / Q000378:metabolism* / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D015095:3-Hydroxyanthranilic Acid; D014364:Tryptophan