Allo-HSCT后NEU1介导GPIbα去唾液酸化在持续性血小板减少症发生机制中的作用

Prolonged thrombocytopenia (PT) is a severe complication after allo-hematopoietic stem cell transplantation (allo-HSCT). Long-time survival of PT patients is much shorter compared with others. Therefore, further investigation into the mechanism of prolonged thrombocytopenia is of great significance both clinically and theoretically. Our previous study first demonstrated that NEU1 mediated GPIbα desialylation is a character of patients with prolonged thrombocytopenia after HSCT and is closely related to B lymphocytes producing antibodies against GPIbα. This discovery strongly suggest that NEU1 mediated GPIbα desialylation and B cell abnormally activation may play a key role in the development of PT and this theory has never been published before. This project is designed to further investigate the function of NEU1/GPIbα to GPIbα, aiming to interpret its role on platelets and megakarycytes of PT patients as well as its impact on β-galactose and ST6Gal. NEU1/GPIbα may become a specific biological marker to predict the occurrence of prolonged thrombocytopenia after allo-HSCT. Desialylated GPIbα is a potential target for therapy and may provide a theoretical foundation of prevention and treatment of prolonged thrombocytopenia after HSCT.

持续血小板减少症（PT）是异基因造血干细胞移植（allo-HSCT）后严重的合并症，PT患者长期生存显著减低，进一步阐明PT发病机制，有重要的临床和理论意义；在前期研究中，首次发现PT患者的NEU1介导GPIbα去唾液酸化是移植后PT的特征性改变；并与产生GPIbα抗体B细胞密切关联，这一发现目前国内外未见报道。强烈提示NEU1对血小板GPIbα去唾液酸化，CD22+B细胞异常活化，可能在PT发病中起关键作用；本课题拟进一步深入研究NEU1/GPIbα对去唾液酸化的作用；初步阐明NEU1/GPIbα对PT患者血小板和巨核细胞的作用，探讨其对β-半乳糖和ST6GaI的影响；NEU1/GPIbα可能成为预测移植后PT特异的生物标记物，去唾液酸化的GPIbα有望成为临床潜在治疗靶点，为临床移植后PT的防治策略提供新的理论依据。

持续性血小板减少症是异基因造血干细胞移植术后的常见并发症，与不良预后密切关联。而目前移植后PT的发病机制尚未完全明确。课题组研究发现：移植后PT患者的血小板表面GPIbα去唾液酸化增加；去唾液酸化与血小板凋亡增加相关，凋亡与去唾液酸化的GPIbα与14-3-3ζ结合增加相关；巨噬细胞对移植后PT患者的血小板吞噬增多，应用奥司他韦显著减少血小板的吞噬而减少血小板的破坏。抗GPIIb/IIIa血小板抗体介导的免疫性血小板减少症中低表达的β2-糖蛋白I与异常补体活化相关联，提示β2-糖蛋白I可能作为免疫性血小板减少症患者的潜在诊断及治疗靶点。内源性TPO水平可能与移植后血小板恢复以及移植预后相关。单倍体移植后病毒性脑炎不同病毒引起的脑炎中，临床特征，例如发病的时间、对治疗的反应以及预后差异很大。TMA合并aGVHD是allo-HSCT后一大并发症，伴有不良结局（包括生存降低及非复发死亡增高），临床上存在一些提示因素与该并发症的发生和死亡相关。大剂量糖皮质激素使用与异基因造血干细胞移植患者中导管相关血栓发生相关。甲状腺功能减退症与乙型肝炎相关的代偿性肝硬化中的严重血小板减少症有关。泼尼松加左旋甲状腺素治疗可能为这些患者提供了一种新方法。本课题的发现为allo-HSCT后持续性血小板减少的治疗提供了新的潜在的治疗方法，为揭示allo-HSCT后持续性血小板减少症，及其发病机制提供了新的多角度理论基础。研究课题进一步深入并拓展到异基因造血干细胞移植后并发症的诊治如病毒性脑炎、TMA合并aGVHD。