γδ T细胞在脓毒症免疫抑制中的作用及其分子机制研究

Sepsis therapy is a prominent problem of the modern critical care medicine, and improving the level of sepsis treament by immune intervention measures is a hot research topic with close attention. Gammadelta T cells is considered as one new T lymphocyte subset in recent years, which playing an important role in resistance to infection, anti-tumor and immune regulating function in the body. First, we payed attention to the function characteristics of gamma delta T cells in peripheral blood of sepsis patients including differentiation marker, subtype and production of related cytokine, and then the molecular mechanism of insufficient gamma delta T cells. At the same time the responsibility of gamma delta T cells of sepsis patients to certain bacteria and viral antigen and the regulation of gamma delta T cells on other natural immune cells including of NK cells and mononuclear cells were studied to identify the status and role of gamma delta T cells in sepsis immunosuppression by culture in vitro; further we studied the effect of specific stimulants on proliferation and activation of gamma delta T cells in patients with sepsis and also the anti-infection acquired by gamma delta T cells, expecting as an entry point to explore new treatment strategy to sepsis.This study is a basic and clinical combined closely with the subject, precious resources. Our research has important significance on elucidating the mechanism of immunosuppression of sepsis and exploring new treament strategy of immune intervention to sepsis.

脓毒症（sepsis)治疗是现代危重病医学面临的突出难题，通过免疫干预提高脓毒症救治水平是当今倍受关注的研究热点。 γδ T细胞是-类功能独特的T淋巴细胞新亚群，在机体抗感染、抗肿瘤及免疫调节功能中发挥重要作用。本课题拟通过当今先进的细胞分离、培养及测试手段，首先研究在脓毒症病理状态下γδ T细胞的数量及功能特征变化，包括脓毒症患者γδ T细胞对特定抗原的应答能力以及γδ T细胞与NK细胞、单核细胞的相互作用关系；并通过细胞凋亡、增殖及信号通路等技术探讨γδ T细胞功能变化的分子机制；同时课题也将进一步研究脓毒症患者γδ T细胞的体外增殖方法以及由此获得的 γδ T细胞的生物学功能，探索以γδ T细胞为切入点纠正脓毒症免疫抑制状态的可能性。该研究是一项基础与临床密切结合的课题，资源珍贵，所获结果对阐明脓毒症的免疫抑制机制、探索免疫干预治疗新措施都具有特别重要的意义。

脓毒症（sepsis)治疗是现代危重病医学面临的突出难题，通过免疫干预措施提高脓毒症救治水平是当今倍受关注的研究课题。 本项目主要研究天然免疫细胞尤其是γδ T细胞及NK细胞在脓毒症病理状态下的功能变化及其相关分子机制。研究首先针对脓毒症患者γδ T细胞的表型及功能特征进行了研究，结果显示脓毒症患者外周血γδ T细胞的数量及比例较对照组显著下降，脓毒症γδ T细胞的促炎性细胞因子及抑炎性细胞因子表达水平明显变化，同时亦伴有细胞增殖活化能力的下降；我们亦对不同阶段的脓毒症患者的NK细胞功能进行了较全面的的研究，结果发现，随着脓毒症进程，CD3-CD56+NK细胞比例明显下降，尤其以CD3- CD56dim NK 亚群下降为主；NK细胞对K562细胞的杀伤功能明显减弱，其细胞表面的活化性受体及抑制性受体亦发生相应变化。同时我们还利用蛋白芯片技术对有助于脓毒症预后判断的生物marker进行了筛选，并通过反复验证后结果显示，血浆MCP-1（Monocyte Chemoattractant Protein 1） 水平对预测脓毒症患者预后的敏感度及特异度分别为76.8% 和71.3%，有望成为临床脓毒症患者预后判断的新的生物标志物。上述研究成果高度提示γδ T细胞与NK细胞功能的明显减弱可能是脓毒症免疫抑制的重要因素，调控机体固有免疫细胞的功能可能成为脓毒症免疫治疗的新举措。