滤泡辅助T细胞及其表观遗传修饰与肾移植慢性排斥发病机制相关性研究

Chronic renal allograft rejection is still a global thorny concern which seriously affects the life quality of patients with end stage renal disease after the kidney transplantation. Multiple factors may participate in the pathogenesis and among which, the cell and humoral immune responses induced by T/B cells, especially the existence of anti-donor specific antibodies in patients may play a crucial role. Recent studies indicate that follicular helper T cells (Tfh cells) regulate the differentiation, maturation and antibody production of B cells by activating co-stimulatory molecules on their surface. In addition, Tfh cells secrete IL-21, which has multiple effects on different kinds of immune cells, affecting the homeostasis of immune microenvironment in vivo and all of which mediate the onset of chronic renal allograft rejection. Epigenetic modifications act as crucial factors in the fate of T cell's differentiation and they are assumed to regulate the polarization and proliferation of Tfh cells as well. As a conclusion, Tfh cells can affect the occurrence and development of chronic renal allograft rejection through two mechanisms mentioned above. This time, based on our previous work, we aimed to study the direct and indirect roles of Tfh cells in the pathogenesis of chronic renal allograft rejection, and also to explore the impact of epigenetic modifications on the polarization and proliferation of Tfh cells. All our research works will provide a theoretical and experimental foundation for new means of clinical intervention of chronic renal allograft rejection.

肾移植慢性排斥是目前无法解决并严重影响晚期肾病患者生存质量的关键因素。多因素共同参与其发病，而免疫因素介导的发病机制主要为T/B细胞参与的细胞/体液免疫应答，尤以患者体内存在抗供体特异性抗体关系重大。近期研究发现：滤泡辅助T细胞（Tfh细胞）可通过表面协同刺激分子的作用而对B细胞的分化、成熟、抗体产生发挥调节作用。此外，Tfh细胞分泌IL-21，对多种免疫细胞产生作用而影响移植受者体内免疫微环境稳态，介导肾移植慢性排斥的发生。表观遗传修饰可关键性调控T细胞的分化命运，对Tfh细胞的极化、增殖具调控作用，进而通过上述两种机制影响肾移植慢性排斥的发生发展。为此，项目组在前期工作基础上，拟进一步对Tfh细胞直接和间接介导肾移植慢性排斥的发病机制进行深入研究，并探索表观遗传修饰对其极化和增殖的影响，藉此，为以Tfh细胞为核心的临床干预肾移植慢性排斥新手段提供理论依据和实验基础。

肾移植慢性排斥（CAN）是影响肾移植患者长期存活的关键因素，而T/B细胞介导的免疫损伤是其重要的发病机制。滤泡辅T细胞（Tfh）可调控移植物内B细胞活性和免疫微环境稳态，影响同种异体免疫反应，而Tfh细胞在CAN中的作用尚不明确。本研究利用肾移植慢性排斥患者临床标本和相关动物模型，通过对ICOS-ICOSL，PD-1-PDL-1以及BAFF-BAFFR等重要分子和信号通路的研究，发现肾移植慢性排斥患者外周血中Tfh细胞比例升高并且表型改变，CAN大鼠模型移植肾中Tfh细胞浸润增多，其与B细胞交互作用增强，从而初步阐明了Tfh细胞对CAN的调控机理。通过阻断CAN大鼠体内IL-21信号，证实了以IL-21为干预靶点，可以改变移植肾中Th1/Th2平衡，上调Treg细胞活性，抑制Tfh细胞功能，影响免疫微环境稳态。通过联合运用组蛋白乙酰化抑制剂SAHA和FK506处理原代Tfh细胞和CAN大鼠，发现其可以下调Tfh细胞活性，增加凋亡比率，抑制其分化，并且明显改善移植肾损伤，从而揭示了表现遗传修饰对Tfh极化及增殖的调控方式和作用机制。本研究创新性的以Tfh细胞为切入点，为临床监测与治疗CAN提供了新的理论依据和防治手段。