岩藻糖基化抑制剂调控树突状细胞抗原提呈和T细胞耗竭诱导肾移植免疫耐受的分子机制研究

Leukocyte infiltration mediated by selectin-selectin ligand interactions is an important initiator for allograft rejection after organ transplantation..Fucosylation mediated by fucosyltransferase (FUT) is the last key process for biosynthesis of selectin ligands. Our previous studies have established model of chronic allograft vasculopathy and chronic rejection and showed that mice cardiac allograft in FUT7(-/-) recipients and renal allograft treated with fucosylation inhibor exhibited prolonged survival time, along with minimal vasculopathy featured by reduced T cell infiltration in the graft and enhanced T cell exhausion phenotype in the spleen and graft; suggesting fucosylation may have novel regulatory function on immune tolerance. To verify the role of fucosylation in transplantation immunity, here we investigate the exhibition of FUT7/ recipients and the effects of a fucosylation inhibitor, 2F-Peracetyl-Fucose on the dendritic cell acivation, maturation, migration, antigen presenting funcion, and T cell activation,proliferation, differentiation, and exhaustion after antigen stimulation in vitro and in vivo in the context of transplantation. Our study will explore the immune mechanism of rejection and tolaerance of transplanted kidney through the selectin ligands synthesis pathway mediated by fucosylation and find new molecular target for inhibiting transplant rejection and inducing immune tolerance after kidney transplantation, which will provide new targeted intervention approaches and experimental evidences for clinically improving the survival of transplanted organs.

选择素及配体介导的白细胞浸润启动肾移植术后排斥反应，岩藻糖转移酶（Fucosyltransferase，FUT）催化的糖基化过程是选择素配体合成的最后关键环节。课题组前期发现FUT-Ⅶ敲除心脏移植小鼠和岩藻糖基化抑制剂2F-Peracetyl-Fucose干预异基因肾移植小鼠模型中移植物组织白细胞浸润减少，T细胞程序性死亡分子1表达增加出现细胞耗竭，提示靶向岩藻糖基化反应可能具有尚未见报道的抑制免疫排斥诱导免疫耐受效应。为此本项目分别以FUT7(-/-)异基因肾移植小鼠和体外培养树突状细胞和T细胞为模型，探讨FUT7基因敲除或2F-Peracetyl-Fucose干预对免疫细胞成熟、分化、抗原提呈、免疫耐受、增殖活化及耗竭失能的调控作用及可能机制。研究将从靶向岩藻糖基化反应这一崭新角度探讨移植排斥反应和免疫耐受的分子机制及作用靶点，为提高移植器官官存活提供新的干预途径和实验依据。