肾移植受者PD-1/PD-L1信号通路的基础和临床研究
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摘要
研究背景：负性调控共刺激分子PD-1 (programmed death-1)为T、B淋巴细胞表面受体,属于免疫球蛋白超家族Ⅰ型跨膜糖蛋白,生理条件下在淋巴细胞表面少量表达,在T、B细胞抗原受体激发后呈诱导性表达。PD-1与其两个配体PD-L1和PD-L2结合,在免疫应答中起着负性调控作用。关于PD-1/PD-L信号通路与临床疾病的关系,如自身免疫性疾病、肿瘤、病毒感染、移植等,其表现的免疫调节作用受到越来越多的关注。
目的：本课题通过对比肾移植术前术后与健康对照者外周血单个核细胞表面PD-1的表达,了解PD-1与器官移植耐受的相关性；以及进一步探讨肾移植术后发生急性排斥反应时检测PD-1mRNA的表达能否其作为器官移植术后急性排斥反应预警；同时探讨PD-1分子在器官移植患者外周血淋巴细胞上的表达与循环中CD4+CD25highTreg的相关性,从而进一步研究其诱导免疫耐受的机制。
方法：应用实时定量RT-PCR技术和流式细胞学技术分别检测PD-1在健康对照者组和肾移植受者术前术后外周血上表达情况；应用RT-PCR技术检测PD-1mRNA在肾移植术后急性排斥反应受者外周血的表达,免疫组化方法用来进一步鉴定PD-1的表达；应用单向混合淋巴细胞培养和流式细胞学检测进一步探讨PD-1通路和CD4+CD25highTreg细胞的相关性从而研究其诱导免疫耐受的机制；应用SPSS16统计软件统计临床及实验数据。
结果：实时定量RT-PCR检测健康对照组、肾移植d0组、肾移植后d28组PD-1mRNA相对表达量,使用Kruskal-Wallis法秩和检验法,健康对照组1.5±1.101,肾移植d0组4.221±1.106,肾移植后d28组9.633±2.101,三组间两两比较P<0.01,差异有统计学意义。PD-1的表达随病程阶段呈现先降低后增高的趋势,流式细胞学检测PD-1+CD3+Tcell百分比呈现先增高后降低的趋势。应用Kruskal-Wallis检验,三组外周血中PD-1mRNA的相对表达量发现急性排斥反应受者外周血PD-1mRNA显著高于肾功能稳定者,P<0.01.三组中位数值分别为4.52±1.1,1.12±0.6,0.7±0.4。PD-1mRNA的相对表达量与急性排斥反应患者血清肌酐呈正比关系。使用Spearman's相关检验(r=0.81,P=0.03),在急性排斥反应患者组发现了PD-1mRNA和血清肌酐的显著相关性Spearman's相关检验(r=0.81,P=0.03)。而移植肾功能延迟恢复受者(r=0.02,P=0.73)、移植肾功能稳定受者(r=0.06,P=0.58)不具有这种相关性。急性排斥反应发生时PD-1mRNA表达与急性排斥反应的严重性呈正相关。使用Spearman's相关检验,我们观察到在急性排斥反应患者组PD-1mRNA的相对表达量和从肾移植手术到发生急性排斥反应时间的显著相关性(r=-0.71,P=0.04)。同时我们用免疫组化的方法证实了急性排斥反应时浸润淋巴细胞表面大量PD-1的表达。三组均显CD4+CD25+Treg表面PD-1的表达比CD4+CD25-Treg表面PD-1的表达高,具有统计学差异；而三组之间比较发现,急排组PD-1的表达水平和CD4+CD25highTreg最高,具有统计学差异。单向混合淋巴细胞培养后检测到逐渐减少的CD4+CD25+Treg数量,分别为19.1%(处理组)、27.4%(对照组),而CD69在受抑制的CD4+CD25-细胞上的表达增加,分别为41.2%(处理组)、25.1%(对照组)。这些结果说明在急性排斥反应患者外周血PBMC的体外实验中,PD-1通路的抑制可能调节CD4+CD25+Treg细胞的功能,从而导致被CD4+CD25+Treg细胞抑制的T细胞的激活。
结论：PD-1在健康人群中可有表达,肾移植术前组、肾移植术后组明显高于健康对照组,具有显著统计学差异,并且肾移植术后不同时间点PD-1mRNA呈先降低后升高的趋势,PD-1+CD3+T细胞比例呈现先降低后增高的趋势；肾移植术后早期PD-1mRNA表达升高可以作为排斥反应的预警信号指导临床治疗,同时患者PD-1表达与急性排斥反应严重程度呈正比,和发生急性排斥反应的时间呈反比,免疫组化结果再次证实了急性排斥反应时淋巴细胞表面大量的PD-1分子的表达；在急性排斥反应发生时外周血CD4+CD25highTreg数量增加,而使用抗PD-L1单克隆抗体抑制PD-1通路后CD4+CD25highTreg数量明显降低,而CD69作为T细胞活化信号在CD4+CD25-T细胞表面增加,说明了PD-1通路参与了肾移植术后急性排斥反应患者外周CD4+CD25highTreg的免疫耐受的诱导和维持。
Background:The negative costimulative molecule Programmed death-1 (PD-1), a type I transmembrane protein composed of one immunoglobulin(Ig) superfamily domain, can be expressed on T cells, B cells, natural killer T cells, activated monocytes, and dendritic cells (DCs). PD-1 is not expressed on resting T cells but is inducibly expressed after activation. The ligation of PD-1 with its ligands PD-L1, PD-L2 deliveries negative signals during the immune response. Recently, a lot of concerns were focus on the relationship between PD-1 pathway and clincal diseases, such as autoimmune disease, cancer diseases, viral infections and transplantation.
