STAT5/STAT3转录因子活化与Treg/Th17细胞平衡在慢性移植物抗宿主病发病中的作用

Chronic graft versus host disease (cGvHD) are potentially lethal complications after stem cell transplantation (SCT).Because little was known about the cGvHD pathogenesis, the effective treatments of cGvHD were lacking.Our previous data showed that donor Th17 cells contributed to the pathogenesis of cGVHD.Meanwhile,there are controversial conclusions demonstrated by different units according to the correlationship between donor Treg cells and the occurrence of cGVHD.However, there was close relationship between the development of Th17 and Treg cells.It suggested that the ratio of Treg/Th17 cells might play more important roles in the pathogenesis of cGVHD. The relative basic study had showed that STAT5/STAT3 pathway were the key elements in regulating the balance of Treg/Th17 cells and low dose of IL2 could alter the Treg/Th17 balance through the STAT5/STAT3 pathway. Therefore, the aims of this study were to build the cGVHD mice model to investigate the roles of Treg/Th17 ratio on the deveolpment of cGVHD and to demonstrate that low dose of IL2 adminstration in the cGVHD mice model or in patients after transplantation could expand Treg cells and reduce the development of Th17 cells in vivo through influencing the STAT5/STAT3 pathway, therefore preventing the development of cGVHD. Furthermore, randomized and controlled study would be further collected to demonstrate that low dose of IL2 administrated early post-transplantation would reduce the probability of cGVHD occurrence, therefore increasing the efficiency of the transplantation.

移植后慢性移植物抗宿主病（cGVHD）发病率高，治疗效果差，严重影响患者生存质量，原因为目前cGVHD的发病机制不清，故缺乏有效治疗手段。我们前期工作显示Th17细胞与移植后cGVHD的发病呈正相关，而Treg细胞在cGVHD中的作用相关报道结论不一；相关基础研究显示Th17与Treg分化发育密切相关，提示Treg/Th17细胞平衡可能在cGVHD发病中起重要作用。而STAT5/STAT3转录因子是调节Treg/Th17细胞平衡的主要途径之一，且IL2可通过STAT5/STAT3影响Treg/Th17细胞平衡。本研究旨在通过建立cGVHD小鼠动物模型，证实Treg/Th17细胞平衡在cGVHD发病中的作用；并通过动物实验及临床研究证实，移植后早期体内应用小剂量IL2可通过影响STAT5/STAT3转录因子活化，调节Treg/Th17细胞平衡，降低cGVHD的发生率，改善患者移植预后。

造血干细胞移植是血液恶性疾病的有效治疗方法。供者来源匮乏是限制HSCT 发展的世界性难题。北京大学人民医院应用粒细胞集落刺激因子和抗胸腺球蛋白抗体诱导免疫耐受，成功跨越了HLA屏障、建立了国际原创的非体外去除T细胞的单倍型相合造血干细胞移植体系，治疗急性白血病和重型再生障碍性贫血与同胞全合移植获得了一致的长期疗效，形成原创的单倍型相合移植体系，被国际同行广泛称为“北京方案”。但移植后慢性GVHD 发病率高，无有效治疗手段，严重影响患者生活质量，是移植失败的主要原因，筛选慢性GVHD 高危因素进而分层防治，是进一步降低慢性GVHD 的关键。本课题通过对移植物免疫细胞组分、移植后细胞因子水平及免疫重建等多种生物学标记进行检测，发现了Th17 细胞、Treg 细胞及IL21 与GVHD 发生密切相关，初步实现了慢性GVHD 的早期预警预测；并首次通过前瞻随机对照研究，在移植后早期应用小剂量白介素2 免疫治疗调控Treg 细胞和Th17 细胞比例，降低了移植后慢性GVHD 发病，将基础研究转化至临床，为白介素2 用于降低慢性GVHD 临床应用提供循证医学证据，推动了移植后慢性GVHD 发病机制的研究，提高了移植患者的生存质量。该结果有助于探讨针对慢性GVHD早期特异性细胞亚群的靶向干预方法，通过促进特异性细胞亚群的重建，促进慢性GVHD“早期预警-早期干预”新治疗方法的建立，有望进一步改善造血干细胞移植患者预后，节省患者在控制aGVHD的医疗消费，优化并完善白血病等血液系统疾病的治疗体系。