肝再生增强因子免疫抑制作用与调节性T细胞的关系及相关机制研究
|
摘要
第一部分肝再生增强因子对PBMC增殖的影响与调节性T细胞的关系’
目的：肝再生增强因子(Augmenter of liver regeneration, ALR)具有免疫调节作用,但其发挥负性免疫调控作用的机制尚未明确。本部分课题拟通过观察人肝再生增强因子(Human augmenter of liver regeneration, hALR)在体外对ConA刺激的正常人外周血单个核细胞(Peripheral blood mononuclear cells, PBMC)的增殖和凋亡的影响以及对其中CD4+CD25+FoxP3+调节性T细胞(Regulatory T cell, Treg)亚群分化增殖的影响,探讨hALR免疫抑制作用的可能机制。
方法：以ConA刺激的健康人PBMC为实验细胞,分别设Control组、ConA组和ConA+hALR组。体外培养60h后用MTS法检测各组细胞增殖率,流式及免疫印迹法检测各组细胞的早期细胞凋亡率及凋亡相关蛋白表达,实时荧光定量PCR检测各组FoxP3的表达,流式检测各组细胞CD4+CD25+FoxP3+Treg的比例及细胞周期变化。
结果：hALR能够明显抑制ConA刺激的PBMC增殖(ConA组vs ConA+hALR组,P<0.01),且hALR降低ConA引起的细胞凋亡(ConA组vs ConA+hALR组,P<0.01)。hALR在抑制细胞增殖的同时,上调FoxP3基因的表达,提高Treg的比例(ConA组vs ConA+hALR组,P<0.01),并且能够解除ConA导致的Treg亚群细胞周期G2/M期阻滞(ConA组vs ConA+hALR组,P<0.01)。
结论：hALR能够显著抑制ConA刺激的PBMC增殖,但不是通过诱导PBMC凋亡实现的,而是具有抗凋亡作用,hALR同时上调CD4+CD25+FoxP3+Treg的比例,提示hALR可能通过诱导Treg来抑制ConA刺激的PBMC增殖。
第二部分肝再生增强因子诱导调节性T细胞发挥免疫抑制作用的机制
目的：细胞因子在Treg的分化增殖及免疫抑制作用中发挥重要作用,本研究拟通过观察hALR对各组细胞上清中细胞因子(TGF-β1、 IL-10、IL-2)水平的影响,以及对各组细胞信号通路分子(ERK1/2、 NF-κB)舌性及表达的影响,探讨hALR促进Treg分化增殖以及发挥免疫抑制作用的可能机制。
方法：以ConA刺激的健康人PBMC为实验细胞,分别设Control组、ConA组和ConA+hALR组。用ELISA方法分别检测培养16h和40h各组细胞上清中TGF-β1、IL-10、IL-2的水平,用免疫印迹法检测培养60h的各组细胞ERK1/2的活性和NF-κB (p65)的表达。
结果：hALR能够显著增加细胞培养上清中TGF-β1和IL-10的水平,降低IL-2的水平(ConA组vs ConA+hALR组,P<0.01)。hALR能够显著抑制ERK1/2的活性和NF-κB (p65)的表达(ConA组vsConA+hALR组,P<0.01)。
结论：hALR可以促进TGF-β1和IL-10产生而抑制IL-2产生,能够抑制ERK1/2的活性和NF-κB (p65)的表达,提示hALR对细胞因子的调控可能既是hALR上调Treg的条件也是其发挥免疫抑制作用的机制,在分子机制上则表现为对信号通路分子的调控。
第三部分肝再生增强因子对大鼠腹腔肝细胞移植免疫排斥的影响
目的：hALR体外能够上调Treg并抑制ConA活化的免疫细胞增殖,本部分研究拟通过观察腹腔内同种异体肝细胞移植(Hepatocyte transplantation, HCT)联合hALR治疗急性肝衰竭(Acute liver failure,ALF)大鼠的疗效,以及hALR对大鼠免疫排斥反应的影响,探讨hALR体内的免疫抑制作用及机制。
方法：以D-氨基半乳糖(D-galactosamine, D-GalN)诱导ALF的S-D大鼠为动物模型,半原位胶原酶灌注法新鲜分离的大鼠肝细胞腹腔内移植联合hALR治疗ALF大鼠,分为生理盐水(PS)组、HCT组、HCT+hALR组、hALR组。观察各组大鼠生存率,组织学分析腹腔内移植肝细胞存活情况,免疫组化检测大网膜免疫细胞CD68、CD4、CD8及Foxp3阳性率,流式检测腹腔内大网膜免疫细胞中CD4+CD25+FoxP3+Treg的比例,实时荧光定量PCR检测移植物周围大网膜免疫细胞TGF-β1、IL-10mRNA表达水平,ELISA检测腹水及血清中TNF-a和IL-1β水平。
结果：hALR联合HCT治疗能够显著提高大鼠生存率(P<0.05),且hALR明显改善腹腔移植物存活情况,减少炎症细胞浸润。hALR明显降低大网膜免疫细胞CD68、CD4、CD8阳性率,增加Foxp3阳性率,上调大网膜免疫细胞中Treg的比例和TGF-β1、IL-10mRNA的表达,降低前炎症介质TNF-a和IL-1β水平(HCT组vs HCT+hALR组,P<0.05)。
结论：hALR能够通过上调腹腔HCT的ALF大鼠腹腔大网膜内Treg的比例,抑制机体炎症反应和对腹腔移植物的免疫排斥反应,改善腹腔移植物存活,最终提高ALF大鼠存活率。这提示hALR在ALF大鼠体内同样具有免疫抑制作用,能够抑制机体对移植物的免疫排斥反应,促进移植耐受,而上调Treg可能是hALR发挥免疫调节作用的机制。
Part Ⅰ The Effect of hALR on Proliferation of PBMC and the Relationship to Treg
Objective:Augmenter of liver regeneration (ALR) has effect of immunoloregulation, but the underlying mechanism is not completely understood. The objective of this study is to observe the effect of hALR on proliferation of ConA-stimulated PBMC and on differentiation and proliferation of CD4+CD25+FoxP3+Tregs, and to investigate the underlying mechanism of immunosuppressive role of hALR.
Methods:The PBMC from healthy donors was isolated and stimulated with ConA, then cultured in three groups(Control、ConA and ConA+hALR) in vitro for60h. MTS assay was used to determine the cellular viability. Flow cytometry (FCM) and western blot assay were used to detect the early apoptotic ratios and the main proteins of apoptosis. FoxP3mRNA was detected by Real-time fluorescent quantitation PCR, and the ratios of CD4+CD25+FoxP3+Treg and the mitotic cycle of Treg were observed by FCM.
Results:The proliferation of ConA-stimulated PBMC was obviously inhibited by hALR (ConA group vs ConA+hALR group, P<0.01), and the apoptosis of ConA-stimulated PBMC was decreased by hALR (ConA group vs ConA+hALR group, P<0.01). Meanwhile, hALR increased the expression of FoxP3mRNA and up-regulated the percentage of Tregs (ConA group vs ConA+hALR group, P<0.01). In addition, hALR could relieve the G2/M cell cycle arrest of Treg induced by ConA (ConA group vs ConA+hALR group,P<0.01)
Conclusions:The data demonstrated that hALR inhibited the proliferation of ConA-stimulated PBMC and up-regulated the percentages of Treg. It indicated us that hALR inhibited the proliferation of ConA-stimulated PBMC through the pathway of induction of Tregs possibly.
Part Ⅱ The Mechanism of Induction of Treg and the Pathways of Immunosuppression of hALR
Objective:Cytokines played important roles in the differentiation and proliferation of Treg. In this study, we detected the levels of the cytokines (TGF-β1、IL-10、IL-2) in the supernatant and observed the main signaling pathway related molecular (ERK1/2、NF-κB), then discussed the possible mechanism of hALR on induction of Treg and the underlying signaling pathway of immunosuppressive role.
Methods:The PBMC from healthy donors was isolated and stimulated with ConA, then cultured in three groups(Control、ConA and ConA+hALR) in vitro. The levels of TGF-β1, IL-10and IL-2in the supernatant were determined by ELISA, and the expressions of the main signaling pathway related molecular were detected by western blot assay.
Results:The levels of TGF-β1and IL-10in the supernatant were significantly increased by hALR. On the contrary, the level of IL-2was decreased notably (ConA group vs ConA+hALR group, P<0.01) Meanwhile, hALR inhibited the activation of ERK1/2and the expression of NF-κB (p65) obviously (ConA group vs ConA+hALR group, P<0.01).
Conclusions:The levels of the cytokines in the supernatant were regulated by hALR, increasing the production of TGF-β1and IL-10, but decreasing IL-2. Notably, hALR inhibited the activation or expression of the signaling pathway relative molecular. On one hand, it was indicated that cytokines regulated by hALR might be the mechanism of induction of Treg and the approach of immunosuppressive role. On the other hand, the molecular mechanism of hALR on immunosuppressive role was the regulation of the signaling pathway molecular.
Part Ⅲ The Effect of hALR on Immunological Rejection of HCT in ALF Rats
Objective:As hALR up-regulated Treg and inhibited proliferation of immunocytes in vitro, in this part of study, we investigated the potential effect and mechanism of hALR on ALF rats treated with intraperitoneal HCT in vivo.
Methods:ALF rats induced by D-GalN were studied, and were intraperitoneal injected with or without hepatocytes and hALR24h after the induction. The hepatocytes were isolated from healthy S-D rats with an improved two-step semi-situ recirculating collagenase perfusion method. The ALF rats were divided in four groups (PS group, HCT group、 HCT+hALR group and hALR group). Animal survival was assessed, and the levels of TNF-α and IL-1β were detected by ELISA. Histological examination was performed and immunological responses were identified by immunohistochemistry assay. FCM was used to determinate the percentages of Treg in immunocytes in the greater omentum. The expressions of TGF-β1and IL-10mRNA were detected by Real-time fluorescent quantitation PCR.
Results:It showed that hALR improved the survival of ALF rats treated with HCT (P<0.05). The inflammatory damage was reduced significantly in the transplanted islets by hALR after being strained with PAS. Markedly lower percentages of CD68, CD4and CD8positive immunocytes and a higher percentage of Foxp3positive immunocytes in the greater omentum were observed in HCT+hALR group. Additionally, hALR up-regulated the percentage of Treg of the immunocytes in the greater omentum, and increased the expression of TGF-β1and IL-10mRNA, decreased pro-inflammation cytokines (HCT group vs HCT+hALR group, P<0.05)。
Conclusions:In the treatment of ALF rats, hALR up-regulated Treg, inhibited the inflammation, attenuated the damage of immunological rejection, and improved the overall survival. It indicated that hALR inhibited the immunological rejection, promoted the transplantation tolerance of ALF rats, and the underlying mechanism was the up-regulation of Treg by hALR.
