淋巴瘤相关噬血细胞综合症全血细胞减少发病机制研究

Lymphoma associated hemophagocytic syndrome is a common complication of advanced lymphoma. Pancytopenia is a major obstacle to the treatment, and therefore poor efficacy and high mortality. Predecessors and our preliminary findings in both peripheral blood and bone marrow high concentrations of Mir-133 and Mir-141, and not only the function of hematopoietic stem cells and bone marrow mesenchymal stem cells significantly impaired but also the number of them were significantly down. Hematopoietic stem cells downregulated CD47 macrophage excessive phagocytosis of hematopoietic stem cells and bone marrow mesenchymal stem cells, resulting in reduction in the number of hematopoietic stem cells and bone marrow mesenchymal stem cells, the hematopoietic microenvironment injury is the main reason pancytopenia .To research the relationship between the CD47 down with the high concentrations of Mir-133 and Mir-141, using a lentivirus vector, RNAi, cultured cells in vivo. We want to find the relationship Mir-133 and Mir-141 between the down regulation of the expression of CD47 on hematopoietic stem cells and bone marrow mesenchymal in patients who whit lymphoma associated hemophagocytic syndrome and promote macrophages phagocytosis hematopoietic stem cell-cell and bone marrow mesenchymal stem cells. We would find out the Mir-141and Mir-133 were come from lymphoma of other cells. We may find out while the high concentrations of Inflammatory cytokines probable in lymphoma cells, and to look for possible incentives Mir-133 Mir-141 expression and elevated whether ex cessive inflammation induced by high concentrations of inflammatory cytokines act on lymphoma, lymphoma caused cells synthesize excessive Mir-133 and Mir-141, turn down the hematopoietic stem cells express CD47. Lymphoma associated hemophagocytic syndrome and find new ways to control the incidence of pancytopenia offers possible theories 。

LAHS是晚期淋巴瘤常见并发症之一，全血细胞减少是治疗上的主要障碍，疗效差，病死率高。前人及我们前期研究发现外周血及骨髓液中均有高浓度Mir-133及Mir-141,且有HSC及MSC功能及数量明显受损，其表达CD47表达明显下调，巨噬细胞过度吞噬HSC及MSC，造成HSC数量减少及造血微环境损伤是全血细胞减少的主要原因。为研究CD47下调与Mir-133及Mir-141关系，利用慢病毒载体、RNAi、体外培养等方法证明Mir-133及Mir-141在LAHS时下调HSC及MSCR的CD47表达，促进巨噬细胞对HSC及MSC的吞噬，并进一步证明Mir-133及Mir-141的可能来源及寻找表达升高的可能诱因是否为高浓度炎症因子作用于淋巴瘤细胞，引起淋巴瘤细胞合成过多Mir-133及Mir-141，进而下调造血干细胞表达CD47。为LAHS发病及寻找控制全血细胞减少的新方法提供可能的理论。

淋巴瘤相关噬血细胞综合征是淋巴瘤患者严重度发症之一，且临床治疗效果极差，多数患者于数月内死亡。目前无特殊性的早期诊断标记物，同时无特殊方法鉴别诊断淋巴瘤相关噬血细胞综合征与非淋巴瘤相关噬血细胞综合征；而淋巴瘤相关噬细胞综合征治疗要是需要解决的是患者全血细胞减少，我们基于本单位充足的淋巴瘤相关噬血细胞综合征患者基础上，对淋巴瘤相关噬血细胞综合征的诊断及全血细胞减少的原因进行了相关研究。该项目的研究过程中明确淋巴瘤相关噬血细胞综合症与未发生噬血细胞综合症患者造血干细胞 CD47 表达水平明显下调，因而自身吞噬细胞将正常造血干细胞吞噬，从而造成严重的全血细胞减少。明确了MiR-133在淋巴瘤相关噬血细胞综合症与未发生噬血细胞综合症患者外周血及骨髓培养液中表达水平。明确了MiR-133的可能来源为患者骨髓间充质干细胞。 明确了 TNF-α、INF-γ、IL-6、IL-2 可诱导 MiR-133表达水平升高。构建了高表达CD47的慢病毒载体。通过研究３０例患者的临床表现及相关实验室检查，对这部分淋巴瘤噬血细胞综合征患者的临床特点及相关高危因素，对于早期识别高危患者有一定的指导意义。研究后发现miＲ－133水平改变可能提示患者为淋巴瘤相关噬血细胞综合征。