人造血淋巴系统小鼠在急性白血病模型构建中的应用进展

Progress in application of humanized hemato-lymphoid system mice in human acute leukemia model

为了研究人类造血功能异常,学者们不断改进和发展白血病干细胞的异种移植模型。构建理想的异种移植模型,真实地模拟疾病,在研究人类白血病的分子机制及完善其治疗方案中尤为重要。人造血淋巴系统小鼠(humanized hematolymphoid system mice,HHLS)是异种移植了人源血细胞或组织的免疫缺陷鼠或者表达人类基因的人鼠嵌合体(mouse-human chimaeras)或称人源化小鼠(humanized mice)。理想的人源化小鼠即是人类移植物在空间和功能上完全替代小鼠的内源性造血和免疫系统。要实现这一目标,需要满足三个基本要求:首先,受体小鼠需要具有先天或者后天的免疫缺陷,以防止小鼠内源性免疫系统对人体移植物的异种移植排斥;第二,小鼠体内需要产生适合人类细胞生存的微环境;第三,人类细胞需要从小鼠体内获得支持性交叉反应信号。本文对HHLS模型的最新研究进展作一综述。

Despite a continuous improvement in xenograft models, engraftment of human malignant cells remains challenging in research of human hematopoiesis. In order to investigate the molecular mechanism involved in human leukemia and to improve therapy, establishing xenograft models that faithfully replicated the disease is critically important. Humanized mice are generated by transplanting human hematopoietic cells into recipient mice. An ideal model would be a humanized mouse in which the human graft fully replaces the endogenous mouse hematopoietic and immune systems. For this purpose, there are three basic requirements： tolerance by the mouse host, correct spatial location and appropriately cross-reactive support and interaction factors such as cytokines and major histocompatibility complex molecules. Here we review the achievements, most recent developments, and the remaining challenges in the generation of preclinicallypredictive systems for human hematology, which closely resembling the human situation in the xenogeneic mouse environment.