目的：肝再生增强因子(Augmenter of liver regeneration, ALR)具有免疫调节作用,但其发挥负性免疫调控作用的机制尚未明确。本部分课题拟通过观察人肝再生增强因子(Human augmenter of liver regeneration, hALR)在体外对ConA刺激的正常人外周血单个核细胞(Peripheral blood mononuclear cells, PBMC)的增殖和凋亡的影响以及对其中CD4+CD25+FoxP3+调节性T细胞(Regulatory T cell, Treg)亚群分化增殖的影响,探讨hALR免疫抑制作用的可能机制。
方法：以ConA刺激的健康人PBMC为实验细胞,分别设Control组、ConA组和ConA+hALR组。体外培养60h后用MTS法检测各组细胞增殖率,流式及免疫印迹法检测各组细胞的早期细胞凋亡率及凋亡相关蛋白表达,实时荧光定量PCR检测各组FoxP3的表达,流式检测各组细胞CD4+CD25+FoxP3+Treg的比例及细胞周期变化。
结果：hALR能够明显抑制ConA刺激的PBMC增殖(ConA组vs ConA+hALR组,P<0.01),且hALR降低ConA引起的细胞凋亡(ConA组vs ConA+hALR组,P<0.01)。hALR在抑制细胞增殖的同时,上调FoxP3基因的表达,提高Treg的比例(ConA组vs ConA+hALR组,P<0.01),并且能够解除ConA导致的Treg亚群细胞周期G2/M期阻滞(ConA组vs ConA+hALR组,P<0.01)。
结论：hALR能够显著抑制ConA刺激的PBMC增殖,但不是通过诱导PBMC凋亡实现的,而是具有抗凋亡作用,hALR同时上调CD4+CD25+FoxP3+Treg的比例,提示hALR可能通过诱导Treg来抑制ConA刺激的PBMC增殖。
第二部分肝再生增强因子诱导调节性T细胞发挥免疫抑制作用的机制
目的：细胞因子在Treg的分化增殖及免疫抑制作用中发挥重要作用,本研究拟通过观察hALR对各组细胞上清中细胞因子(TGF-β1、 IL-10、IL-2)水平的影响,以及对各组细胞信号通路分子(ERK1/2、 NF-κB)舌性及表达的影响,探讨hALR促进Treg分化增殖以及发挥免疫抑制作用的可能机制。
方法：以ConA刺激的健康人PBMC为实验细胞,分别设Control组、ConA组和ConA+hALR组。用ELISA方法分别检测培养16h和40h各组细胞上清中TGF-β1、IL-10、IL-2的水平,用免疫印迹法检测培养60h的各组细胞ERK1/2的活性和NF-κB (p65)的表达。
结果：hALR能够显著增加细胞培养上清中TGF-β1和IL-10的水平,降低IL-2的水平(ConA组vs ConA+hALR组,P<0.01)。hALR能够显著抑制ERK1/2的活性和NF-κB (p65)的表达(ConA组vsConA+hALR组,P<0.01)。
结论：hALR可以促进TGF-β1和IL-10产生而抑制IL-2产生,能够抑制ERK1/2的活性和NF-κB (p65)的表达,提示hALR对细胞因子的调控可能既是hALR上调Treg的条件也是其发挥免疫抑制作用的机制,在分子机制上则表现为对信号通路分子的调控。
第三部分肝再生增强因子对大鼠腹腔肝细胞移植免疫排斥的影响
目的：hALR体外能够上调Treg并抑制ConA活化的免疫细胞增殖,本部分研究拟通过观察腹腔内同种异体肝细胞移植(Hepatocyte transplantation, HCT)联合hALR治疗急性肝衰竭(Acute liver failure,ALF)大鼠的疗效,以及hALR对大鼠免疫排斥反应的影响,探讨hALR体内的免疫抑制作用及机制。
方法：以D-氨基半乳糖(D-galactosamine, D-GalN)诱导ALF的S-D大鼠为动物模型,半原位胶原酶灌注法新鲜分离的大鼠肝细胞腹腔内移植联合hALR治疗ALF大鼠,分为生理盐水(PS)组、HCT组、HCT+hALR组、hALR组。观察各组大鼠生存率,组织学分析腹腔内移植肝细胞存活情况,免疫组化检测大网膜免疫细胞CD68、CD4、CD8及Foxp3阳性率,流式检测腹腔内大网膜免疫细胞中CD4+CD25+FoxP3+Treg的比例,实时荧光定量PCR检测移植物周围大网膜免疫细胞TGF-β1、IL-10mRNA表达水平,ELISA检测腹水及血清中TNF-a和IL-1β水平。
结果：hALR联合HCT治疗能够显著提高大鼠生存率(P<0.05),且hALR明显改善腹腔移植物存活情况,减少炎症细胞浸润。hALR明显降低大网膜免疫细胞CD68、CD4、CD8阳性率,增加Foxp3阳性率,上调大网膜免疫细胞中Treg的比例和TGF-β1、IL-10mRNA的表达,降低前炎症介质TNF-a和IL-1β水平(HCT组vs HCT+hALR组,P<0.05)。
结论：hALR能够通过上调腹腔HCT的ALF大鼠腹腔大网膜内Treg的比例,抑制机体炎症反应和对腹腔移植物的免疫排斥反应,改善腹腔移植物存活,最终提高ALF大鼠存活率。这提示hALR在ALF大鼠体内同样具有免疫抑制作用,能够抑制机体对移植物的免疫排斥反应,促进移植耐受,而上调Treg可能是hALR发挥免疫调节作用的机制。
Part Ⅰ The Effect of hALR on Proliferation of PBMC and the Relationship to Treg
Objective:Augmenter of liver regeneration (ALR) has effect of immunoloregulation, but the underlying mechanism is not completely understood. The objective of this study is to observe the effect of hALR on proliferation of ConA-stimulated PBMC and on differentiation and proliferation of CD4+CD25+FoxP3+Tregs, and to investigate the underlying mechanism of immunosuppressive role of hALR.
Methods:The PBMC from healthy donors was isolated and stimulated with ConA, then cultured in three groups(Control、ConA and ConA+hALR) in vitro for60h. MTS assay was used to determine the cellular viability. Flow cytometry (FCM) and western blot assay were used to detect the early apoptotic ratios and the main proteins of apoptosis. FoxP3mRNA was detected by Real-time fluorescent quantitation PCR, and the ratios of CD4+CD25+FoxP3+Treg and the mitotic cycle of Treg were observed by FCM.
Results:The proliferation of ConA-stimulated PBMC was obviously inhibited by hALR (ConA group vs ConA+hALR group, P<0.01), and the apoptosis of ConA-stimulated PBMC was decreased by hALR (ConA group vs ConA+hALR group, P<0.01). Meanwhile, hALR increased the expression of FoxP3mRNA and up-regulated the percentage of Tregs (ConA group vs ConA+hALR group, P<0.01). In addition, hALR could relieve the G2/M cell cycle arrest of Treg induced by ConA (ConA group vs ConA+hALR group,P<0.01)
Conclusions:The data demonstrated that hALR inhibited the proliferation of ConA-stimulated PBMC and up-regulated the percentages of Treg. It indicated us that hALR inhibited the proliferation of ConA-stimulated PBMC through the pathway of induction of Tregs possibly.
Part Ⅱ The Mechanism of Induction of Treg and the Pathways of Immunosuppression of hALR
Objective:Cytokines played important roles in the differentiation and proliferation of Treg. In this study, we detected the levels of the cytokines (TGF-β1、IL-10、IL-2) in the supernatant and observed the main signaling pathway related molecular (ERK1/2、NF-κB), then discussed the possible mechanism of hALR on induction of Treg and the underlying signaling pathway of immunosuppressive role.
Methods:The PBMC from healthy donors was isolated and stimulated with ConA, then cultured in three groups(Control、ConA and ConA+hALR) in vitro. The levels of TGF-β1, IL-10and IL-2in the supernatant were determined by ELISA, and the expressions of the main signaling pathway related molecular were detected by western blot assay.
Results:The levels of TGF-β1and IL-10in the supernatant were significantly increased by hALR. On the contrary, the level of IL-2was decreased notably (ConA group vs ConA+hALR group, P<0.01) Meanwhile, hALR inhibited the activation of ERK1/2and the expression of NF-κB (p65) obviously (ConA group vs ConA+hALR group, P<0.01).
Conclusions:The levels of the cytokines in the supernatant were regulated by hALR, increasing the production of TGF-β1and IL-10, but decreasing IL-2. Notably, hALR inhibited the activation or expression of the signaling pathway relative molecular. On one hand, it was indicated that cytokines regulated by hALR might be the mechanism of induction of Treg and the approach of immunosuppressive role. On the other hand, the molecular mechanism of hALR on immunosuppressive role was the regulation of the signaling pathway molecular.
Part Ⅲ The Effect of hALR on Immunological Rejection of HCT in ALF Rats
Objective:As hALR up-regulated Treg and inhibited proliferation of immunocytes in vitro, in this part of study, we investigated the potential effect and mechanism of hALR on ALF rats treated with intraperitoneal HCT in vivo.
Methods:ALF rats induced by D-GalN were studied, and were intraperitoneal injected with or without hepatocytes and hALR24h after the induction. The hepatocytes were isolated from healthy S-D rats with an improved two-step semi-situ recirculating collagenase perfusion method. The ALF rats were divided in four groups (PS group, HCT group、 HCT+hALR group and hALR group). Animal survival was assessed, and the levels of TNF-α and IL-1β were detected by ELISA. Histological examination was performed and immunological responses were identified by immunohistochemistry assay. FCM was used to determinate the percentages of Treg in immunocytes in the greater omentum. The expressions of TGF-β1and IL-10mRNA were detected by Real-time fluorescent quantitation PCR.
Results:It showed that hALR improved the survival of ALF rats treated with HCT (P<0.05). The inflammatory damage was reduced significantly in the transplanted islets by hALR after being strained with PAS. Markedly lower percentages of CD68, CD4and CD8positive immunocytes and a higher percentage of Foxp3positive immunocytes in the greater omentum were observed in HCT+hALR group. Additionally, hALR up-regulated the percentage of Treg of the immunocytes in the greater omentum, and increased the expression of TGF-β1and IL-10mRNA, decreased pro-inflammation cytokines (HCT group vs HCT+hALR group, P<0.05)。
Conclusions:In the treatment of ALF rats, hALR up-regulated Treg, inhibited the inflammation, attenuated the damage of immunological rejection, and improved the overall survival. It indicated that hALR inhibited the immunological rejection, promoted the transplantation tolerance of ALF rats, and the underlying mechanism was the up-regulation of Treg by hALR.
引文
[1]Williams R. Global challenges in liver disease [J]. Hepatology.2006,44(3):521-6.
[2]Bauer T, Sprinzl M, Protzer U. Immune control of hepatitis B virus [J]. Dig Dis. 2011,29(4):423-33.
[3]Chang KM. Immunopathogenesis of hepatitis C virus infection [J]. Clin Liver Dis. 2003,7(1):89-105.
[4]Antoniades CG, Berry PA, Wendon JA, et al. The importance of immune dysfunction in determining outcome in acute liver failure [J]. J Hepatol. 2008,49(5):845-61.
[5]Korangy F, Hochst B, Manns MP, et al. Immune responses in hepatocellular carcinoma [J]. Dig Dis.2010,28(1):150-4.
[6]Nakano T, Lai CY, Goto S, et al. Immunological and regenerative aspects of hepatic mast cells in liver allograft rejection and tolerance. PLoS One.2012,7(5):e37202.
[7]Sakaguchi S. Regulatory T cells:key controllers of immunologic self-tolerance[J]. Cell.2000,101(5):455-8.
[8]Miroux C, Vausselin T, Delhem N. Regulatory T cells in HBV and HCV liver diseases:implication of regulatory T lymphocytes in the control of immune response[J]. Expert Opin Biol Ther.2010,10(11):1563-72.
[9]Aalaei-Andabili SH, Alavian SM. Regulatory T cells are the most important determinant factor of hepatitis B infection prognosis:a systematic review and meta-analysis [J]. Vaccine.2012,30(38):5595-602.
[10]Zhai S, Zhang L, Dang S, et al. The ratio of Th-17 to Treg cells is associated with survival of patients with acute-on-chronic hepatitis B liver failure [J]. Viral Immunol.2011,24(4):303-10.
[11]Yang XH, Yamagiwa S, Ichida T, et al. Increase of CD4+ CD25+ regulatory T-cells in the liver of patients with hepatocellular carcinoma[J]. J Hepatol. 2006,45(2):254-62.
[12]Zhang HH, Mei MH, Fei R, et al. Regulatory T cells in chronic hepatitis B patients affect the immunopathogenesis of hepatocellular carcinoma by suppressing the anti-tumour immune responses [J]. J Viral Hepat.2010,17 Suppl 1:34-43.
