北京大学医学部机构知识库
Advanced  
IR@PKUHSC  > 北京大学第二临床医学院  > 肝胆外科  > 期刊论文
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

Files in This Item:

There are no files associated with this item.


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.
Service
Recommend this item
Sava as my favorate item
Show this item's statistics
Export Endnote File
Google Scholar
Similar articles in Google Scholar
[Li Tao]'s Articles
[Ma Rui]'s Articles
[Zhu Jiye]'s Articles
CSDL cross search
Similar articles in CSDL Cross Search
[Li Tao]‘s Articles
[Ma Rui]‘s Articles
[Zhu Jiye]‘s Articles
Related Copyright Policies
Null
Social Bookmarking
Add to CiteULike Add to Connotea Add to Del.icio.us Add to Digg Add to Reddit

Items in IR are protected by copyright, with all rights reserved, unless otherwise indicated.

 

 

Valid XHTML 1.0!
Copyright © 2007-2017  北京大学医学部 - Feedback
Powered by CSpace