原发免疫性血小板减少症患者中髓源抑制性细胞的免疫调控功能及机制研究

Primary Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by reduced platelet survival, suppression of megakaryocyte and platelet development. While the underlying mechanisms remain largely unclear, abnormalities of humoral immunity, cellular immunity and innate immunity are known to contribute to the pathologic process. Myeloid-derived suppressor cells (MDSCs), deriving from myeloid progenitor cells, is a newly uncovered regulatory cell, shedding its suppressive function through secreting immune regulating medium, such as IL-10. Our pilot study has revealed the Treg/Th17 imbalance and Breg dysfunction in ITP patients, and that Treg and Breg suppress immune responses via IL-10 secretion; MDSCs, as a major producer of IL-10, are thought to be capable to regulate Treg and Breg. Thus, we propose that MDSCs contribute to the Breg dysfunction and Treg/Th17 imbalance in ITP patients. By separating immune cells from ITP patients and establishing a mice ITP model, the current study is aimed to investigate the immune regulatory role of MDSCs and its dysfunction in ITP patients; to discover the interaction of MDSCs with Breg and the Treg/Th17 balance; to test if HD-DXM treatment could correct the dysfunction of MDSCs; and to investigate the effect of MDSCs on the productivity, differentiation and apoptosis of myeloid megakaryocytes in ITP patients. The significance of the proposed work is to shed light on the role of MDSCs in the pathogenesis of ITP and the possibility of developing new venues to target ITP, and even other autoimmune diseases.

原发免疫性血小板减少症(ITP)是一种自身免疫介导的获得性出血性疾病,体液免疫、细胞免疫和固有免疫都参与其发病。髓源抑制性细胞(MDSCs)是重要的免疫调控细胞,通过分泌IL-10等介质负向调控免疫。我们研究发现①ITP患者存在Treg/Th17失衡和Breg功能障碍,Treg和Breg通过IL-10发挥免疫调节作用;②MDSCs在体内数量远高于Treg和Breg,是主要的IL-10来源细胞。因此推测MDSCs对ITP的Breg和Treg/Th17异常有重要调控作用。本课题拟研究ITP患者和ITP小鼠的MDSCs亚群功能,探讨ITP常用治疗方案对MDSCs功能的改善,揭示MDSCs调控Treg/Th17和Breg机制,阐明MDSCs在ITP骨髓巨核细胞增殖分化和凋亡中的作用。研究MDSCs在ITP中的免疫调控功能，有助于深化理解ITP发病机制，为ITP以及其它自身免疫性疾病的治疗拓展思路。

原发免疫性血小板减少症 (ITP)是一种自身免疫介导的获得性出血性疾病，其病因不明、迁延难愈，严重者可引发致命性颅内出血。体液免疫、细胞免疫、固有免疫都参与其发病。髓源抑制性细胞(MDSCs) 来源于骨髓祖细胞，可通过分泌一系列调控介质如IL-10等负向调控免疫。我们在前期研究中发现，ITP患者存在Treg/Th17失衡和Breg细胞功能障碍，而Treg和Breg通过IL-10发挥免疫调节作用。MDSCs作为重要的免疫调控细胞，其在体内的绝对数量可能高于Treg或Breg，是重要甚至是主要的IL-10来源细胞，并可能对ITP患者中已知的Breg功能异常和Treg/Th17失衡起到调控作用。本研究以ITP患者和小鼠ITP模型为研究对象，研究ITP患者体内的MDSCs亚群的功能，研究HD-DXM等常用ITP治疗方案改善MDSCs功能失常的作用及机制，以及研究MDSCs在ITP骨髓巨核细胞增殖分化与凋亡异常过程中的作用，探讨MDSCs在ITP发病中的作用机制。我们的研究结果发现ITP患者治疗前后外周血CD4+ITP患者M2样巨噬细胞与MDSCs间的相关性，M2样巨噬细胞(CD68+ CD163+)及MDSCs (CD11b+ CD33+ HLA-DR-)细胞在ITP发病中可能起着重要的作用，两者间呈正相关可能与其分化过程中存在相似的遗传背景因素有关。ITP患者中M2样巨噬细胞与MDSCs的作用可能与一些关键细胞因子的作用有关。研究显示人类FoxP3+CD4+T细胞由3种表型和功能不同的亚群组成，磁珠分选MDSC细胞选CD4+CD25-Teffs 细胞和CD4+CD25+Tregs细胞，MDSC对Treg细胞有调节作用。亦研究了ITP患者中CD4+与CD8+T细胞之间免疫组库差异以及治疗对其影响。研究结果可为ITP以及其它自身免疫性疾病的治疗拓展新疗法。