[13]Shalev I, Selzner N, Shyu W, et al. Role of regulatory T cells in the promotion of transplant tolerance [J]. Liver Transpl.2012,18(7):761-70.
[14]Hagiya M, Francavilla A, Polimeno L, et al. Cloning and sequence analysis of the rat augmenter of liver regeneration (ALR) gene:expression of biologically active recombinant ALR and demonstration of tissue distribution[J].Proc Natl Acad Sci U SA.1994,91 (17):8142-6.
[15]Song M, Yi X, Chen W, et al. Augmenter of liver regeneration (ALR) gene therapy attenuates CCl4-induced liver injury and fibrosis in rats [J]. Biochem Biophys Res Commun.2011,415(1):152-6.
[16]Yang X, Wang A, Zhou P, et al. Protective effect of recombinant human augmenter of liver regeneration on CC14-induced hepatitis in mice[J]. Chin Med J (Engl). 1998,111(7):625-9.
[17]Francavilla A, Vujanovic NL, Polimeno L, et al. The in vivo effect of hepatotrophic factors augmenter of liver regeneration, hepatocyte growth factor, and insulin-like growth factor-II on liver natural killer cell functions [J]. Hepatology.1997,25, 411-5.
[18]Vujanovic NL, Polimeno L, Azzarone A, et al. Changes of liver-resident NK cells during liver regeneration in rats[J]. J Immunol.1995,154(12):6324-38.
[19]Polimeno L, Margiotta M, Marangi L, et al. Molecular mechanisms of augmenter of liver regeneration as immunoregulator:its effect on interferon-gamma expression in rat liver[J]. Dig Liver Dis.2000,32,217-25.
[20]Tanigawa K, Sakaida I, Masuhara M, et al. Augmenter of liver regeneration (ALR) may promote liver regeneration by reducing natural killer (NK) cell activity in human liver diseases [J]. J Gastroenterol.2000,35,112-9.
[21]Adams GA, Maestri M, Squiers EC, et al. Augmenter of liver regeneration enhances the success rate of fetal pancreas transplantation in rodents [J]. Transplantation.1998,65(1):32-6.
[22]Hongbo S, Yu C, Ming K, et al. Augmenter of liver regeneration may be a candidate for prognosis of HBV related acute-on-chronic liver failure as a regenerative marker [J]. Hepatogastroenterology.2012,59(118):1933-8.
[23]Yu HY, Xiang DR, Huang HJ, et al. Expression level of augmenter of liver regeneration in patients with hepatic failure and hepatocellular carcinoma[J]. Hepatobiliary Pancreat Dis Int.2010,9(5):492-8.
[24]孙航,余慧峰,吴传新,等.肝再生增强因子在肝癌细胞中的表达及意义[J].中华肝脏病杂志.2005,13(3)：205-8.
[25]Liang S, Chen Y, Long F, et al. Correlation between augmenter of liver regeneration and IFN-y expression in graft after rat orthotopic liver transplantation[J]. J Surg Res. 2012,178(2):968-73.
[26]Chen Y, Yuan G, Sun H, et al. Intrasplenic transplantation of newborn rat hepatocytes with rALR for treating rats with acute hepatic failure [J]. Zhonghua Gan Zang Bing Za Zhi.2007,15(5):378-82.
[27]谢华,孙航,郭辉,等.肝再生增强因子对大鼠脾单个核细胞增殖及IL-2产生能力的影响[J].中国免疫学杂志.2007,23(5)：85-8.
[28]Cao M, Cabrera R, Xu Y, et al. Hepatocellular carcinoma cell supernatants increase expansion and function of CD4+CD25+ regulatory T cells[J]. Laboratory Investigation.2007,87:582-90.
[29]Kondo Y, Ninomiya M, Kakazu E, et al. Hepatitis B surface antigen could contribute to the immunopathogenesis of hepatitis B virus infection [J]. ISRN Gastroenterol.2013,2013:935295.
[30]Op den Brouw ML, Binda RS, van Roosmalen MH, et al. Hepatitis B virus surface antigen impairs myeloid dendritic cell function:a possible immune escape mechanism of hepatitis B virus [J]. Immunology.2009,126(2):280-9.
[31]Li Y, Farooq M, Sheng D, et al. Augmenter of liver regeneration (alr) promotes liver outgrowth during zebrafish hepatogenesis[J]. PLoS One 2012,7, e30835.
[32]Polimeno L, Pesetti B, Annoscia E, et al. Alrp, a survival factor that controls the apoptotic process of regenerating liver after partial hepatectomy in rats [J]. Free Radic Res.2011,45,534-49.
[33]Gandhi CR Augmenter of liver regeneration [J]. Fibrogenesis Tissue Repair. 2012,5(1):10.
[34]Gandhi CR, Kuddus R, Subbotin VM, et al. A fresh look at augmenter of liver regeneration in rats [J]. Hepatology.1999,29,1435-45.
[35]Demirkiran A, Kok A, Kwekkeboom J, et al. Low circulating regulatory T-cell levels after acute rejection in liver transplantation [J]. Liver Transpl. 2006,12(2):277-84.
[36]Allan SE, Broady R, Gregori S, et al. CD4+ T-regulatory cells:toward therapy for human diseases [J]. Immunol Rev.2008,223:391-421.
[37]肖序仁,徐衍盛,敖建华.不同免疫抑制剂诱导外周血活化T淋巴细胞凋亡的研究[J].中华器官移植杂志.2006,27(11)：644-7.
[38]Thirunavukkarasu C, Wang LF, Harvey SA, et al. Augmenter of liver regeneration: an important intracellular survival factor for hepatocytes [J]. J Hepatol.2008,48, 578-88.
[39]Polimeno L, Pesetti B, Lisowsky T, et al. Protective effect of augmenter of liver regeneration on hydrogen peroxide-induced apoptosis in SH-SY5Y human neuroblastoma cells [J]. Free Radic Res.2009,43,865-75.
[40]Polimeno L, Pesetti B, De Santis F, et al. Decreased expression of the Augmenter of Liver Regeneration results in increased apoptosis and oxidative damage in human-derived glioma cells [J]. Cell Death Dis.2012,3,e289.
[41]Liao XH, Chen GT, Li Y, et al. Augmenter of liver regeneration attenuates tubular cell apoptosis in acute kidney injury in rats:the possible mechanisms [J]. Ren Fail. 2012,34,590-9.
[42]Ilowski M, Kleespies A, de Toni EN, et al. Augmenter of liver regeneration (ALR) protects human hepatocytes against apoptosis [J]. Biochem Biophys Res Commun. 2011,404,148-52.
[43]Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases [J]. J Immunol.1995,155(3):1151-64.
[44]Ng WF, Duggan PJ, Ponchel F, et al. Human CD4(+)CD25(+) cells:a naturally occurring population of regulatory T cells [J]. Blood.2001,98(9):2736-44.
[45]Sakaguchi S, Yamaguchi T, Nomura T, et al. Regulatory T cells and immune tolerance[J]. Cell.2008,133(5):775-87.
[46]Ito T, Hanabuchi S, Wang YH, et al.Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery [J]. Immunity.2008,28(6):870-80.
[47]Meloche S, Pouyssegur J. The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the Gl- to S-phase transition [J]. Oncogene.2007, 26(22):3227-39.
[48]Xue F, Takahara T, Yata Y, et al. Hepatocyte growth factor gene therapy accelerates regeneration in cirrhotic mouse livers after hepatectomy [J]. Gut. 2003,52(5):694-700.
[49]Fremin C, Bessard A, Ezan F, et al. Multiple division cycles and long-term survival of hepatocytes are distinctly regulated by extracellular signal-regulated kinases ERK1 and ERK2[J]. Hepatology.2009,49(3):930-9.
[50]Fremin C, Ezan F, Boisselier P, et al. ERK2 but not ERK1 plays a key role in hepatocyte replication:an RNAi-mediated ERK2 knockdown approach in wild-type and ERK1 null hepatocytes [J]. Hepatology.2007,45(4):1035-45.
[51]Lee KH, Choi EY, Hyun MS, et al. Role of hepatocyte growth factor/c-Met signaling in regulating urokinase plasminogen activator on invasiveness in human hepatocellular carcinoma:a potential therapeutic target [J]. Clin Exp Metastasis. 2008,25(1):89-96.
[52]Fremin C, Ezan F, Guegan JP, et al. The complexity of ERK1 and ERK2 MAPKs in multiple hepatocyte fate responses [J]. J Cell Physiol.2012,227(1):59-69.
[53]Park PH, Aroor AR, Shukla SD. Role of Ras in ethanol modulation of angiotensin II activated p42/p44 MAP kinase in rat hepatocytes [J]. Life Sci.2006, 79(25):2357-63.
[54]Carr EL, Kelman A, Wu GS, et al. Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation [J]. J Immunol.2010,185(2):1037-44.
[55]Yasuda T, Kurosaki T. Regulation of lymphocyte fate by Ras/ERK signals [J]. Cell Cycle.2008,7(23):3634-40.
[56]Lin JT, Stein EA, Wong MT, et al. Differential mTOR and ERK pathway utilization by effector CD4 T cells suggests combinatorial drug therapy of arthritis[J]. Clin Immunol.2012,142(2):127-38.
[57]唐琳,孙航,张林,等.阻断肝再生增强因子的表达对人肝癌细胞株HepG2增殖的抑制作用[J].癌症.2006,25(6)：671-6.
[58]Acuna-Castillo C, Aravena M, Leiva-Salcedo E, et al. T-kininogen, a cystatin-like molecule, inhibits ERK-dependent lymphocyte proliferation [J]. Mech Ageing Dev. 2005,126(12):1284-91.
[59]Wang JX, Tang W, Shi LP, et al. Investigation of the immunosuppressive activity of artemether on T-cell activation and proliferation [J]. Br J Pharmacol. 2007,150(5):652-61.
[60]Kamo N, Shen XD, Ke B, et al. Sotrastaurin, a protein kinase C inhibitor, ameliorates ischemia and reperfusion injury in rat orthotopic liver transplantation[J]. Am J Transplant.2011,11(11):2499-507.
[61]Abboushi N, El-Hed A, El-Assaad W, et al. Ceramide inhibits IL-2 production by preventing protein kinase C-dependent NF-kappaB activation:possible role in protein kinase Ctheta regulation[J]. J Immunol.2004,173 (5):3193-200.
[62]Han Y, Meng T, Murray NR, et al. Interleukin-1-induced nuclear factor-kappaB-IkappaBalpha autoregulatory feedback loop in hepatocytes. A role for protein kinase calpha in post-transcriptional regulation of ikappabalpha resynthesis [J]. J Biol Chem.1999,274(2):939-47.
[63]Liang Zhou, Dan R Littman. Transcriptional regulatory networks in Th17 cell differentiation [J]. Curr Opin Immunol.2009,21(2):146-52.
[64]Liang Zhou, Jared E. Lopes, Mark M. W. Chong, et al. TGF-(3-induced Foxp3 inhibits Th17 cell differentiation by antagonizing RORyt function [J]. Nature. 2008,453(7192):236-40.
[65]Dorothy K Sojka, Yu-Hui Huang, Deborah J Fowell. Mechanisms of regulatory T-cell suppression-a diverse arsenal for a moving target [J]. Immunology. 2008,124(1):13-22.
[66]Yamazaki S, Steinman RM. Dendritic cells as controllers of antigen-specific Foxp3+ regulatory T cells [J]. J Dermatol Sci.2009,54(2):69-75.
[67]WanJun Chen, Joanne E. Konkel. TGF-β and 'Adaptive' Foxp3+ Regulatory T cells[J]. J Mol Cell Biol.2010,2(1):30-6.
[68]Brad E Hoffman, Ashley T Martino, Brandon K Sack, et al. Nonredundant Roles of IL-10 and TGF-β in Suppression of Immune Responses to Hepatic AAV-Factor IX Gene Transfer [J]. Mol Ther. 2011,19(7):1263-72.
