基于B7-1/2信号通路探讨扶正透毒祛毒复方干预AML-CR患者CD34+细胞源DC生物学效应的机制

The primary cause for the post recurrence of AML-CR is the minimal residuals of leukemic cells in corpora. An important idea to cure MRD-L is to activate the organism’s immunologic function to eliminate the residuals of leukemic cells; but given the patient’s lower immunologic function, it is hard to trigger the effective tumor immune response. After the antigen presenting cells DC endocytose tumor antigens, the MHC-antigen peptide compounds are formed to stimulate T cells,which activate immune response under the stimulation of co-stimulatory molecules.Under the guidance of minimal residual disease in leukemia (MRD-L) theory of pathological mechanism “the body is weak, there leaves pernicious influence in the Yin components” and the therapeutic theory “strengthening the body resistance and detoxicating”, thods and techniques such as serum pharmacology,cell culture, flow cytometry, RT-PCR and so forth are adopted in this project. By researching the influence of the signal access of B7-1/2, a member of co-stimulatory molecular family B7, upon the biological effect of AML-CR patients’ autologous source of CD34+ cells DC, the effect of B7-1/2 signal access on AML-CR patients’ tumor immune response is xplored. The mechanism of action of AML-CR patients’ source of CD34+ cells DC playing tumor immunologic function is explored and iscussed. Further, through the research on compound prescriptions intervention, the mechanism to cure MRD-L with TCM is explored and discussed, and new methods to cure MRD-L with TCM are explored so as to lay a foundation for developing effective TCM preparations.

AML-CR复发的根本原因是体内残留白血病细胞，调动机体免疫能力清除残留白血病细胞是AML-CR的重要治疗思路，但患者免疫功能低下，难以启动有效的肿瘤免疫应答。抗原提呈细胞DC内噬肿瘤抗原后形成MHC-抗原肽复合物刺激T细胞，T细胞在共刺激分子刺激下启动免疫应答。本项目以微小残留白血病“正气虚弱、余毒留伏阴分”的病机理论及“扶正透毒祛毒”的治疗理论为指导，采用血清药理学、细胞培养、流式细胞技术、RT-PCR等方法与技术，通过研究B7-1/2信号通路对AML-CR患者自体CD34+细胞源DC生物学效应的影响，探索B7-1/2信号通路在AML-CR患者肿瘤免疫应答的作用，探讨AML-CR患者CD34+细胞源DC发挥肿瘤免疫功能的作用机制，进一步通过扶正透毒复方中药干预研究，探讨中医药治疗MRD-L的机制，探索中医药治疗MRD-L的新方法，为研发有效的中药制剂打基础。

项目为2019年国家自然基金委立项地区基金项目，研究期四年（2019.01～2022.12）。.项目以微小残留白血病“正虚余毒伏阴”的病机理论及“扶正透毒祛毒”的治疗理论为指导，采用血清药理学、细胞培养、流式细胞技术、RT-PCR等方法与技术，通过研究B7-1/2信号通路对AML-CR患者自体CD34+细胞源DC生物学效应的影响，探索B7-1/2信号通路在AML-CR患者肿瘤免疫应答的作用，探讨AML-CR患者CD34+细胞源DC发挥肿瘤免疫功能的作用机制。.项目以扶正透毒祛毒复方加味青蒿鳖甲汤为核心，并与扶正祛毒复方扶正祛毒汤、透毒复方青蒿鳖甲汤进行对照研究。研究发现加味青蒿鳖甲汤、扶正祛毒汤、青蒿鳖甲汤含药血清均能促进AML-CR患者骨髓CD34＋细胞向DC分化，含药血清参与诱导分化的DC能促进T细胞激活，杀伤白血病细胞，加味青蒿鳖甲汤的效用更具有优势。通过对AML-CR患者CD34+细胞源DC激活T细胞过程中B7-1/2信号通路CD28、CTLA-4、PP2A、SHP2、PI3K、PIP3、AKT的基因及蛋白表达的检测，发现B7-1/2信号通路不仅在实体肿瘤领域对DC发挥生物学效应产生重要影响，对AML-CR患者CD34+细胞源DC的生物学效应同样具有调控作用。发现加味青蒿鳖甲汤、扶正祛毒汤、青蒿鳖甲汤含药血清均能促进B7-1/2信号通路正向调节、抑制B7-1/2信号通路负向调节，复方中药含药血清组AML-CR患者CD34+细胞源DC激活T细胞过程中B7-1/2信号通路CD28、PI3K、PIP3、AKT的基因及蛋白表达明显高于空白对照组，而CTLA-4、PP2A、SHP2的基因及蛋白表达又明显低于空白对照组。.项目以中医基本理论为指导，在深刻理解急性白血病缓解后基本病机的基础上，以因论治，确定治疗方法，拟定治疗方药，是中医核心理论辨证论治在白血病诊治中的具体体现。项目研究为中医药在急性白血病缓解的诊治提供了中医理论依据，其治疗机制通过实验在细胞水平、分子水平得到了有力证明。项目虽以急性白血病缓解后为研究目标，但其他恶性血液病的病机变化尤其是缓解后的病机变化与急性白血病高度吻合，因此，急性白血病缓解后的中医诊治思路和方法可以向其他恶性血液拓展延伸。

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