CTLA-4/B7通路在调节性γδ T细胞调控造血干细胞移植后异源反应性T细胞活性中的作用

项目名称： CTLA-4/B7通路在调节性γδ T细胞调控造血干细胞移植后异源反应性T细胞活性中的作用

项目编号： No.81471582

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 谭亚敏

作者单位： 浙江大学

项目金额： 65万元

中文摘要： 急性移植物抗宿主病（aGVHD）是异基因造血干细胞移植（HSCT）的主要并发症，异源反应性T细胞直接介导aGVHD的发生发展。调节性γδT(γδTreg)细胞是新发现的细胞亚群；前期我们建立了γδTreg的诱导扩增富集体系，首次发现该细胞能够直接抑制异源反应性T细胞增殖活化并负向调控HSCT后aGVHD。B7分子高表达于异源反应性T细胞表面，预实验表明γδTreg高表达CTLA-4，提示CTLA-4/B7通路在调控aGVHD中可能起关键作用。本项目拟利用SiRNA、慢病毒转染和病理活检等技术阐明CTLA-4/B7通路抑制异源反应性T细胞活性致负向调控aGVHD的重要作用，进一步采用流式细胞术、ELISA、免疫印迹、荧光定量PCR等技术从细胞和分子水平研究γδTreg经该通路直接抑制T淋巴活化相关信号分子从而抑制T淋巴细胞活化的分子机制。本研究为发现γδTreg调控aGVHD的新机制奠定基础

中文关键词： 异基因造血干细胞移植；移植物抗宿主病；调节性γδT(γδTregs)细胞；CTLA-4/B7通路；T细胞

英文摘要： Acute graft-versus-host disease (aGVHD) is one of the most severe complications after allogeneic hematopoietic stem cell tranplantation. Regulatory γδT cells (γδTregs) is a novel kind of T cell subset with immunosuppressive properties. In our previous study we have established an efficient inducing and enriching system of γδTregs in vitro. Moreover, we found for the first time that γδTregs could negatively regulate aGVHD after allogeneic HSCT and CTLA-4/B4 pathway might play vital roles. Based on these, in the current study we will illucidate the important role of CTLA-4 in aGVHD regulation by γδ Tregs via CTLA-4 siRNA in mice models. Then we further study the molecular mechanisms that γδTregs activate CTLA-4/B7 pathway to reduce alloreactive T cells via inhibiting T cell activating pathways , then leading to negative regulation of aGVHD in molecular and cellular levels. We will also provide more evidences for the above mechanisms by using cell coculture system in vitro. Our research will provide exprimental evidences for establishing a novel strategy for aGVHD prevention and treatment. It will also lay the foundation of finding novel targets for aGVHD regulation.

英文关键词： allogeneic hematopoietic stem cell transplantation;GVHD;regulatory γδ T cells;CTLA-4/B7 pathway;T cell