[69]Paul L. Bollyky, Ben A. Falk, Alice Long, et al. CD44 co-stimulation promotes FoxP3+ regulatory T-cell persistence and function via production of IL-2, IL-10 and TGF-beta [J]. J Immunol.2009,183(4):2232-41.
[70]Edgar JD. Clinical immunology [J]. Ulster Med J.2011,80(1):5-14.
[71]Chao-Lien Liu, Peiqing Ye, Benjamin C Yen, et al. In Vivo Expansion of Regulatory T cells With IL-2/IL-2 mAb Complexes Prevents Anti-factor VIII Immune Responses in Hemophilia A Mice Treated With Factor VIII Plasmid-mediated Gene Therapy [J]. Mol Ther.2011,19(8):1511-20.
[72]Lee SJ, Lim KT Inhibitory effect of 30-kDa phytoglycoprotein on expression of TNF-alpha and COX-2 via activation of PKCalpha and ERK 1/2 in LPS-stimulated RAW 264.7 cells [J]. Mol Cell Biochem.2008,317(1-2):151-9.
[73]Lio CW, Hsieh CS. A two-step process for thymic regulatory T cell development [J]. Immunity.2008,28(1):100-11.
[74]Schmidt A, Oberle N, Weiss EM, et al. Human regulatory T cells rapidly suppress T cell receptor-induced Ca(2+), NF-κB, and NFAT signaling in conventional T cells [J]. Sci Signal.2011,4(204):ra90.
[75]Ting-Ting Tang, You Song, Ying-Jun Ding, et al. Atorvastatin upregulates regulatory T cells and reduces clinical disease activity in patients with rheumatoid arthritis[J]. J Lipid Res.2011,52(5):1023-32.
[76]Skvorak KJ, Paul HS, Dorko K, et al. Hepatocyte transplantation improves phenotype and extends survival in a murine model of intermediate maple syrup urine disease [J]. Mol Ther.2009,17(7):1266-73.
[77]Cameron AM, Ghobrial RM, Yersiz H, et al. Optimal utilization of donor grafts with extended criteria:a single-center experience in over 1000 liver transplants[J]. Ann Surg.2006,243(6):748-53.
[78]Fisher RA, Strom SC. Human hepatocyte transplantation:worldwide results[J]. Transplantation.2006,82(4):441-9.
[79]Park JK, Lee DH. Bioartificial liver systems:current status and future perspective [J]. J Biosci Bioeng.2005,99(4):311-9.
[80]Meyburg J, Alexandrova K, Barthold M, et al. Liver cell transplantation:basic investigations for safe application in infants and small children [J]. Cell Transplant. 2009,18(7):777-86.
[81]Baccarani U, Adani GL, Sanna A, et al. Portal vein thrombosis after intraportal hepatocytes transplantation in a liver transplant recipient[J]. Transpl Int. 2005,18(6):750-4.
[82]Habibullah CM, Syed IH, Qamar A, et al. Human fetal hepatocyte transplantation in patients with fulminant hepatic failure [J]. Transplantation.1994,58(8):951-2.
[83]Allen KJ, Soriano HE. Liver cell transplantation:the road to clinical application[J]. J Lab Clin Med.2001,138(5):298-312.
[84]Najimi M, Sokal E. Update on liver cell transplantation[J]. J Pediatr Gastroenterol Nutr.2004,39(4):311-9.
[85]Newsome PN, Plevris JN, Nelson LJ, et al. Animal models of fulminant hepatic failure:a critical evaluation [J]. Liver Transpl.2000,6(1):21-31.
[86]Strom SC, Fisher RA, Thompson MT, et al. Hepatocyte transplantation as a bridge to orthotopic liver transplantation in terminal liver failure[J]. Transplantation. 1997,63(4):559-69.
[87]Bumgardner GL, Li J, Heininger M, et al. In vivo immunogenicity of purified allogeneic hepatocytes in a murine hepatocyte transplant model [J]. Transplantation. 1998,65(1):47-52.
[88]Home PH, Lunsford KE, Walker JP, et al. Recipient immune repertoire and engraftment site influence the immune pathway effecting acute hepatocellular allograft rejection[J]. Cell Transplant.2008,17(7):829-44.
[89]Bemal W, Auzinger Q Dhawan A, et al. Acute liver failure[J]. Lancet. 2010,376(9736):190-201.
[90]Zimmerer JM, Home PH, Fiessinger LA, et al. Cytotoxic effector function of CD4-independent, CD8(+) T cells is mediated by TNF-α/TNFR [J]. Transplantation. 2012,94(11):1103-10.
[91]Lunsford KE, Gao D, Eiring AM, et al. Evidence for tissue-directed immune responses:analysis of CD4- and CD8-dependent alloimmunity. Transplantation [J]. 2004,78(8):1125-33.
[92]Home PH, Lunsford KE, Eiring AM, et al. CD4+T-cell-dependent immune damage of liver parenchymal cells is mediated by alloantibody [J]. Transplantation. 2005,80(4):514-21.
[93]Lin YC, Goto S, Tateno C, et al. Induction of indoleamine 2,3-dioxygenase in livers following hepatectomy prolongs survival of allogeneic hepatocytes after transplantation [J]. Transplant Proc.2008,40(8):2706-8.
[94]Keri E. Lunsford, Kartika Jayanshankar, Anna M. Eiring, et al. Alloreactive (CD4-independent) CD8+ T cells jeopardize long-term survival of intrahepatic islet allografts [J]. Am J Transplant.2008,8(6):1113-28.
[95]Bhatt S, Fung JJ, Lu L, et al. Tolerance-inducing strategies in islet transplantation[J]. Int J Endocrinol.2012,2012:396524.
[96]Oluwole SF, Oluwole OO, Adeyeri AO, et al. New strategies in immune tolerance induction [J]. Cell Biochem Biophys.2004,40(3 Suppl):27-48.
[1]Fehervari Z, Sakaguchi S. CD4+ Tregs and immune control [J]. J Clin Invest. 2004,114(9):1209-17.
[2]Thompson JA, Perry D, Brusko TM. Autologous regulatory T cells for the treatment of type 1 diabetes [J]. Curr Diab Rep.2012,12(5):623-32.
[3]Boncheva V, Bonney SA, Brooks SE, et al. New targets for the immunotherapy of colon cancer-does reactive disease hold the answer? [J]. Cancer Gene Ther. 2013,20(3):157-68.
[4]Zhao W, Su W, Kuang P, et al. The role of hepatic stellate cells in the regulation of T-cell function and the promotion of hepatocellular carcinoma [J]. Int J Oncol. 2012,41 (2):457-64.
[5]Han YF, Cao GW. Role of nuclear receptor NR4A2 in gastrointestinal inflammation and cancers [J]. World J Gastroenterol.2012,18(47):6865-73.
[6]Du Y, Chen X, Huang ZM, et al. Increased frequency of Foxp3+ regulatory T cells in mice with hepatocellular carcinoma [J]. Asian Pac J Cancer Prev. 2012,13(8):3815-9.
[7]Singh K, Gatzka M, Peters T, et al. Reduced CD18 Levels Drive Regulatory T Cell Conversion into Th17 Cells in the CD18hypo PL/J Mouse Model of Psoriasis [J]. J Immunol.2013,190(6):2544-53.
[8]Liu Y, Wang H, Wang X, et al. The mechanism of effective electroacupuncture on T cell response in rats with experimental autoimmune encephalomyelitis [J]. PLoS One.2013,8(l):e51573.
[9]Veiga-Parga T, Suryawanshi A, Mulik S, et al. On the role of regulatory T cells during viral-induced inflammatory lesions [J]. J Immunol.2012,189(12):5924-33.
[10]Chevalier MF, Weiss L. The split personality of regulatory T cells in HIV infection [J]. Blood.2013,121(1):29-37.
[11]Kilshaw PJ, Brent L, Pinto M. Suppressor T cells in mice made unresponsive to skin allografts [J]. Nature.1975,255(5508):489-91.
[12]Kilshaw PJ, Brent L, Pinto M. An active suppressor mechanism preventing skin allograft rejection in mice [J]. Transplant Proc.1975,7(2):225-8.
[13]Hall BM, Jelbart ME, Gurley KE, et al. Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. Mediation of specific suppression by T helper/inducer cells [J]. J Exp Med.1985,162(5):1683-94.
[14]Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases [J]. J Immunol.1995,155(3):1151-64.
[15]Itoh M, Takahashi T, Sakaguchi N, et al. Thymus and autoimmunity:production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance [J]. J Immunol.1999, 162(9):5317-26.
[16]Takahashi T, Sakaguchi S. Naturally arising CD25+CD4+ regulatory T cells in maintaining immunologic self-tolerance and preventing autoimmune disease [J]. Curr Mol Med.2003,3(8):693-706.
[17]Schubert LA, Jeffery E, Zhang Y, et al. Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation [J]. J Biol Chem. 2001,276(40):37672-9.
[18]Lopes JE, Torgerson TR, Schubert LA, et al. Analysis of FOXP3 reveals multiple domains required for its function as a transcriptional repressor [J]. J Immunol. 2006,177(5):3133-42.
[19]Whiteside TL, Schuler P, Schilling B. Induced and natural regulatory T cells in human cancer [J]. Expert Opin Biol Ther.2012,12(10):1383-97.
[20]Bilate AM, Lafaille JJ. Induced CD4+Foxp3+ regulatory T cells in immune tolerance [J]. Annu Rev Immunol.2012,30:733-58.
[21]Wu Y, Borde M, Heissmeyer V, et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell [J].2006,126(2):375-87.
[22]Bacchetta R, Passerini L, Gambineri E, et al. Defective regulatory and effector T cell functions in patients with FOXP3 mutations [J]. J Clin Invest. 2006,116(6):1713-22.
[23]Bettini ML, Pan F, Bettini M, et al. Loss of epigenetic modification driven by the Foxp3 transcription factor leads to regulatory T cell insufficiency [J]. Immunity. 2012,36(5):717-30.
[24]Chen Z, Lin F, Gao Y, et al. FOXP3 and RORyt:transcriptional regulation of Treg and Th17. Int Immunopharmacol [J].2011,11(5):536-42.
[25]Schmetterer KQ Neunkirchner A, Pickl WF. Naturally occurring regulatory T cells: markers, mechanisms, and manipulation [J]. FASEB J.2012,26(6):2253-76.
[26]Bettini ML, Vignali DA. Development of thymically derived natural regulatory T cells [J]. Ann N Y Acad Sci.2010,1183:1-12.
[27]Hori S, Takahashi T, Sakaguchi S. Control of autoimmunity by naturally arising regulatory CD4+ T cells [J]. Adv Immunol.2003,81:331-71.
[28]Sakaguchi S, Ono M, Setoguchi R, et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease [J]. Immunol Rev. 2006,212:8-27.
[29]Pot C, Apetoh L, Kuchroo VK. Type 1 regulatory T cells (Trl) in autoimmunity [J]. Semin Immunol.2011,23(3):202-8.
[30]Faria AM, Weiner HL. Oral tolerance and TGF-beta-producing cells [J]. Inflamm Allergy Drug Targets.2006,5(3):179-90.
[31]Weiner HL. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells [J]. Immunol Rev.2001,182:207-14.
[32]Carrier Y, Yuan J, Kuchroo VK, et al. Th3 cells in peripheral tolerance. I. Induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-beta T cell-transgenic mice [J]. J Immunol.2007,178(1):179-85.
[33]Dons EM, Raimondi G, Cooper DK, et al. Induced regulatory T cells:mechanisms of conversion and suppressive potential [J]. Hum Immunol.2012,73(4):328-34.
[34]Lin X, Chen M, Liu Y, et al. Advances in distinguishing natural from induced Foxp3(+) regulatory T cells [J]. Int J Clin Exp Pathol.2013,6(2):116-23.
