Inhibition of indoleamine 2,3-dioxygenase by stereoisomers of 1-methyl tryptophan in an experimental graft-versus-tumor model

Ji-Young Lim; Sung-Eun Lee; Gyenogsin Park; Eun Young Choi; Chang-Ki Min

doi:10.1016/j.exphem.2014.06.006

Inhibition of indoleamine 2,3-dioxygenase by stereoisomers of 1-methyl tryptophan in an experimental graft-versus-tumor model

Exp Hematol. 2014 Oct;42(10):862-6.e3. doi: 10.1016/j.exphem.2014.06.006. Epub 2014 Jun 24.

Authors

Ji-Young Lim¹, Sung-Eun Lee¹, Gyenogsin Park², Eun Young Choi³, Chang-Ki Min⁴

Affiliations

¹ Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
² Department of Pathology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
³ Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
⁴ Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea. Electronic address: [email protected].

PMID: 24971697
DOI: 10.1016/j.exphem.2014.06.006

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.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Allografts
Animals
Bone Marrow Transplantation
Cell Line, Tumor
Cytotoxicity, Immunologic
Drug Evaluation, Preclinical
Enzyme Induction
Graft vs Tumor Effect / drug effects
Graft vs Tumor Effect / physiology*
Immunologic Factors / pharmacology*
Immunologic Factors / therapeutic use
Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
Indoleamine-Pyrrole 2,3,-Dioxygenase / physiology
Interferon-gamma / biosynthesis
Kynurenine / biosynthesis
Kynurenine / blood
Leukocyte Transfusion
Lymph Nodes / enzymology
Lymphocyte Culture Test, Mixed
Mastocytoma / drug therapy
Mastocytoma / enzymology
Mastocytoma / immunology
Mastocytoma / therapy*
Mice
Mice, Inbred C57BL
Neoplasm Proteins / antagonists & inhibitors*
Neoplasm Proteins / physiology
Radiation Chimera
Spleen / enzymology
Stereoisomerism
Time Factors
Transplantation Chimera
Tryptophan / analogs & derivatives*
Tryptophan / chemistry
Tryptophan / metabolism
Tryptophan / pharmacology
Tryptophan / therapeutic use

Substances

IDO1 protein, mouse
Immunologic Factors
Indoleamine-Pyrrole 2,3,-Dioxygenase
Neoplasm Proteins
Kynurenine
Interferon-gamma
Tryptophan
1-methyltryptophan