title: Inhibition of indoleamine 2,3-dioxygenase by stereoisomers of 1-methyl tryptophan in an experimental graft-versus-tumor model.
abstract: Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme in tryptophan catabolism that plays an important role in the induction of immune tolerance. Its role in graft-versus-tumor effect after allogeneic stem cell transplantation (allo-SCT) remains unclear. Using a murine graft-versus-tumor model of reduced-intensity allo-HSCT followed by donor leukocyte infusion (DLI), we examined the role of IDO inhibition. Two stereoisomers of 1-methyl tryptophan (1-MT), a small-molecule inhibitor of IDO, reduced the growth of inoculated tumor in the mice that received DLI and had higher expression of IDO1 and IFNγ. However, L-1MT, but not D-1MT, mitigated tumor growth in mice that did not receive DLI and did not express IDO1 and IFNγ. Accordingly, both stereoisomers reduced plasma kynurenine concentrations early after DLI and enhanced in vitro cytotoxic lymphocyte function after allogeneic mixed lymphocyte reaction. Furthermore, L-1MT was more efficient in causing direct cytotoxic effects than D-1MT. Our results suggest that IDO inhibition can benefit anti-tumor therapy in the setting of reduced-intensity allo-SCT using DLI.
authors: Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
authors: Ji-Young
authors: JY
authors: Lim
authors: Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
authors: Sung-Eun
authors: SE
authors: Lee
authors: Department of Pathology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
authors: Gyenogsin
authors: G
authors: Park
authors: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors: Eun Young
authors: EY
authors: Choi
authors: Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea. Electronic address: ckmin@catholic.ac.kr.
authors: Chang-Ki
authors: CK
authors: Min
mesh_terms: D064591:Allografts; D000818:Animals; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004353:Drug Evaluation, Preclinical; D004790:Enzyme Induction; D020350:Graft vs Tumor Effect / Q000187:drug effects / Q000502:physiology*; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis; D007737:Kynurenine / Q000096:biosynthesis / Q000097:blood; D017708:Leukocyte Transfusion; D008198:Lymph Nodes / Q000201:enzymology; D007959:Lymphocyte Culture Test, Mixed; D034801:Mastocytoma / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D011828:Radiation Chimera; D013154:Spleen / Q000201:enzymology; D013237:Stereoisomerism; D013997:Time Factors; D018183:Transplantation Chimera; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C583637:IDO1 protein, mouse; D007155:Immunologic Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D009363:Neoplasm Proteins; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan; C525396:1-methyltryptophan