[35]Beal AM, Ramos-Hernandez N, Riling CR, et al. TGF-β induces the expression of the adaptor Ndfipl to silence IL-4 production during iTreg cell differentiation [J]. Nat Immunol.2011,13(1):77-85.
[36]Regateiro FS, Howie D, Cobbold SP, et al. TGF-β in transplantation tolerance [J]. Curr Opin Immunol.2011,23(5):660-9.
[37]Zhou X, Kong N, Zou H, et al. Therapeutic potential of TGF-β-induced CD4(+) Foxp3(+) regulatory T cells in autoimmune diseases. Autoimmunity [J]. 2011,44(1):43-50.
[38]Lan Q, Zhou X, Fan H, et al. Polyclonal CD4+Foxp3+ Treg cells induce TGFβ-dependent tolerogenic dendritic cells that suppress the murine lupus-like syndrome [J]. J Mol Cell Biol.2012,4(6):409-19.
[39]Picarda E, Anegon I, Guillonneau C. T-cell receptor specificity of CD8(+) Tregs in allotransplantation [J]. Immunotherapy.2011,3(4 Suppl):35-7.
[40]Liao W, Lin JX, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy [J]. Immunity.2013,38(1):13-25.
[41]Cheng G, Yu A, Malek TR. T-cell tolerance and the multi-functional role of IL-2R signaling in T-regulatory cells [J]. Immunol Rev.2011,241(1):63-76.
[42]Malek TR, Castro I. Interleukin-2 receptor signaling:at the interface between tolerance and immunity [J]. Immunity.2010,33(2):153-65.
[43]McHugh RS, Whitters MJ, Piccirillo CA, et al. CD4(+)CD25(+) immunoregulatory T cells:gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor [J]. Immunity.2002,16(2):311-23.
[44]Ward FJ, Dahal LN, Wijesekera SK, et al. The soluble isoform of CTLA-4 as a regulator of T-cell responses [J]. Eur J Immunol.2013,11.
[45]Barnes MJ, Griseri T, Johnson AM, et al. CTLA-4 promotes Foxp3 induction and regulatory T cell accumulation in the intestinal lamina propria [J]. Mucosal Immunol.2013,6(2):324-34.
[46]Ziegler SF, Buckner JH. FOXP3 and the regulation of Treg/Th17 differentiation [J]. Microbes Infect.2009,11 (5):594-8.
[47]Klingenberg R, Gerdes N, Badeau RM, et al. Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis [J]. J Clin Invest.2013, 123(3):1323-34
[48]Khattri R, Cox T, Yasayko SA, et al. An essential role for Scurfin in CD4+CD25+ T regulatory cells [J]. Nat Immunol.2003,4(4):337-42.
[49]Khattri R, Kasprowicz D, Cox T, et al.The amount of scurfin protein determines peripheral T cell number and responsiveness [J]. J Immunol.2001,167(11): 6312-6320.
[50]Bettelli E, Dastrange M, Oukka M. Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells [J]. Proc Natl Acad Sci U S A.2005,102(14):5138-43.
[51]Rudensky AY, Gavin M, Zheng Y. FOXP3 and NFAT:partners in tolerance [J]. Cell.2006,126(2):253-6.
[52]Vaeth M, Schliesser U, Muller Q et al. Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3+ regulatory T cells [J]. Proc Natl Acad Sci U S A.2012,109(40):16258-63.
[53]Heinze E, Chan G, Mory R, et al. Tumor suppressor and T-regulatory functions of Foxp3 are mediated through separate signaling pathways [J]. Oncol Lett. 2011,2(4):665-668.
[54]Schmidt A, Oberle N, Krammer PH. Molecular mechanisms of treg-mediated T cell suppression [J]. Front Immunol.2012,3:51.
[55]Lee SM, Gao B, Fang D. FoxP3 maintains Treg unresponsiveness by selectively inhibiting the promoter DNA-binding activity of AP-1 [J]. Blood.2008, 111(7):3599-606.
[56]Gavin MA, Rasmussen JP, Fontenot JD, et al. Foxp3-dependent programme of regulatory T-cell differentiation [J]. Nature.2007,445(7129):771-5.
[57]Cobbold SP, Nolan KF, Graca L, et al. Regulatory T cells and dendritic cells in transplantation tolerance:molecular markers and mechanisms [J]. Immunol Rev 2003,196(1):109-24
[58]Chen ZF, Xu Q, Ding JB, et al. CD4+CD25+Foxp3+ Treg and TGF-beta play important roles in pathogenesis of Uygur cervical carcinoma [J]. Eur J Gynaecol Oncol.2012,33(5):502-7.
[59]Prado C, de Paz B, Lopez P, et al. Relationship between FOXP3 positive populations and cytokine production in systemic lupus erythematosus. Cytokine [J]. 2013,61(1):90-6.
[60]Mays LE, Ammon-Treiber S, Mothes B, et al. Modified Foxp3 mRNA protects against asthma through an IL-10-dependent mechanism [J]. J Clin Invest. 2013,123(3):1216-28.
[61]Lou W, Wang C, Wang Y, et al. Responses of CD4(+) CD25(+) Foxp3(+) and IL-10-secreting type I T regulatory cells to cluster-specific immunotherapy for allergic rhinitis in children [J]. Pediatr Allergy Immunol.2012,23(2):140-9.
[62]Olson BM, Jankowska-Gan E, Becker JT, et al. Human prostate tumor antigen-specific CD8+ regulatory T cells are inhibited by CTLA-4 or IL-35 blockade [J]. J Immunol.2012,189(12):5590-601.
[63]Shen E, Zhao K, Wu C, et al. The suppressive effect of CD25+Treg cells on Thl differentiation requires cell-cell contact partially via TGF-β production [J]. Cell Biol Int 2011,35(7):705-12.
[64]Singh AK, Seavey CN, Horvath KA, et al. Ex-vivo expanded baboon CD4+ CD25 Hi Treg cells suppress baboon anti-pig T and B cell immune response [J]. Xenotransplantation.2012,19(2):102-11.
[65]Trzonkowski P, Szmit E, Mysliwska J, et al. CD4+CD25+ T regulatory cells inhibit cytotoxic activity of CTL and NK cells in humans-impact of immunosenescence [J]. Clin Immunol.2006,119(3):307-16.
[66]Zhong RK, Loken M, Lane TA, et al. CTLA-4 blockade by a human MAb enhances the capacity of AML-derived DC to induce T-cell responses against AML cells in an autologous culture system [J]. Cytotherapy.2006,8(1):3-12.
[67]Hubo M, Jonuleit H. Plasmacytoid dendritic cells are inefficient in activation of human regulatory T cells [J]. PLoS One.2012,7(8):e44056.
[68]Farias AS, Spagnol GS, Bordeaux-Rego P, et al. Vitamin D3 Induces IDO(+) Tolerogenic DCs and Enhances Treg, Reducing the Severity of EAE [J]. CNS Neurosci Ther. 2013,19(4):269-77.
[69]Baban B, Chandler PR, Johnson BA 3rd, et al. Physiologic control of IDO competence in splenic dendritic cells. J Immunol [J].2011,187(5):2329-35.
[70]Lewkowicz N, Klink M, Mycko MP, et al. Neutrophil-CD4(+)CD25(+) T regulatory cell interactions:A possible new mechanism of infectious tolerance [J]. Immunobiology.2013,218(4):455-64.
[71]Li YN, Huang F, Liu XL, et al. Allium sativum-derived allitridin inhibits Treg amplification in cytomegalovirus infection [J]. J Med Virol.2013,85(3):493-500.
[72]Aranzamendi C, de Bruin A, Kuiper R, et al. Protection against allergic airway inflammation during the chronic and acute phases of Trichinella spiralis infection [J]. Clin Exp Allergy.2013,43(1):103-15.
[73]Zhuang Y, Wei X, Li Y, et al. HCV coinfection does not alter the frequency of regulatory T cells or CD8+ T cell immune activation in chronically infected HIV+ Chinese subjects [J]. AIDS Res Hum Retroviruses.2012,28(9):1044-51.
[74]Radziewicz H, Dunham RM, Grakoui A. PD-1 tempers Tregs in chronic HCV infection [J]. J Clin Invest.2009,119(3):450-3.
[75]Miroux C, Vausselin T, Delhem N. Regulatory T cells in HBV and HCV liver diseases:implication of regulatory T lymphocytes in the control of immune response [J]. Expert Opin Biol Ther.2010,10(11):1563-72.
[76]Alatrakchi N, Koziel M. Regulatory T cells and viral liver disease [J]. J Viral Hepat. 2009,16(4):223-9.
[77]Manigold T, Racanelli V. T-cell regulation by CD4 regulatory T cells during hepatitis B and C virus infections:facts and controversies [J]. Lancet Infect Dis. 2007,7(12):804-13.
[78]Chattopadhyay S, Chakraborty NG, Mukherji B. Regulatory T cells and tumor immunity [J]. Cancer Immunol Immunother.2005,54(12):1153-61.
[79]Pedroza-Gonzalez A, Verhoef C, Ijzermans JN, et al. Activated tumor-infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer [J]. Hepatology.2013,57(1):183-94.
[80]Afzali B, Lombardi G, Lechler RI, et al. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease [J]. Clin Exp Immunol.2007,148(1):32-46.
[81]Abarbanel DN, Seki SM, Davies Y, et al. Immunomodulatory effect of vancomycin on treg in pediatric inflammatory bowel disease and primary sclerosing cholangitis [J]. J Clin Immunol.2013,33(2):397-406.
[82]Azab NA, Bassyouni IH, Emad Y, et al. CD4+CD25+ regulatory T cells (TREG) in systemic lupus erythematosus (SLE) patients:the possible influence of treatment with corticosteroids [J]. Clin Immunol.2008,127(2):151-7.
[83]Longhi MS, Meda F, Wang P, et al. Expansion and de novo generation of potentially therapeutic regulatory T cells in patients with autoimmune hepatitis [J]. Hepatology.2008,47(2):581-91.
[84]Lourenco EV, La Cava A. Natural regulatory T cells in autoimmunity [J]. Autoimmunity.2011,44(1):33-42.
[85]Peiseler M, Sebode M, Franke B, et al. FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency [J]. J Hepatol. 2012,57(1):125-32.
[86]Burrell BE, Nakayama Y, Xu J, et al. Regulatory T cell induction, migration, and function in transplantation [J]. J Immunol.2012,189(10):4705-11.
[87]Guo X, Jie Y, Ren D, et al. In vitro-expanded CD4(+)CD25(high)Foxp3(+) regulatory T cells controls corneal allograft rejection [J]. Hum Immunol. 2012,73(11):1061-7.
[88]Li W, Carper K, Liang Y, et al. Anti-CD25 mAb administration prevents spontaneous liver transplant tolerance [J]. Transplant Proc.2006,38(10):3207-8.
[2]Bauer T, Sprinzl M, Protzer U. Immune control of hepatitis B virus [J]. Dig Dis. 2011,29(4):423-33.
[3]Chang KM. Immunopathogenesis of hepatitis C virus infection [J]. Clin Liver Dis. 2003,7(1):89-105.
[4]Antoniades CG, Berry PA, Wendon JA, et al. The importance of immune dysfunction in determining outcome in acute liver failure [J]. J Hepatol. 2008,49(5):845-61.
[5]Korangy F, Hochst B, Manns MP, et al. Immune responses in hepatocellular carcinoma [J]. Dig Dis.2010,28(1):150-4.
[6]Nakano T, Lai CY, Goto S, et al. Immunological and regenerative aspects of hepatic mast cells in liver allograft rejection and tolerance. PLoS One.2012,7(5):e37202.
[7]Sakaguchi S. Regulatory T cells:key controllers of immunologic self-tolerance[J]. Cell.2000,101(5):455-8.
[8]Miroux C, Vausselin T, Delhem N. Regulatory T cells in HBV and HCV liver diseases:implication of regulatory T lymphocytes in the control of immune response[J]. Expert Opin Biol Ther.2010,10(11):1563-72.
