Lim Ji-Young, Lee Sung-Eun, Park Gyenogsin, Choi Eun Young, Min Chang-Ki
Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
Department of Pathology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
Exp Hematol. 2014 Oct;42(10):862-6.e3. doi: 10.1016/j.exphem.2014.06.006. Epub 2014 Jun 24.
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.
吲哚胺2,3-双加氧酶（IDO）是色氨酸分解代谢中的一种限速酶，在诱导免疫耐受中起重要作用。其在异基因干细胞移植（allo-SCT）后的移植物抗肿瘤效应中的作用仍不清楚。我们使用了一种低强度allo-HSCT后进行供体白细胞输注（DLI）的小鼠移植物抗肿瘤模型，研究了IDO抑制的作用。IDO的小分子抑制剂1-甲基色氨酸（1-MT）的两种立体异构体，减少了接受DLI且IDO1和IFNγ表达较高的小鼠中接种肿瘤的生长。然而，L-1MT而非D-1MT减轻了未接受DLI且不表达IDO1和IFNγ的小鼠的肿瘤生长。因此，两种立体异构体在DLI后早期均降低了血浆犬尿氨酸浓度，并增强了异基因混合淋巴细胞反应后的体外细胞毒性淋巴细胞功能。此外，L-1MT在产生直接细胞毒性作用方面比D-1MT更有效。我们的结果表明，IDO抑制可有益于在使用DLI的低强度allo-SCT背景下的抗肿瘤治疗。
