造血干细胞移植后EZH2调控树突状细胞免疫重建和干预策略研究

Allo-hematopoietic stem cell transplantation is the most popular curative therapy against malignant leukemia and congenital immunodeficiency diseases. However, impaired immune reconstitution which leads to multiple complications severely decreased the survival of the recipients. Quantitatively and functionally impaired reconstitution of dendritic cells has been associated with opportunistic viral infection and tumor relapse. The detailed mechanisms remain unclear yet. Our previous work found that: ⑴the number of DC precursors in HSCT recipients is significantly lower than that in healthy donors, accompanied by decreased number and ratio of mature DC, indicating impaired DC development and generation from HSC. ⑵DC derived from HSC in EZH2-KO mice was significantly lower than that in WT mice, and type I IFN produced by KO DC dramatically increased. This suggests that EZH2 regulate the development of DC from HSC and the function of DC. We plan to study the role of EZH2 in DC differentiation from HSC and DC function and related mechanisms, identify the upstream inflammatory factors that affect EZH2 in hematopoietic progenitor cells, and evaluate the beneficial effect of EZH2 intervention in anti-viral and anti-tumor immune response. This will leads to development of new strategies to improve the survival of HSCT recipients.

异体造血干细胞移植(allo-HSCT)是目前临床治愈难治性白血病和先天免疫功能缺陷病的有效方法，移植后免疫系统重建异常与治疗失败密切相关。树突状细胞(DC)是连接固有免疫和适应性免疫的关键桥梁, DC重建受损与移植后病毒感染死亡显著相关。DC重建异常机制复杂且认识相对局限，亟待理论突破。我们前期研究发现: HSCT病人体内DC及其前体细胞较健康人显著降低，并伴随髓系抑制性细胞(MDSC）增加，造血干细胞HSC表达EZH2水平显著低于健康志愿者；EZH2缺失小鼠HSC产生DC能力显著受损, 而MDSC数量增加，且pDC产生I型干扰素显著升高，推测EZH2调节HSC向DC免疫重建。本项目拟系统研究EZH2调节HSC产生DC及DC功能，并探讨分子机制；解析临床HSCT受者体内影响EZH2功能的炎症因子；开展靶向EZH2实验性干预策略研究，藉此为提高HSCT原发病治愈率提供新的理论突破。

异体造血干细胞移植(allo-HSCT)是目前临床治愈难治性白血病和先天免疫功能缺陷病的有效方法，移植后免疫系统重建异常与治疗失败密切相关。树突状细胞(DC)是连接固有免疫和适应性免疫的关键桥梁, DC重建受损与移植后病毒感染死亡显著相关。DC重建异常机制复杂且认识相对局限，亟待理论突破。我们的研究明确发现CD11c+细胞中条件性敲除了Ezh2基因的小鼠体内的树突状细胞的分化平衡被打破，pDC分化增加，而cDC分化减少。体外细胞培养试验也证明EZH2敲除后pDC分化增多而cDC分化减少。此外，EZH2敲除后可上调pDC的成熟以及分泌干扰素水平。我们明确了GVHD损伤DC祖细胞及DC的产生，且发现祖细胞中EZH2的表达降低可能是GVHD损伤DC祖细胞的关键因素。而GVHD小鼠中高表达的炎症因子如GM-CSF以及TNF-a可能是引起祖细胞MDP中EZH2下降的原因。在骨髓移植的临床患者中，GVHD患者体内的DC和DC前体也显著低于无GVHD的患者和健康供体，进一步证实了临床也存在GVHD导致DC前体和DC发育受损的情况，机制分析表明该现象与EZH2降低有关DC关键转录因子IRF8和TCF4有关。该研究成果可以为GVHD患者的预后及治疗提供新思路。