[9]Aalaei-Andabili SH, Alavian SM. Regulatory T cells are the most important determinant factor of hepatitis B infection prognosis:a systematic review and meta-analysis [J]. Vaccine.2012,30(38):5595-602.
[10]Zhai S, Zhang L, Dang S, et al. The ratio of Th-17 to Treg cells is associated with survival of patients with acute-on-chronic hepatitis B liver failure [J]. Viral Immunol.2011,24(4):303-10.
[11]Yang XH, Yamagiwa S, Ichida T, et al. Increase of CD4+ CD25+ regulatory T-cells in the liver of patients with hepatocellular carcinoma[J]. J Hepatol. 2006,45(2):254-62.
[12]Zhang HH, Mei MH, Fei R, et al. Regulatory T cells in chronic hepatitis B patients affect the immunopathogenesis of hepatocellular carcinoma by suppressing the anti-tumour immune responses [J]. J Viral Hepat.2010,17 Suppl 1:34-43.
[13]Shalev I, Selzner N, Shyu W, et al. Role of regulatory T cells in the promotion of transplant tolerance [J]. Liver Transpl.2012,18(7):761-70.
[14]Hagiya M, Francavilla A, Polimeno L, et al. Cloning and sequence analysis of the rat augmenter of liver regeneration (ALR) gene:expression of biologically active recombinant ALR and demonstration of tissue distribution[J].Proc Natl Acad Sci U SA.1994,91 (17):8142-6.
[15]Song M, Yi X, Chen W, et al. Augmenter of liver regeneration (ALR) gene therapy attenuates CCl4-induced liver injury and fibrosis in rats [J]. Biochem Biophys Res Commun.2011,415(1):152-6.
[16]Yang X, Wang A, Zhou P, et al. Protective effect of recombinant human augmenter of liver regeneration on CC14-induced hepatitis in mice[J]. Chin Med J (Engl). 1998,111(7):625-9.
[17]Francavilla A, Vujanovic NL, Polimeno L, et al. The in vivo effect of hepatotrophic factors augmenter of liver regeneration, hepatocyte growth factor, and insulin-like growth factor-II on liver natural killer cell functions [J]. Hepatology.1997,25, 411-5.
[18]Vujanovic NL, Polimeno L, Azzarone A, et al. Changes of liver-resident NK cells during liver regeneration in rats[J]. J Immunol.1995,154(12):6324-38.
[19]Polimeno L, Margiotta M, Marangi L, et al. Molecular mechanisms of augmenter of liver regeneration as immunoregulator:its effect on interferon-gamma expression in rat liver[J]. Dig Liver Dis.2000,32,217-25.
[20]Tanigawa K, Sakaida I, Masuhara M, et al. Augmenter of liver regeneration (ALR) may promote liver regeneration by reducing natural killer (NK) cell activity in human liver diseases [J]. J Gastroenterol.2000,35,112-9.
[21]Adams GA, Maestri M, Squiers EC, et al. Augmenter of liver regeneration enhances the success rate of fetal pancreas transplantation in rodents [J]. Transplantation.1998,65(1):32-6.
[22]Hongbo S, Yu C, Ming K, et al. Augmenter of liver regeneration may be a candidate for prognosis of HBV related acute-on-chronic liver failure as a regenerative marker [J]. Hepatogastroenterology.2012,59(118):1933-8.
[23]Yu HY, Xiang DR, Huang HJ, et al. Expression level of augmenter of liver regeneration in patients with hepatic failure and hepatocellular carcinoma[J]. Hepatobiliary Pancreat Dis Int.2010,9(5):492-8.
[24]孙航,余慧峰,吴传新,等.肝再生增强因子在肝癌细胞中的表达及意义[J].中华肝脏病杂志.2005,13(3)：205-8.
[25]Liang S, Chen Y, Long F, et al. Correlation between augmenter of liver regeneration and IFN-y expression in graft after rat orthotopic liver transplantation[J]. J Surg Res. 2012,178(2):968-73.
[26]Chen Y, Yuan G, Sun H, et al. Intrasplenic transplantation of newborn rat hepatocytes with rALR for treating rats with acute hepatic failure [J]. Zhonghua Gan Zang Bing Za Zhi.2007,15(5):378-82.
[27]谢华,孙航,郭辉,等.肝再生增强因子对大鼠脾单个核细胞增殖及IL-2产生能力的影响[J].中国免疫学杂志.2007,23(5)：85-8.
[28]Cao M, Cabrera R, Xu Y, et al. Hepatocellular carcinoma cell supernatants increase expansion and function of CD4+CD25+ regulatory T cells[J]. Laboratory Investigation.2007,87:582-90.
[29]Kondo Y, Ninomiya M, Kakazu E, et al. Hepatitis B surface antigen could contribute to the immunopathogenesis of hepatitis B virus infection [J]. ISRN Gastroenterol.2013,2013:935295.
[30]Op den Brouw ML, Binda RS, van Roosmalen MH, et al. Hepatitis B virus surface antigen impairs myeloid dendritic cell function:a possible immune escape mechanism of hepatitis B virus [J]. Immunology.2009,126(2):280-9.
[31]Li Y, Farooq M, Sheng D, et al. Augmenter of liver regeneration (alr) promotes liver outgrowth during zebrafish hepatogenesis[J]. PLoS One 2012,7, e30835.
[32]Polimeno L, Pesetti B, Annoscia E, et al. Alrp, a survival factor that controls the apoptotic process of regenerating liver after partial hepatectomy in rats [J]. Free Radic Res.2011,45,534-49.
[33]Gandhi CR Augmenter of liver regeneration [J]. Fibrogenesis Tissue Repair. 2012,5(1):10.
[34]Gandhi CR, Kuddus R, Subbotin VM, et al. A fresh look at augmenter of liver regeneration in rats [J]. Hepatology.1999,29,1435-45.
[35]Demirkiran A, Kok A, Kwekkeboom J, et al. Low circulating regulatory T-cell levels after acute rejection in liver transplantation [J]. Liver Transpl. 2006,12(2):277-84.
[36]Allan SE, Broady R, Gregori S, et al. CD4+ T-regulatory cells:toward therapy for human diseases [J]. Immunol Rev.2008,223:391-421.
[37]肖序仁,徐衍盛,敖建华.不同免疫抑制剂诱导外周血活化T淋巴细胞凋亡的研究[J].中华器官移植杂志.2006,27(11)：644-7.
[38]Thirunavukkarasu C, Wang LF, Harvey SA, et al. Augmenter of liver regeneration: an important intracellular survival factor for hepatocytes [J]. J Hepatol.2008,48, 578-88.
[39]Polimeno L, Pesetti B, Lisowsky T, et al. Protective effect of augmenter of liver regeneration on hydrogen peroxide-induced apoptosis in SH-SY5Y human neuroblastoma cells [J]. Free Radic Res.2009,43,865-75.
[40]Polimeno L, Pesetti B, De Santis F, et al. Decreased expression of the Augmenter of Liver Regeneration results in increased apoptosis and oxidative damage in human-derived glioma cells [J]. Cell Death Dis.2012,3,e289.
[41]Liao XH, Chen GT, Li Y, et al. Augmenter of liver regeneration attenuates tubular cell apoptosis in acute kidney injury in rats:the possible mechanisms [J]. Ren Fail. 2012,34,590-9.
[42]Ilowski M, Kleespies A, de Toni EN, et al. Augmenter of liver regeneration (ALR) protects human hepatocytes against apoptosis [J]. Biochem Biophys Res Commun. 2011,404,148-52.
[43]Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases [J]. J Immunol.1995,155(3):1151-64.
[44]Ng WF, Duggan PJ, Ponchel F, et al. Human CD4(+)CD25(+) cells:a naturally occurring population of regulatory T cells [J]. Blood.2001,98(9):2736-44.
[45]Sakaguchi S, Yamaguchi T, Nomura T, et al. Regulatory T cells and immune tolerance[J]. Cell.2008,133(5):775-87.
[46]Ito T, Hanabuchi S, Wang YH, et al.Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery [J]. Immunity.2008,28(6):870-80.
[47]Meloche S, Pouyssegur J. The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the Gl- to S-phase transition [J]. Oncogene.2007, 26(22):3227-39.
[48]Xue F, Takahara T, Yata Y, et al. Hepatocyte growth factor gene therapy accelerates regeneration in cirrhotic mouse livers after hepatectomy [J]. Gut. 2003,52(5):694-700.
[49]Fremin C, Bessard A, Ezan F, et al. Multiple division cycles and long-term survival of hepatocytes are distinctly regulated by extracellular signal-regulated kinases ERK1 and ERK2[J]. Hepatology.2009,49(3):930-9.
[50]Fremin C, Ezan F, Boisselier P, et al. ERK2 but not ERK1 plays a key role in hepatocyte replication:an RNAi-mediated ERK2 knockdown approach in wild-type and ERK1 null hepatocytes [J]. Hepatology.2007,45(4):1035-45.
[51]Lee KH, Choi EY, Hyun MS, et al. Role of hepatocyte growth factor/c-Met signaling in regulating urokinase plasminogen activator on invasiveness in human hepatocellular carcinoma:a potential therapeutic target [J]. Clin Exp Metastasis. 2008,25(1):89-96.
[52]Fremin C, Ezan F, Guegan JP, et al. The complexity of ERK1 and ERK2 MAPKs in multiple hepatocyte fate responses [J]. J Cell Physiol.2012,227(1):59-69.
[53]Park PH, Aroor AR, Shukla SD. Role of Ras in ethanol modulation of angiotensin II activated p42/p44 MAP kinase in rat hepatocytes [J]. Life Sci.2006, 79(25):2357-63.
[54]Carr EL, Kelman A, Wu GS, et al. Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation [J]. J Immunol.2010,185(2):1037-44.
[55]Yasuda T, Kurosaki T. Regulation of lymphocyte fate by Ras/ERK signals [J]. Cell Cycle.2008,7(23):3634-40.
[56]Lin JT, Stein EA, Wong MT, et al. Differential mTOR and ERK pathway utilization by effector CD4 T cells suggests combinatorial drug therapy of arthritis[J]. Clin Immunol.2012,142(2):127-38.
[57]唐琳,孙航,张林,等.阻断肝再生增强因子的表达对人肝癌细胞株HepG2增殖的抑制作用[J].癌症.2006,25(6)：671-6.
[58]Acuna-Castillo C, Aravena M, Leiva-Salcedo E, et al. T-kininogen, a cystatin-like molecule, inhibits ERK-dependent lymphocyte proliferation [J]. Mech Ageing Dev. 2005,126(12):1284-91.
[59]Wang JX, Tang W, Shi LP, et al. Investigation of the immunosuppressive activity of artemether on T-cell activation and proliferation [J]. Br J Pharmacol. 2007,150(5):652-61.
[60]Kamo N, Shen XD, Ke B, et al. Sotrastaurin, a protein kinase C inhibitor, ameliorates ischemia and reperfusion injury in rat orthotopic liver transplantation[J]. Am J Transplant.2011,11(11):2499-507.
[61]Abboushi N, El-Hed A, El-Assaad W, et al. Ceramide inhibits IL-2 production by preventing protein kinase C-dependent NF-kappaB activation:possible role in protein kinase Ctheta regulation[J]. J Immunol.2004,173 (5):3193-200.
[62]Han Y, Meng T, Murray NR, et al. Interleukin-1-induced nuclear factor-kappaB-IkappaBalpha autoregulatory feedback loop in hepatocytes. A role for protein kinase calpha in post-transcriptional regulation of ikappabalpha resynthesis [J]. J Biol Chem.1999,274(2):939-47.
[63]Liang Zhou, Dan R Littman. Transcriptional regulatory networks in Th17 cell differentiation [J]. Curr Opin Immunol.2009,21(2):146-52.
