电压门控型钠通道中介的树突状细胞免疫调节在急性髓系白血病治疗中的作用

The lack of efficient cytotoxic T lymphocytes ( CTLs ) that results from the abnormal function and differentiation of dendritic cell ( DC ) is one of the mechanisms of acute myeloid leukemia ( AML ). The majority of DC in tumor is immature that expresses low levels of costimulatory molecules and adhesion molecules, shows week mixed lymphocyte reaction. Mature DC expresses high levels of surface molecules and costimulatory molecules, secretes T cell stimulates factors, induces the creation of CTLs, mediates powerful activating immune system. These results suggest that the shift from immature DC into mature DC would enhance specific antitumor immune response. Previous studies showed that the voltage-gated sodium channel ( VGSC ) regulated the cell phenotypic transition. Hence, we put forward hypothesis that the regulation of DC-expressed VGSC would influence the immune response in AML. In this project, the methods of pharmacology ( VGSC antagonist and agonist ), pharmacy ( mannosylated liposomes ) and molecular biology ( RNA interference ) would be used to investigate the role of VGSC as therapeutic target in DC phenotype and antitumor immune response. Expected results could contribute to an in-depth explanation of the affect of DC in antitumor immune response and have underlying clinical value.

树突状细胞（DC）分化和功能的异常，使其不能有效诱导特异性细胞毒性T淋巴细胞（CTLs）的生成是急性髓系白血病（AML）发病的主要机制之一。肿瘤组织中的DC大多为不成熟DC，表达低水平的共刺激分子和粘附分子，体外激发混合淋巴细胞反应的能力低。成熟DC的表面分子和共刺激分子表达上调，分泌T细胞刺激因子，诱导CTLs的生成，能有效介导免疫激活。促使DC由不成熟向成熟表型转变，有助于增强抗肿瘤免疫应答。研究显示，DC的电压门控型钠通道（VGSC）参与表型转变。提示，也许能够通过调节VGSC活性影响DC在AML中的免疫调控。本项目将通过药理学（VGSC阻断剂和激动剂）、药剂学（以甘露糖修饰脂质体为载体实现DC靶向性给药）和分子生物学方法（RNA干扰），探讨以VGSC为治疗靶点的干预措施对DC生物学表型和AML中免疫应答的影响。结果有助于深入阐释DC在抗肿瘤免疫应答中的作用，具有潜在的临床应用价值。

研究背景：树突状细胞是已知体内功能最强的抗原提呈细胞，能激发T细胞反应，因此是肿瘤免疫治疗的潜在靶点。最近的研究发现，电压门控型钠通道（VGSCs）调节免疫细胞的活化和迁移，但其在树突状细胞介导的肿瘤杀伤效应中的作用并未阐明。结果：小鼠脾脏树突状细胞表达多种VGSCs：NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.9, Scn1b 及Scn4b。VGSCs激动剂藜芦定（VER）能够增强树突状细胞的活化，细胞因子分泌，细胞迁移和抗原提呈，但并不影响细胞的凋亡。VGSC阻断剂（苯妥英钠）则能够降低细胞的活化，细胞因子分泌，细胞迁移和抗原提呈。VER处理过后的树突状细胞能增强T细胞的活化，增殖和干扰素γ的分泌，同时降低BIM的表达，最终抑制肿瘤细胞的增殖。结论：VER激活的树突状细胞具有肿瘤杀伤作用是潜在的抗肿瘤疫苗靶点。