|Blockade of the OX40/OX40L pathway and induction of PD-L1 synergistically protects mouse islet allografts from rejection|
|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|
|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|
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.
|项目编号||30872498 ; RDB2012-11|
|资助机构||National Natural Science Foundation of China ; Peking University People&prime ; s Hospital Research and Development Funds|
|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
|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.|
|APA||Li Tao,Ma Rui,Zhu Jiye,Wang Fushun,Huang Lei,&Leng Xisheng.(2014).Blockade of the OX40/OX40L pathway and induction of PD-L1 synergistically protects mouse islet allografts from rejection.CHINESE MEDICAL JOURNAL,127(14),2686-2692.|
|MLA||Li Tao,et al."Blockade of the OX40/OX40L pathway and induction of PD-L1 synergistically protects mouse islet allografts from rejection".CHINESE MEDICAL JOURNAL 127.14(2014):2686-2692.|