[64]Liang Zhou, Jared E. Lopes, Mark M. W. Chong, et al. TGF-(3-induced Foxp3 inhibits Th17 cell differentiation by antagonizing RORyt function [J]. Nature. 2008,453(7192):236-40.
[65]Dorothy K Sojka, Yu-Hui Huang, Deborah J Fowell. Mechanisms of regulatory T-cell suppression-a diverse arsenal for a moving target [J]. Immunology. 2008,124(1):13-22.
[66]Yamazaki S, Steinman RM. Dendritic cells as controllers of antigen-specific Foxp3+ regulatory T cells [J]. J Dermatol Sci.2009,54(2):69-75.
[67]WanJun Chen, Joanne E. Konkel. TGF-β and 'Adaptive' Foxp3+ Regulatory T cells[J]. J Mol Cell Biol.2010,2(1):30-6.
[68]Brad E Hoffman, Ashley T Martino, Brandon K Sack, et al. Nonredundant Roles of IL-10 and TGF-β in Suppression of Immune Responses to Hepatic AAV-Factor IX Gene Transfer [J]. Mol Ther. 2011,19(7):1263-72.
[69]Paul L. Bollyky, Ben A. Falk, Alice Long, et al. CD44 co-stimulation promotes FoxP3+ regulatory T-cell persistence and function via production of IL-2, IL-10 and TGF-beta [J]. J Immunol.2009,183(4):2232-41.
[70]Edgar JD. Clinical immunology [J]. Ulster Med J.2011,80(1):5-14.
[71]Chao-Lien Liu, Peiqing Ye, Benjamin C Yen, et al. In Vivo Expansion of Regulatory T cells With IL-2/IL-2 mAb Complexes Prevents Anti-factor VIII Immune Responses in Hemophilia A Mice Treated With Factor VIII Plasmid-mediated Gene Therapy [J]. Mol Ther.2011,19(8):1511-20.
[72]Lee SJ, Lim KT Inhibitory effect of 30-kDa phytoglycoprotein on expression of TNF-alpha and COX-2 via activation of PKCalpha and ERK 1/2 in LPS-stimulated RAW 264.7 cells [J]. Mol Cell Biochem.2008,317(1-2):151-9.
[73]Lio CW, Hsieh CS. A two-step process for thymic regulatory T cell development [J]. Immunity.2008,28(1):100-11.
[74]Schmidt A, Oberle N, Weiss EM, et al. Human regulatory T cells rapidly suppress T cell receptor-induced Ca(2+), NF-κB, and NFAT signaling in conventional T cells [J]. Sci Signal.2011,4(204):ra90.
[75]Ting-Ting Tang, You Song, Ying-Jun Ding, et al. Atorvastatin upregulates regulatory T cells and reduces clinical disease activity in patients with rheumatoid arthritis[J]. J Lipid Res.2011,52(5):1023-32.
[76]Skvorak KJ, Paul HS, Dorko K, et al. Hepatocyte transplantation improves phenotype and extends survival in a murine model of intermediate maple syrup urine disease [J]. Mol Ther.2009,17(7):1266-73.
[77]Cameron AM, Ghobrial RM, Yersiz H, et al. Optimal utilization of donor grafts with extended criteria:a single-center experience in over 1000 liver transplants[J]. Ann Surg.2006,243(6):748-53.
[78]Fisher RA, Strom SC. Human hepatocyte transplantation:worldwide results[J]. Transplantation.2006,82(4):441-9.
[79]Park JK, Lee DH. Bioartificial liver systems:current status and future perspective [J]. J Biosci Bioeng.2005,99(4):311-9.
[80]Meyburg J, Alexandrova K, Barthold M, et al. Liver cell transplantation:basic investigations for safe application in infants and small children [J]. Cell Transplant. 2009,18(7):777-86.
[81]Baccarani U, Adani GL, Sanna A, et al. Portal vein thrombosis after intraportal hepatocytes transplantation in a liver transplant recipient[J]. Transpl Int. 2005,18(6):750-4.
[82]Habibullah CM, Syed IH, Qamar A, et al. Human fetal hepatocyte transplantation in patients with fulminant hepatic failure [J]. Transplantation.1994,58(8):951-2.
[83]Allen KJ, Soriano HE. Liver cell transplantation:the road to clinical application[J]. J Lab Clin Med.2001,138(5):298-312.
[84]Najimi M, Sokal E. Update on liver cell transplantation[J]. J Pediatr Gastroenterol Nutr.2004,39(4):311-9.
[85]Newsome PN, Plevris JN, Nelson LJ, et al. Animal models of fulminant hepatic failure:a critical evaluation [J]. Liver Transpl.2000,6(1):21-31.
[86]Strom SC, Fisher RA, Thompson MT, et al. Hepatocyte transplantation as a bridge to orthotopic liver transplantation in terminal liver failure[J]. Transplantation. 1997,63(4):559-69.
[87]Bumgardner GL, Li J, Heininger M, et al. In vivo immunogenicity of purified allogeneic hepatocytes in a murine hepatocyte transplant model [J]. Transplantation. 1998,65(1):47-52.
[88]Home PH, Lunsford KE, Walker JP, et al. Recipient immune repertoire and engraftment site influence the immune pathway effecting acute hepatocellular allograft rejection[J]. Cell Transplant.2008,17(7):829-44.
[89]Bemal W, Auzinger Q Dhawan A, et al. Acute liver failure[J]. Lancet. 2010,376(9736):190-201.
[90]Zimmerer JM, Home PH, Fiessinger LA, et al. Cytotoxic effector function of CD4-independent, CD8(+) T cells is mediated by TNF-α/TNFR [J]. Transplantation. 2012,94(11):1103-10.
[91]Lunsford KE, Gao D, Eiring AM, et al. Evidence for tissue-directed immune responses:analysis of CD4- and CD8-dependent alloimmunity. Transplantation [J]. 2004,78(8):1125-33.
[92]Home PH, Lunsford KE, Eiring AM, et al. CD4+T-cell-dependent immune damage of liver parenchymal cells is mediated by alloantibody [J]. Transplantation. 2005,80(4):514-21.
[93]Lin YC, Goto S, Tateno C, et al. Induction of indoleamine 2,3-dioxygenase in livers following hepatectomy prolongs survival of allogeneic hepatocytes after transplantation [J]. Transplant Proc.2008,40(8):2706-8.
[94]Keri E. Lunsford, Kartika Jayanshankar, Anna M. Eiring, et al. Alloreactive (CD4-independent) CD8+ T cells jeopardize long-term survival of intrahepatic islet allografts [J]. Am J Transplant.2008,8(6):1113-28.
[95]Bhatt S, Fung JJ, Lu L, et al. Tolerance-inducing strategies in islet transplantation[J]. Int J Endocrinol.2012,2012:396524.
[96]Oluwole SF, Oluwole OO, Adeyeri AO, et al. New strategies in immune tolerance induction [J]. Cell Biochem Biophys.2004,40(3 Suppl):27-48.
[1]Fehervari Z, Sakaguchi S. CD4+ Tregs and immune control [J]. J Clin Invest. 2004,114(9):1209-17.
[2]Thompson JA, Perry D, Brusko TM. Autologous regulatory T cells for the treatment of type 1 diabetes [J]. Curr Diab Rep.2012,12(5):623-32.
[3]Boncheva V, Bonney SA, Brooks SE, et al. New targets for the immunotherapy of colon cancer-does reactive disease hold the answer? [J]. Cancer Gene Ther. 2013,20(3):157-68.
[4]Zhao W, Su W, Kuang P, et al. The role of hepatic stellate cells in the regulation of T-cell function and the promotion of hepatocellular carcinoma [J]. Int J Oncol. 2012,41 (2):457-64.
[5]Han YF, Cao GW. Role of nuclear receptor NR4A2 in gastrointestinal inflammation and cancers [J]. World J Gastroenterol.2012,18(47):6865-73.
[6]Du Y, Chen X, Huang ZM, et al. Increased frequency of Foxp3+ regulatory T cells in mice with hepatocellular carcinoma [J]. Asian Pac J Cancer Prev. 2012,13(8):3815-9.
[7]Singh K, Gatzka M, Peters T, et al. Reduced CD18 Levels Drive Regulatory T Cell Conversion into Th17 Cells in the CD18hypo PL/J Mouse Model of Psoriasis [J]. J Immunol.2013,190(6):2544-53.
[8]Liu Y, Wang H, Wang X, et al. The mechanism of effective electroacupuncture on T cell response in rats with experimental autoimmune encephalomyelitis [J]. PLoS One.2013,8(l):e51573.
[9]Veiga-Parga T, Suryawanshi A, Mulik S, et al. On the role of regulatory T cells during viral-induced inflammatory lesions [J]. J Immunol.2012,189(12):5924-33.
[10]Chevalier MF, Weiss L. The split personality of regulatory T cells in HIV infection [J]. Blood.2013,121(1):29-37.
[11]Kilshaw PJ, Brent L, Pinto M. Suppressor T cells in mice made unresponsive to skin allografts [J]. Nature.1975,255(5508):489-91.
[12]Kilshaw PJ, Brent L, Pinto M. An active suppressor mechanism preventing skin allograft rejection in mice [J]. Transplant Proc.1975,7(2):225-8.
[13]Hall BM, Jelbart ME, Gurley KE, et al. Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. Mediation of specific suppression by T helper/inducer cells [J]. J Exp Med.1985,162(5):1683-94.
[14]Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases [J]. J Immunol.1995,155(3):1151-64.
[15]Itoh M, Takahashi T, Sakaguchi N, et al. Thymus and autoimmunity:production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance [J]. J Immunol.1999, 162(9):5317-26.
[16]Takahashi T, Sakaguchi S. Naturally arising CD25+CD4+ regulatory T cells in maintaining immunologic self-tolerance and preventing autoimmune disease [J]. Curr Mol Med.2003,3(8):693-706.
[17]Schubert LA, Jeffery E, Zhang Y, et al. Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation [J]. J Biol Chem. 2001,276(40):37672-9.
[18]Lopes JE, Torgerson TR, Schubert LA, et al. Analysis of FOXP3 reveals multiple domains required for its function as a transcriptional repressor [J]. J Immunol. 2006,177(5):3133-42.
[19]Whiteside TL, Schuler P, Schilling B. Induced and natural regulatory T cells in human cancer [J]. Expert Opin Biol Ther.2012,12(10):1383-97.
[20]Bilate AM, Lafaille JJ. Induced CD4+Foxp3+ regulatory T cells in immune tolerance [J]. Annu Rev Immunol.2012,30:733-58.
[21]Wu Y, Borde M, Heissmeyer V, et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell [J].2006,126(2):375-87.
[22]Bacchetta R, Passerini L, Gambineri E, et al. Defective regulatory and effector T cell functions in patients with FOXP3 mutations [J]. J Clin Invest. 2006,116(6):1713-22.
[23]Bettini ML, Pan F, Bettini M, et al. Loss of epigenetic modification driven by the Foxp3 transcription factor leads to regulatory T cell insufficiency [J]. Immunity. 2012,36(5):717-30.
[24]Chen Z, Lin F, Gao Y, et al. FOXP3 and RORyt:transcriptional regulation of Treg and Th17. Int Immunopharmacol [J].2011,11(5):536-42.
[25]Schmetterer KQ Neunkirchner A, Pickl WF. Naturally occurring regulatory T cells: markers, mechanisms, and manipulation [J]. FASEB J.2012,26(6):2253-76.
[26]Bettini ML, Vignali DA. Development of thymically derived natural regulatory T cells [J]. Ann N Y Acad Sci.2010,1183:1-12.
[27]Hori S, Takahashi T, Sakaguchi S. Control of autoimmunity by naturally arising regulatory CD4+ T cells [J]. Adv Immunol.2003,81:331-71.
[28]Sakaguchi S, Ono M, Setoguchi R, et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease [J]. Immunol Rev. 2006,212:8-27.
