Tim-3/Galectin-9对T细胞亚群的免疫负性调控在CLL病程进展中的作用机制研究

Chronic lymphocytic leukemia （CLL) is a monoclonal disorder characterized by a progressive accumulation of lymphocytes and its mechanism is not completely clear. Previous studies have shown that PD-1 could down-regulate T cell function in CLL, and cause tumors. In further studies, our group found that the other negative regulatory molecules Tim-3 was significantly increased in CLL. Tim-3, as a new negative regulatory molecule, combined with Galectin-9, can down-regulate the response of Th1 and Th17 cells, and plays an important role on pathogenesis of autoimmune diseases and malignant tumors. Therefore, our research group will detecte the expression of Tim-3 in CD4+ and CD8+ cells and the cytokines of T cells, by using the plasmid transfection, RNAi technology, receptor blocking technology, to validate the immune regulation mechanism of Tim-3/Galectin-9 on T cell and provide the theory basis of its target therapy for CLL.

慢性淋巴细胞白血病（CLL）是一种淋巴细胞克隆增殖性疾病，其发病机制目前尚不明确。前期研究证实PD-1在CLL中下调T细胞功能，导致肿瘤发生。本课题组在进一步的研究中发现与PD-1具有等同地位的负性协同刺激分子Tim-3在CLL中表达明显升高。Tim-3作为一种新型的Th1、Th17负性调控分子，与Galectin-9结合可下调Th1及Th17细胞的反应，在自身免疫性疾病和恶性肿瘤发病中起重要作用。为了探索Tim-3/Galectin-9在CLL病程进展中的免疫调控机制，本项目组拟以Tim-3在CD4+和CD8+细胞中的表达为切入点，以T细胞因子为检测靶点，应用质粒转染技术、RNAi干扰技术、受体特异性阻断技术等，从临床实验、细胞培养和动物体内实验三个层面验证CLL疾病状态下Tim-3/Galectin-9对T细胞的免疫调控机制，为Tim-3成为新的治疗靶点提供理论依据。

慢性淋巴细胞白血病(CLL) 是一种主要以CD19+CD5+B淋巴细胞克隆性增殖为特点的常发于老年人的血液系统恶性肿瘤，其发病机制目前尚不明确。故进一步探索CLL的发病机制是目前临床上亟待解决的关键问题。本研究通过临床层面检测CLL患者外周血中T细胞亚群及其上Tim-3的表达情况、血清中Galectin-9、IL-10等细胞因子的浓度，结合临床指标，阐述了Tim-3/Galectin-9通路在CLL患者中的临床意义。细胞层面分选CD4+T、Tim-3+Treg及Th1细胞分别与CLL细胞株共培养，并通过抗Tim-3特异性单克隆抗体阻断等干预，通过观察培养体系中细胞因子的变化水平及CLL细胞的增殖、凋亡情况，进一步验证了CLL中Tim-3/Galectin-9通路对T细胞亚群的免疫调控机制。动物实验层面初步构建了裸鼠成瘤，正在构建国际上应用最为广泛的TCL-1转基因小鼠模型。本项目研究结果提示CLL中上调的Tim-3/Galectin-9通路促进Treg细胞而抑制Th1细胞，导致T细胞亚群失衡，参与T细胞的负性调控，诱导CLL细胞发生免疫逃逸。Tim-3/Galectin-9有望成为新的CLL潜在治疗靶点。