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.
Dai
Xiangchen
X
Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Zhu
Bao Ting
BT
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