Department of Hematology and Oncological Sciences L. & A. Seràgnoli, Via Massarenti, 9, 40138, Bologna, Italy.
Haematologica. 2010 Dec;95(12):2022-30. doi: 10.3324/haematol.2010.025924. Epub 2010 Aug 26.
The immunoregulatory enzyme indoleamine 2,3-dioxygenase, which catalyzes the conversion of tryptophan into kynurenine, is expressed in a significant subset of patients with acute myeloid leukemia, resulting in the inhibition of T-cell proliferation and the induction of regulatory T cells. Acute myeloid leukemia cells can be differentiated into dendritic cells, which have increased immunogenicity and have been proposed as vaccines against leukemia.
Leukemic dendritic cells were generated from acute myeloid leukemia cells and used as stimulators in functional assays, including the induction of regulatory T cells. Indoleamine 2,3-dioxygenase expression in leukemic dendritic cells was evaluated at molecular, protein and enzymatic levels.
We demonstrate that, after differentiation into dendritic cells, both indoleamine 2,3-dioxygenase-negative and indoleamine 2,3-dioxygenase-positive acute myeloid leukemia samples show induction and up-regulation of indoleamine 2,3-dioxygenase gene and protein, respectively. Indoleamine 2,3-dioxygenase-positive acute myeloid leukemia dendritic cells catabolize tryptophan into kynurenine metabolite and inhibit T-cell proliferation through an indoleamine 2,3-dioxygenase-dependent mechanism. Moreover, indoleamine 2,3-dioxygenase-positive leukemic dendritic cells increase the number of allogeneic and autologous CD4(+)CD25(+) Foxp3(+) T cells and this effect is completely abrogated by the indoleamine 2,3-dioxygenase-inhibitor, 1-methyl tryptophan. Purified CD4(+)CD25(+) T cells obtained from co-culture with indoleamine 2,3-dioxygenase-positive leukemic dendritic cells act as regulatory T cells as they inhibit naive T-cell proliferation and impair the complete maturation of normal dendritic cells. Importantly, leukemic dendritic cell-induced regulatory T cells are capable of in vitro suppression of a leukemia-specific T cell-mediated immune response, directed against the leukemia-associated antigen, Wilms' tumor protein.
These data identify indoleamine 2,3-dioxygenase-mediated catabolism as a tolerogenic mechanism exerted by leukemic dendritic cells and have clinical implications for the use of these cells for active immunotherapy of leukemia.
免疫调节酶吲哚胺 2,3-双加氧酶可催化色氨酸转化为犬尿氨酸，在很大一部分急性髓系白血病患者中表达，导致 T 细胞增殖受到抑制，并诱导调节性 T 细胞。急性髓系白血病细胞可分化为树突状细胞，其免疫原性增加，并被提议作为白血病疫苗。
从急性髓系白血病细胞中生成白血病树突状细胞，并在功能测定中用作刺激物，包括诱导调节性 T 细胞。在分子、蛋白质和酶水平上评估白血病树突状细胞中的吲哚胺 2,3-双加氧酶表达。
我们证明，在分化为树突状细胞后，吲哚胺 2,3-双加氧酶阴性和吲哚胺 2,3-双加氧酶阳性急性髓系白血病样本分别显示吲哚胺 2,3-双加氧酶基因和蛋白的诱导和上调。吲哚胺 2,3-双加氧酶阳性急性髓系白血病树突状细胞通过吲哚胺 2,3-双加氧酶依赖机制将色氨酸代谢为犬尿氨酸代谢物，并抑制 T 细胞增殖。此外，吲哚胺 2,3-双加氧酶阳性白血病树突状细胞增加同种异体和自体 CD4+CD25+Foxp3+T 细胞的数量，这种效应被吲哚胺 2,3-双加氧酶抑制剂 1-甲基色氨酸完全阻断。从与吲哚胺 2,3-双加氧酶阳性白血病树突状细胞共培养中获得的纯化 CD4+CD25+T 细胞作为调节性 T 细胞起作用，因为它们抑制幼稚 T 细胞增殖并损害正常树突状细胞的完全成熟。重要的是，白血病树突状细胞诱导的调节性 T 细胞能够在体外抑制针对白血病相关抗原 Wilms 瘤蛋白的白血病特异性 T 细胞介导的免疫反应。
这些数据确定了吲哚胺 2,3-双加氧酶介导的代谢作为白血病树突状细胞发挥的耐受机制，并对这些细胞用于白血病主动免疫治疗具有临床意义。