Objective:To investigate the immunomodulatory function of PD-1 following renal transplantation, the comparison of PD-1 expression in KT (kidney transplantation) group and in healthy control group was conducted. We further study the levels of PD-1 expression in peripheral blood after acute rejection and the possibility of PD-1 serving as biomarker for acute rejection. To investigate the mechanism to induce tolerance, we studied the association between PD-1 and CD4+CD25high Treg in peripheral blood in transplant recipients. Methods:The expression levels of PD-1 between the healthy control group and KT group were compared by real-time RT-PCR and Flow cytometry. Real time RT-PCR was used for detection of PD-1 mRNA in transplant recipients after acute rejection. Immunohistochemistry was ultilized for clarifying the expression of PD-1. The interaction between PD-1 and CD4+CD25high Treg in immunogical tolerance was further investigated by MLR and flow cytometry; Using SPSS 16 statistics soft in analyzing clinical and experimental data.
Results:The expression levels of PD-1 in healthy control was 1.5±1.101, comparing with 4.221±1.106 in pre-transplant and 9.633±2.101 in 28days after transplantion. P values<0.01 were considered statistically significant. The expression level of PD-1 mRNA fluctuated with time, a significant decrease followed by a gradual increase after transplantation. The PD-1+CD3+T cell percentage fluctuation correlated with the PD-1 mRNA expression level. This study demonstrated that levels of PD-1 in peripheral blood may act as a biomarker for acute rejection. A significant relationship between the PD-1 mRNA and serum creatinine in patients with acute rejection was observed. And an inverse correlation between PD-1 mRNA and the time from transplantation to acute rejection was observed. Levels of Treg cells and PD-1+/Tregs were significantly increased in patients with acute rejection compared with DGF and stable renal function. To find how PD-1 to interact with Treg, MLR was utilized. Significant inhibition of induced CD4+CD25+highT cells was seen(from 27.4% to 19.1%). The percentage of CD69+CD4+CD25-Tcells increased from 25.1% to 41.2%.
Conclusion:PD-1 can be expressed in the peripheral blood in healthy group, with a significant lower level than that of renal transplantion groups. The expression level of PD-1 mRNA fluctuated with time, a significant increase followed by a gradual decrease after transplantation. PD-1+CD3+T cell percentage fluctuation correlated with the PD-1 mRNA expression level. This study demonstrates that levels of PD-1 in peripheral blood may act as a biomarker for acute rejection. A significant relationship between the PD-1 mRNA and serum creatinine in patients with acute rejection was observed. And an inverse correlation between PD-1 mRNA and the time from transplantation to acute rejection was observed. The number of CD4+CD25hlghTregs and the PD-1 expressed on it have a great increase in AR group. When inhibiting PD-1 pathway, Significant inhibition of induced CD4+CD25highT cells was seen(from 27.4% to 19.1%). The percentage of CD69+CD4+CD25-Tcells increased from 25.1% to 41.2%. This work demonstrated PD-1 pathway involved in the regulatory mechanism of CD4+CD25highTreg.
