Xiang Jianbin, Gu Xiaodong, Qian Shiguang, Chen Zongyou
Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
J Biomed Biotechnol. 2010;2010:705431. doi: 10.1155/2010/705431. Epub 2010 May 16.
Implementation of dendritic cell- (DC-) based therapies in organ transplantation can reduce dependency on nonspecific immunosuppression. Despite extensive research, mechanisms of equipped DCs inducing transplant tolerance remain incomplete. Here, we applied RNA interference technique to inhibit CD80 and CD86 expression in host bone marrow-derived DCs. This approach could specifically and effectively knock down CD80 and CD86 expression. T cells primed by these DCs inhibited allogeneic responses. Administration of recipient DCs loaded with alloantigen after CD80 and CD86 blockade prolonged cardiac allograft survival. We also found a higher percentage of apoptotic T cells in lymph tissues and grafts than that detected in control group. In addition, these T cells expressed high expression of GRP78 than controls, indicating activation of unfolded protein responses. Upregulation of CHOP expression among these cells suggested that the endoplasmic reticulum stress (ERS) response switched to a proapoptotic response. Our results indicated that ERS-induced apoptosis may be involved in allogeneic T-cell apoptosis, and the ERS-mediated apoptosis pathway may be a novel target in clinical prevention and therapy of allograft rejection.
在器官移植中实施基于树突状细胞（DC）的疗法可减少对非特异性免疫抑制的依赖。尽管进行了广泛研究，但装备后的DC诱导移植耐受的机制仍不完整。在此，我们应用RNA干扰技术抑制宿主骨髓来源DC中CD80和CD86的表达。这种方法可特异性且有效地敲低CD80和CD86的表达。由这些DC引发的T细胞抑制了同种异体反应。在CD80和CD86阻断后给予负载同种异体抗原的受体DC可延长心脏同种异体移植物的存活时间。我们还发现，与对照组相比，淋巴组织和移植物中凋亡T细胞的百分比更高。此外，这些T细胞中GRP78的表达高于对照组，表明未折叠蛋白反应被激活。这些细胞中CHOP表达上调表明内质网应激（ERS）反应转变为促凋亡反应。我们的结果表明，ERS诱导的凋亡可能参与同种异体T细胞凋亡，且ERS介导的凋亡途径可能是临床预防和治疗同种异体移植排斥反应的新靶点。
