重组人HLA-G蛋白纠正ITP患者异常细胞免疫功能机制的研究

项目名称： 重组人HLA-G蛋白纠正ITP患者异常细胞免疫功能机制的研究

项目编号： No.81500096

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 马骥

作者单位： 山东省医学科学院

项目金额： 18万元

中文摘要： HLA-G及其受体分子异常在多种自身免疫性疾病中起关键作用。课题组前期研究发现ITP患者MSCs体外诱导调节性DCs、抑制自身反应性T细胞增殖功能障碍，并且患者T细胞亚群向Th1方向趋化过度。MSCs可表达HLA-G，并且MSCs的免疫抑制功能失调很可能与HLA-G的异常有关，但具体机制不详。课题申请者最新研究发现：ITP患者外周血可溶性HLA-G表达下调，并与血小板计数正相关。另外ITP患者外周血单个核细胞中CD19+HLA-G+ILT2+以及CD14+HLA-G+ILT4+细胞比例显著降低。本研究首先提出HLA-G及其受体分子异常是ITP发病的重要机制假说。为验证假说，本研究拟应用基因工程等技术中和、阻断、上调HLA-G表达，观察其对患者免疫细胞功能的影响，双向验证其调节患者细胞免疫功能的机制；同时探讨外源性重组人HLA-G对临床干预ITP发生发展的可能性，为ITP治疗提供新思路。

中文关键词： 免疫性血小板减少症；人类白细胞抗原G；免疫球蛋白样转录物；免疫耐受；信号通路

英文摘要： Altered human leukocyte antigen (HLA)-G and its receptor immunoglobulin-like transcripts (ILTs) is associated with kinds of autoimmune diseases. Our previous study demonstrated that impaired function of mesenchymal stem cell in inducing tolerogenic DCs and suppression self-reactive T cell proliferation as well as elevated profile of Th1 in patients with immune thrombocytopenia (ITP). HLA-G secreted by human mesenchymal stem cells (MSCs), which is probably related with its disorder in cellular immunological modulation, but the precise mechanisms remain to be elucidated. In addition, our recently research revealed that the down-regulated soluble HLA-G was found and which is positively related to the platelet count in ITP. Besides, the ratio of CD19+HLA-G+ILT2+ cells and CD14+HLA-G+ILT4+ cells from peripheral blood mononuclear cells significantly decreased. Based on our above-mentioned study, we speculate that the dysfunction of HLA-G and its receptor molecules played pivotal roles in pathogenesis of ITP. To test the hypothesis, we intend to use a variety of molecular biological methods, such as blocking antibodies, engineering technologies, to neutralize, down-regulate or up-regulate the expression of HLA-G and next evaluate the effect of these interventions on the HLA-G-specific tolerogenicity to cell-mediated immunity. Moreover, the feasibility of exogenous recombinant human HLA-G protein for disrupting the pathophysiology process of ITP will be evaluated, thus providing new clues for the management of ITP.

英文关键词： ITP;HLA-G;ILT;immune tolerance;signal pathway