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抗CD47抗体联合阿糖胞苷靶向治疗NOD/SCID小鼠单核细胞白血病的研究 被引量:11

Effectiveness of Anti-CD47 antibody and Ara-C combination targeting therapy NOD/SCID mouse of myeloid leukemia
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摘要 目的探讨CD47在急性髓细胞白血病NOD/SCID小鼠模型中的预后意义及靶向治疗的最佳策略。方法将分选的CD34+CD38-白血病干细胞(leukemia stem cells,LSCs)移植入NOD/SCID小鼠体内,建立小鼠急性单核细胞白血病模型;抗人CD47单克隆抗体单独或联合阿糖胞苷治疗白血病小鼠7~14 d,并进行疗效分析。将LSCs与小鼠巨噬细胞在含抗CD47单克隆抗体的培养液中共培养,观察CD47对巨噬细胞吞噬LSCs能力的影响。结果 THP-1细胞中存在CD34+CD38-LSCs,比例约为0.12%±0.06%,将分选后的CD34+CD38-LSCs(比例高达97.0%±1.7%)移植入NOD/SCID小鼠后成功建立白血病模型。体内实验表明,阿糖胞苷(7 d)联合抗CD47单克隆抗体(14 d)治疗后,白血病小鼠外周血和骨髓中CD33+CD45+白血病细胞下降最明显(P<0.01),生存时间明显长于其它各组。体外共培养2 h后,抗CD47单克隆抗体组吞噬指数(76.9%±12.2%)明显高于抗CD45单克隆抗体组(7.60%±2.4%,P<0.01)。结论 CD47高表达是急性髓细胞白血病的预后不良因素。阿糖胞苷联合抗CD47单克隆抗体可有效杀灭普通白血病细胞和白血病干细胞,对彻底治愈急性髓细胞白血病具有重要临床意义。 Objective To study the prognostic significance of CD47 in a NOD/SCID mouse model of acute myeloid leukemia (AML) and the best strategy for targeted therapy for this disease. Methods CD34 + CD38 - leukemia stem cells (LSCs) were separated and transplanted into NOD/SCID mice to establish a mouse model of acute monocytic leukemia (AMoL). Anti-human CD47 antibody, alone or combined with cytosine arabinoside (Ara-C), was used to treat the mice with AMoL for 7 - 14 days, and therapeutic efficacy was assessed. LSCs were cultured together with mouse macrophages in culture medium containing anti-CD47 or anti-CIM5 monoclonal antibody for 2 hours, to observe the phagocytic ability of macrophages to LSCs. Results CD34+ CD38- LSCs existed among THP-1 cells, with a content of about (0. 12 + 0.06)%, and a mouse model of AML was successfully established after the purified CD34+ CD38- LSCs (97.0% ± 1.7% ) were transplanted into NOD/SCID mice. The in vivo experiment showed that mice with AMoL had the most significant decrease in CD33 ~ CIM5 ~ leukemia cells in peripheral blood and bone marrow and survived the longest after being treated with Ara-C (7 days) plus anti-CD47 monoclonal antibody (14 days) (P 〈 0.01 ). After 2 hours of in vitro culture, the phagocytic index in the culture medium containing anti-CD47 monoclonal antibody was significantly higher than in the culture medium containing anti-CD45 monoclonal antibody (76.9%±12.2% vs 7.60% + 2.4% ; P 〈 0.05 ). Conclusions High expression of CD47 is an adverse prognostic factor in AML. Combination therapy with anti-CD47 monoclonal antibody and Ara-C can effectively eliminate leukemia cells and LSCs, demonstrating great clinical significance in curing AML.
出处 《中国当代儿科杂志》 CAS CSCD 北大核心 2013年第7期577-582,共6页 Chinese Journal of Contemporary Pediatrics
关键词 急性髓细胞白血病 白血病干细胞 CD47 阿糖胞苷 靶向治疗 小鼠 Acute myeloid leukemia Leukemia stem cell CD47 Cytosine arabinoside Targeted therapy Mice
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同被引文献100

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