Immunology Department, School of Medicine, Tehran University of Medical Sciences, Poorsina Ave., 16 Azar St., Keshavarz Blvd., P.O. Box: 14155-6447, Tehran, Islamic Republic of Iran.
Target Oncol. 2014 Sep;9(3):225-37. doi: 10.1007/s11523-013-0285-6. Epub 2013 Jul 14.
Dendritic cells (DCs) are recognized as key regulators of the immune system. Active DC immunization protocols are quickly obtaining interest as an alternative therapeutic approach in acute myeloid leukemia patients. Despite apparent progress in DC-based immunotherapy, some discrepancies were reported in generating potent DCs and their source. In addition to monocytes, DCs can be differentiated from leukemic blasts of acute myeloid leukemia (AML) patients (AML-DC) possessing the ability of stimulating anti-leukemic immune response. In this study, we differentiated peripheral blood blasts of 16 out of 20 AML patients in vitro in the presence of GM-CSF and IL-4 into immature AML-DC. Then, DCs matured using different combinations of Toll-like receptor (TLR) ligands to obtain functional DCs as demonstrated by cell morphology, immunophenotype, and functional activity. Autologous cytotoxic T cell induction of matured DCs was evaluated in four patients and compared with immature counterparts. Our results showed that although the TLR3 agonist (Poly I:C) has a synergistic effect on the TLR4 agonist (lipopolysaccharide, LPS), the addition of the TLR7/8 agonist (R848) is necessary to reinforce the effect of LPS or LPS + POLY(I:C) to produce efficient DCs with the higher level of IL-12 (30 to 90 times). Such DCs activate allogeneic T cells and effectively prime autologous cytotoxic T cells in vitro. In contrast, FSL-1 as a TLR2/6 agonist has a negative effect on LPS + Poly(I:C) and LPS + R848 to produce IL-12. Thus, DCs prepared using a maturation mixture including a TLR7/8 agonist may be used as a potential tool for DC-based immunotherapy purposes in leukemic patients.
树突状细胞 (DCs) 被认为是免疫系统的关键调节因子。活性 DC 免疫接种方案作为急性髓系白血病患者的一种替代治疗方法，正在迅速受到关注。尽管基于 DC 的免疫疗法取得了明显进展，但在产生有效的 DC 及其来源方面仍存在一些差异。除单核细胞外，DC 还可以从急性髓系白血病 (AML) 患者的白血病细胞 (AML-DC) 分化而来，具有刺激抗白血病免疫反应的能力。在这项研究中，我们在 GM-CSF 和 IL-4 的存在下，将 20 名 AML 患者中的 16 名的外周血白血病细胞体外分化为未成熟的 AML-DC。然后，我们使用不同的 Toll 样受体 (TLR) 配体组合使 DC 成熟，以获得功能成熟的 DC，这可以通过细胞形态、免疫表型和功能活性来证明。我们在 4 名患者中评估了成熟 DC 的自体细胞毒性 T 细胞诱导，并与未成熟的对照进行了比较。我们的结果表明，虽然 TLR3 激动剂（Poly I:C）对 TLR4 激动剂（脂多糖，LPS）具有协同作用，但添加 TLR7/8 激动剂（R848）对于产生具有更高水平 IL-12（30 至 90 倍）的有效 DC 是必要的。这种 DC 可以激活同种异体 T 细胞，并有效地在体外诱导自体细胞毒性 T 细胞。相比之下，作为 TLR2/6 激动剂的 FSL-1 对 LPS+Poly(I:C)和 LPS+R848 产生 IL-12 具有负作用。因此，使用包含 TLR7/8 激动剂的成熟混合物制备的 DC 可作为白血病患者基于 DC 的免疫治疗的潜在工具。
