Paquette R L, Hsu N, Said J, Mohammed M, Rao N P, Shih G, Schiller G, Sawyers C, Glaspy J A
UCLA Department of Medicine, Division of Hematology/Oncology, Los Angeles, CA 90095-1678, USA.
Leukemia. 2002 Aug;16(8):1484-9. doi: 10.1038/sj.leu.2402602.
The ability of interferon-alpha (IFN-alpha) to induce dendritic cell (DC) differentiation in chronic myeloid leukemia (CML) was evaluated. Peripheral blood mononuclear cells from CML patients cultured with IFN-alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF) developed a dendritic morphology. Fluorescence in situ hybridization demonstrated that the DCs harbored the bcr/abl translocation. The DCs prepared with IFN-alpha/GM-CSF expressed significantly higher levels of class I and II HLA than those grown in interleukin-4 (IL-4) and GM-CSF. The DCs prepared from newly diagnosed CML patients using IFN-alpha/GM-CSF expressed immunoregulatory proteins at levels comparable to normal DCs. In contrast, DCs cultured from CML patients who did not achieve a cytogenetic response to IFN-alpha expressed significantly lower levels of class I HLA, CD40, CD54, CD80 and CD86 than normal DCs. The expression of CD86 by CML DCs was enhanced when they were cultured with IFN-alpha/IL-4/GM-CSF, or when IFN-alpha/GM-CSF-treated cells were induced to mature by CD40 ligand. The DCs from IFN-alpha failures were less stimulatory than normal DCs in the allogeneic mixed leukocyte reaction. CML patients who had a cytogenetic response to IFN-alpha initially had low numbers of bone marrow DCs that increased significantly with treatment, while nonresponders had more prevalent DCs at baseline that showed no consistent change with treatment. Therefore, IFN-alpha can induce DC differentiation from CML progenitor cells both in vitro and in vivo. The therapeutic activity of IFN-alpha in CML may be due to its ability to stimulate the generation of DCs that can present CML-specific antigens. Resistance to IFN-alpha may result when DC differentiation becomes impaired.
评估了α-干扰素（IFN-α）在慢性髓性白血病（CML）中诱导树突状细胞（DC）分化的能力。来自CML患者的外周血单个核细胞与IFN-α和粒细胞-巨噬细胞集落刺激因子（GM-CSF）一起培养后呈现出树突状形态。荧光原位杂交显示这些DC含有bcr/abl易位。用IFN-α/GM-CSF制备的DC比用白细胞介素-4（IL-4）和GM-CSF培养的DC表达更高水平的I类和II类 HLA。使用IFN-α/GM-CSF从新诊断的CML患者制备的DC表达免疫调节蛋白的水平与正常DC相当。相比之下，未对IFN-α产生细胞遗传学反应的CML患者培养的DC表达的I类HLA、CD40、CD54、CD80和CD86水平明显低于正常DC。当CML DC与IFN-α/IL-4/GM-CSF一起培养时，或者当IFN-α/GM-CSF处理的细胞被CD40配体诱导成熟时，其CD86的表达会增强。在同种异体混合淋巴细胞反应中，来自对IFN-α治疗无效患者的DC比正常DC的刺激作用更小。最初对IFN-α有细胞遗传学反应的CML患者骨髓DC数量较少，治疗后显著增加，而无反应者基线时DC更普遍，治疗后无一致变化。因此，IFN-α在体外和体内均可诱导CML祖细胞分化为DC。IFN-α在CML中的治疗活性可能归因于其刺激能够呈递CML特异性抗原的DC生成的能力。当DC分化受损时可能会导致对IFN-α产生耐药性。