[29]Pot C, Apetoh L, Kuchroo VK. Type 1 regulatory T cells (Trl) in autoimmunity [J]. Semin Immunol.2011,23(3):202-8.
[30]Faria AM, Weiner HL. Oral tolerance and TGF-beta-producing cells [J]. Inflamm Allergy Drug Targets.2006,5(3):179-90.
[31]Weiner HL. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells [J]. Immunol Rev.2001,182:207-14.
[32]Carrier Y, Yuan J, Kuchroo VK, et al. Th3 cells in peripheral tolerance. I. Induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-beta T cell-transgenic mice [J]. J Immunol.2007,178(1):179-85.
[33]Dons EM, Raimondi G, Cooper DK, et al. Induced regulatory T cells:mechanisms of conversion and suppressive potential [J]. Hum Immunol.2012,73(4):328-34.
[34]Lin X, Chen M, Liu Y, et al. Advances in distinguishing natural from induced Foxp3(+) regulatory T cells [J]. Int J Clin Exp Pathol.2013,6(2):116-23.
[35]Beal AM, Ramos-Hernandez N, Riling CR, et al. TGF-β induces the expression of the adaptor Ndfipl to silence IL-4 production during iTreg cell differentiation [J]. Nat Immunol.2011,13(1):77-85.
[36]Regateiro FS, Howie D, Cobbold SP, et al. TGF-β in transplantation tolerance [J]. Curr Opin Immunol.2011,23(5):660-9.
[37]Zhou X, Kong N, Zou H, et al. Therapeutic potential of TGF-β-induced CD4(+) Foxp3(+) regulatory T cells in autoimmune diseases. Autoimmunity [J]. 2011,44(1):43-50.
[38]Lan Q, Zhou X, Fan H, et al. Polyclonal CD4+Foxp3+ Treg cells induce TGFβ-dependent tolerogenic dendritic cells that suppress the murine lupus-like syndrome [J]. J Mol Cell Biol.2012,4(6):409-19.
[39]Picarda E, Anegon I, Guillonneau C. T-cell receptor specificity of CD8(+) Tregs in allotransplantation [J]. Immunotherapy.2011,3(4 Suppl):35-7.
[40]Liao W, Lin JX, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy [J]. Immunity.2013,38(1):13-25.
[41]Cheng G, Yu A, Malek TR. T-cell tolerance and the multi-functional role of IL-2R signaling in T-regulatory cells [J]. Immunol Rev.2011,241(1):63-76.
[42]Malek TR, Castro I. Interleukin-2 receptor signaling:at the interface between tolerance and immunity [J]. Immunity.2010,33(2):153-65.
[43]McHugh RS, Whitters MJ, Piccirillo CA, et al. CD4(+)CD25(+) immunoregulatory T cells:gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor [J]. Immunity.2002,16(2):311-23.
[44]Ward FJ, Dahal LN, Wijesekera SK, et al. The soluble isoform of CTLA-4 as a regulator of T-cell responses [J]. Eur J Immunol.2013,11.
[45]Barnes MJ, Griseri T, Johnson AM, et al. CTLA-4 promotes Foxp3 induction and regulatory T cell accumulation in the intestinal lamina propria [J]. Mucosal Immunol.2013,6(2):324-34.
[46]Ziegler SF, Buckner JH. FOXP3 and the regulation of Treg/Th17 differentiation [J]. Microbes Infect.2009,11 (5):594-8.
[47]Klingenberg R, Gerdes N, Badeau RM, et al. Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis [J]. J Clin Invest.2013, 123(3):1323-34
[48]Khattri R, Cox T, Yasayko SA, et al. An essential role for Scurfin in CD4+CD25+ T regulatory cells [J]. Nat Immunol.2003,4(4):337-42.
[49]Khattri R, Kasprowicz D, Cox T, et al.The amount of scurfin protein determines peripheral T cell number and responsiveness [J]. J Immunol.2001,167(11): 6312-6320.
[50]Bettelli E, Dastrange M, Oukka M. Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells [J]. Proc Natl Acad Sci U S A.2005,102(14):5138-43.
[51]Rudensky AY, Gavin M, Zheng Y. FOXP3 and NFAT:partners in tolerance [J]. Cell.2006,126(2):253-6.
[52]Vaeth M, Schliesser U, Muller Q et al. Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3+ regulatory T cells [J]. Proc Natl Acad Sci U S A.2012,109(40):16258-63.
[53]Heinze E, Chan G, Mory R, et al. Tumor suppressor and T-regulatory functions of Foxp3 are mediated through separate signaling pathways [J]. Oncol Lett. 2011,2(4):665-668.
[54]Schmidt A, Oberle N, Krammer PH. Molecular mechanisms of treg-mediated T cell suppression [J]. Front Immunol.2012,3:51.
[55]Lee SM, Gao B, Fang D. FoxP3 maintains Treg unresponsiveness by selectively inhibiting the promoter DNA-binding activity of AP-1 [J]. Blood.2008, 111(7):3599-606.
[56]Gavin MA, Rasmussen JP, Fontenot JD, et al. Foxp3-dependent programme of regulatory T-cell differentiation [J]. Nature.2007,445(7129):771-5.
[57]Cobbold SP, Nolan KF, Graca L, et al. Regulatory T cells and dendritic cells in transplantation tolerance:molecular markers and mechanisms [J]. Immunol Rev 2003,196(1):109-24
[58]Chen ZF, Xu Q, Ding JB, et al. CD4+CD25+Foxp3+ Treg and TGF-beta play important roles in pathogenesis of Uygur cervical carcinoma [J]. Eur J Gynaecol Oncol.2012,33(5):502-7.
[59]Prado C, de Paz B, Lopez P, et al. Relationship between FOXP3 positive populations and cytokine production in systemic lupus erythematosus. Cytokine [J]. 2013,61(1):90-6.
[60]Mays LE, Ammon-Treiber S, Mothes B, et al. Modified Foxp3 mRNA protects against asthma through an IL-10-dependent mechanism [J]. J Clin Invest. 2013,123(3):1216-28.
[61]Lou W, Wang C, Wang Y, et al. Responses of CD4(+) CD25(+) Foxp3(+) and IL-10-secreting type I T regulatory cells to cluster-specific immunotherapy for allergic rhinitis in children [J]. Pediatr Allergy Immunol.2012,23(2):140-9.
[62]Olson BM, Jankowska-Gan E, Becker JT, et al. Human prostate tumor antigen-specific CD8+ regulatory T cells are inhibited by CTLA-4 or IL-35 blockade [J]. J Immunol.2012,189(12):5590-601.
[63]Shen E, Zhao K, Wu C, et al. The suppressive effect of CD25+Treg cells on Thl differentiation requires cell-cell contact partially via TGF-β production [J]. Cell Biol Int 2011,35(7):705-12.
[64]Singh AK, Seavey CN, Horvath KA, et al. Ex-vivo expanded baboon CD4+ CD25 Hi Treg cells suppress baboon anti-pig T and B cell immune response [J]. Xenotransplantation.2012,19(2):102-11.
[65]Trzonkowski P, Szmit E, Mysliwska J, et al. CD4+CD25+ T regulatory cells inhibit cytotoxic activity of CTL and NK cells in humans-impact of immunosenescence [J]. Clin Immunol.2006,119(3):307-16.
[66]Zhong RK, Loken M, Lane TA, et al. CTLA-4 blockade by a human MAb enhances the capacity of AML-derived DC to induce T-cell responses against AML cells in an autologous culture system [J]. Cytotherapy.2006,8(1):3-12.
[67]Hubo M, Jonuleit H. Plasmacytoid dendritic cells are inefficient in activation of human regulatory T cells [J]. PLoS One.2012,7(8):e44056.
[68]Farias AS, Spagnol GS, Bordeaux-Rego P, et al. Vitamin D3 Induces IDO(+) Tolerogenic DCs and Enhances Treg, Reducing the Severity of EAE [J]. CNS Neurosci Ther. 2013,19(4):269-77.
[69]Baban B, Chandler PR, Johnson BA 3rd, et al. Physiologic control of IDO competence in splenic dendritic cells. J Immunol [J].2011,187(5):2329-35.
[70]Lewkowicz N, Klink M, Mycko MP, et al. Neutrophil-CD4(+)CD25(+) T regulatory cell interactions:A possible new mechanism of infectious tolerance [J]. Immunobiology.2013,218(4):455-64.
[71]Li YN, Huang F, Liu XL, et al. Allium sativum-derived allitridin inhibits Treg amplification in cytomegalovirus infection [J]. J Med Virol.2013,85(3):493-500.
[72]Aranzamendi C, de Bruin A, Kuiper R, et al. Protection against allergic airway inflammation during the chronic and acute phases of Trichinella spiralis infection [J]. Clin Exp Allergy.2013,43(1):103-15.
[73]Zhuang Y, Wei X, Li Y, et al. HCV coinfection does not alter the frequency of regulatory T cells or CD8+ T cell immune activation in chronically infected HIV+ Chinese subjects [J]. AIDS Res Hum Retroviruses.2012,28(9):1044-51.
[74]Radziewicz H, Dunham RM, Grakoui A. PD-1 tempers Tregs in chronic HCV infection [J]. J Clin Invest.2009,119(3):450-3.
[75]Miroux C, Vausselin T, Delhem N. Regulatory T cells in HBV and HCV liver diseases:implication of regulatory T lymphocytes in the control of immune response [J]. Expert Opin Biol Ther.2010,10(11):1563-72.
[76]Alatrakchi N, Koziel M. Regulatory T cells and viral liver disease [J]. J Viral Hepat. 2009,16(4):223-9.
[77]Manigold T, Racanelli V. T-cell regulation by CD4 regulatory T cells during hepatitis B and C virus infections:facts and controversies [J]. Lancet Infect Dis. 2007,7(12):804-13.
[78]Chattopadhyay S, Chakraborty NG, Mukherji B. Regulatory T cells and tumor immunity [J]. Cancer Immunol Immunother.2005,54(12):1153-61.
[79]Pedroza-Gonzalez A, Verhoef C, Ijzermans JN, et al. Activated tumor-infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer [J]. Hepatology.2013,57(1):183-94.
[80]Afzali B, Lombardi G, Lechler RI, et al. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease [J]. Clin Exp Immunol.2007,148(1):32-46.
[81]Abarbanel DN, Seki SM, Davies Y, et al. Immunomodulatory effect of vancomycin on treg in pediatric inflammatory bowel disease and primary sclerosing cholangitis [J]. J Clin Immunol.2013,33(2):397-406.
[82]Azab NA, Bassyouni IH, Emad Y, et al. CD4+CD25+ regulatory T cells (TREG) in systemic lupus erythematosus (SLE) patients:the possible influence of treatment with corticosteroids [J]. Clin Immunol.2008,127(2):151-7.
[83]Longhi MS, Meda F, Wang P, et al. Expansion and de novo generation of potentially therapeutic regulatory T cells in patients with autoimmune hepatitis [J]. Hepatology.2008,47(2):581-91.
[84]Lourenco EV, La Cava A. Natural regulatory T cells in autoimmunity [J]. Autoimmunity.2011,44(1):33-42.
[85]Peiseler M, Sebode M, Franke B, et al. FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency [J]. J Hepatol. 2012,57(1):125-32.
[86]Burrell BE, Nakayama Y, Xu J, et al. Regulatory T cell induction, migration, and function in transplantation [J]. J Immunol.2012,189(10):4705-11.
[87]Guo X, Jie Y, Ren D, et al. In vitro-expanded CD4(+)CD25(high)Foxp3(+) regulatory T cells controls corneal allograft rejection [J]. Hum Immunol. 2012,73(11):1061-7.
[88]Li W, Carper K, Liang Y, et al. Anti-CD25 mAb administration prevents spontaneous liver transplant tolerance [J]. Transplant Proc.2006,38(10):3207-8.