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学科主题: 临床医学
题名:
Blockade of the OX40/OX40L pathway and induction of PD-L1 synergistically protects mouse islet allografts from rejection
作者: Li Tao1; Ma Rui2; Zhu Jiye1; Wang Fushun1; Huang Lei1; Leng Xisheng1
关键词: OX40 ; OX40 ligand ; programmed death ligand-1 ; programmed death-1 ; costimulatory pathway ; transplantation
刊名: CHINESE MEDICAL JOURNAL
发表日期: 2014-07-20
DOI: 10.3760/cma.j.issn.0366-6999.20140740
卷: 127, 期:14, 页:2686-2692
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Medicine, General & Internal
研究领域[WOS]: General & Internal Medicine
关键词[WOS]: T-CELL-ACTIVATION ; PD-1/PD-L1 PATHWAY ; MESSENGER-RNA ; TOLERANCE ; TRANSPLANTATION ; EXPRESSION ; MICE
英文摘要:

Background OX40/OX40 ligand (OX40/OX40L) and programmed death-1/programmed death ligand-1 (PD-1/PD-L1) costimulatory signals play important roles in T cell-induced immune responses. The aim of this study was to investigate the roles of OX40/OX40L and PD-1/PD-L1 costimulatory pathways in mouse islet allograft rejection.

Methods Lentiviral vectors containing OX40L siRNA sequences and an adenovirus vector containing the PD-L1 gene were constructed. The streptozotocin-induced model of diabetes was established in C57BL/6 (H-2(b)) mice. Diabetic C57BL/6 mice were randomly allocated into five groups: group 1, untreated control; group 2, Ad-EGFP treatment; group 3, Ad-PD-L1 treatment; group 4, OX40L-RNAi-LV treatment; group 5, OX40L-RNAi-LV combined with Ad-PD-L1 treatment. Lentiviral vector and the adenovirus vector were injected, singly or combined, into the caudal vein one day before islet transplantation. The islets of DBA/2 (H-2(d)) mice were transplanted into the renal subcapsular space of the diabetic recipients. Recipient blood glucose and the survival time of the allografts were monitored. Antigen-specific mixed lymphocyte reaction was also evaluated.

Results The recombinant lentiviral RNA interference vector OX40L-RNAi-LV reduced OX40L protein expression by 70%. The recombinant adenovirus vector Ad-PD-L1 increased PD-L1 protein expression in vivo in C57BL/6 recipient mice. Combined OX40L-RNAi-LV/Ad-PD-L1 treatment induced a synergistic protective effect in pancreatic islet allografts. Allograft survival time in the combined treatment group was (92.27+/-9.65) days, not only longer than that of the control ((6.51+/-0.27) days) and Ad-EGFP groups ((7.09+/-0.13) days) (P<0.01), but also significantly longer than that of Ad-PD-L1 and OX40L-RNAi-LV single treatment groups ((40.64+/-3.95) days and (55.14+/-5.48) days respectively, P<0.01). The blood glucose concentration of recipient mice in the combined treatment group was also stable and kept within the normal range. Flow cytometry analysis showed that combined OX40L-RNAi-LV/Ad-PD-L1 treatment significantly decreased proliferation in an antigen-specific mixed lymphocyte reaction. After donor DBA/2 lymphocyte stimulation, 89.71% of lymphocytes from recipient combination treatment C57BL/6 mice were not split and proliferated. In contrast, after stimulation with third party Lewis rat lymphocytes, only 45.84% lymphocytes of C57BL/6 mice were not split and proliferated.

Conclusions This study demonstrates the successful construction of the recombinant lentivirus vector OX40L-RNAi-LV and adenovirus vector Ad-PD-L1 for the blockade of OX40/OX40L and activation of PD-1/PD-L1 costimulatory pathways simultaneously in pancreatic islet allografts in diabetic mice. Combination therapy with these two vectors resulted in inhibition of T cell activation, synergistically prolonging the survival time of pancreatic islet allografts.

语种: 英语
所属项目编号: 30872498 ; RDB2012-11
项目资助者: National Natural Science Foundation of China ; Peking University People&prime ; s Hospital Research and Development Funds
WOS记录号: WOS:000339860900026
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/61831
Appears in Collections:北京大学第二临床医学院_肝胆外科_期刊论文

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作者单位: 1.Peking Univ, Peoples Hosp, Dept Hepatobiliary Surg, Beijing 100044, Peoples R China
2.Peking Univ, Peoples Hosp, Dept Surg Intens Care Unit, Beijing 100044, Peoples R China

Recommended Citation:
Li Tao,Ma Rui,Zhu Jiye,et al. Blockade of the OX40/OX40L pathway and induction of PD-L1 synergistically protects mouse islet allografts from rejection[J]. CHINESE MEDICAL JOURNAL,2014,127(14):2686-2692.
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