目的：本课题通过对比肾移植术前术后与健康对照者外周血单个核细胞表面PD-1的表达,了解PD-1与器官移植耐受的相关性；以及进一步探讨肾移植术后发生急性排斥反应时检测PD-1mRNA的表达能否其作为器官移植术后急性排斥反应预警；同时探讨PD-1分子在器官移植患者外周血淋巴细胞上的表达与循环中CD4+CD25highTreg的相关性,从而进一步研究其诱导免疫耐受的机制。
方法：应用实时定量RT-PCR技术和流式细胞学技术分别检测PD-1在健康对照者组和肾移植受者术前术后外周血上表达情况；应用RT-PCR技术检测PD-1mRNA在肾移植术后急性排斥反应受者外周血的表达,免疫组化方法用来进一步鉴定PD-1的表达；应用单向混合淋巴细胞培养和流式细胞学检测进一步探讨PD-1通路和CD4+CD25highTreg细胞的相关性从而研究其诱导免疫耐受的机制；应用SPSS16统计软件统计临床及实验数据。
结果：实时定量RT-PCR检测健康对照组、肾移植d0组、肾移植后d28组PD-1mRNA相对表达量,使用Kruskal-Wallis法秩和检验法,健康对照组1.5±1.101,肾移植d0组4.221±1.106,肾移植后d28组9.633±2.101,三组间两两比较P<0.01,差异有统计学意义。PD-1的表达随病程阶段呈现先降低后增高的趋势,流式细胞学检测PD-1+CD3+Tcell百分比呈现先增高后降低的趋势。应用Kruskal-Wallis检验,三组外周血中PD-1mRNA的相对表达量发现急性排斥反应受者外周血PD-1mRNA显著高于肾功能稳定者,P<0.01.三组中位数值分别为4.52±1.1,1.12±0.6,0.7±0.4。PD-1mRNA的相对表达量与急性排斥反应患者血清肌酐呈正比关系。使用Spearman's相关检验(r=0.81,P=0.03),在急性排斥反应患者组发现了PD-1mRNA和血清肌酐的显著相关性Spearman's相关检验(r=0.81,P=0.03)。而移植肾功能延迟恢复受者(r=0.02,P=0.73)、移植肾功能稳定受者(r=0.06,P=0.58)不具有这种相关性。急性排斥反应发生时PD-1mRNA表达与急性排斥反应的严重性呈正相关。使用Spearman's相关检验,我们观察到在急性排斥反应患者组PD-1mRNA的相对表达量和从肾移植手术到发生急性排斥反应时间的显著相关性(r=-0.71,P=0.04)。同时我们用免疫组化的方法证实了急性排斥反应时浸润淋巴细胞表面大量PD-1的表达。三组均显CD4+CD25+Treg表面PD-1的表达比CD4+CD25-Treg表面PD-1的表达高,具有统计学差异；而三组之间比较发现,急排组PD-1的表达水平和CD4+CD25highTreg最高,具有统计学差异。单向混合淋巴细胞培养后检测到逐渐减少的CD4+CD25+Treg数量,分别为19.1%(处理组)、27.4%(对照组),而CD69在受抑制的CD4+CD25-细胞上的表达增加,分别为41.2%(处理组)、25.1%(对照组)。这些结果说明在急性排斥反应患者外周血PBMC的体外实验中,PD-1通路的抑制可能调节CD4+CD25+Treg细胞的功能,从而导致被CD4+CD25+Treg细胞抑制的T细胞的激活。
结论：PD-1在健康人群中可有表达,肾移植术前组、肾移植术后组明显高于健康对照组,具有显著统计学差异,并且肾移植术后不同时间点PD-1mRNA呈先降低后升高的趋势,PD-1+CD3+T细胞比例呈现先降低后增高的趋势；肾移植术后早期PD-1mRNA表达升高可以作为排斥反应的预警信号指导临床治疗,同时患者PD-1表达与急性排斥反应严重程度呈正比,和发生急性排斥反应的时间呈反比,免疫组化结果再次证实了急性排斥反应时淋巴细胞表面大量的PD-1分子的表达；在急性排斥反应发生时外周血CD4+CD25highTreg数量增加,而使用抗PD-L1单克隆抗体抑制PD-1通路后CD4+CD25highTreg数量明显降低,而CD69作为T细胞活化信号在CD4+CD25-T细胞表面增加,说明了PD-1通路参与了肾移植术后急性排斥反应患者外周CD4+CD25highTreg的免疫耐受的诱导和维持。
Background:The negative costimulative molecule Programmed death-1 (PD-1), a type I transmembrane protein composed of one immunoglobulin(Ig) superfamily domain, can be expressed on T cells, B cells, natural killer T cells, activated monocytes, and dendritic cells (DCs). PD-1 is not expressed on resting T cells but is inducibly expressed after activation. The ligation of PD-1 with its ligands PD-L1, PD-L2 deliveries negative signals during the immune response. Recently, a lot of concerns were focus on the relationship between PD-1 pathway and clincal diseases, such as autoimmune disease, cancer diseases, viral infections and transplantation.
Objective:To investigate the immunomodulatory function of PD-1 following renal transplantation, the comparison of PD-1 expression in KT (kidney transplantation) group and in healthy control group was conducted. We further study the levels of PD-1 expression in peripheral blood after acute rejection and the possibility of PD-1 serving as biomarker for acute rejection. To investigate the mechanism to induce tolerance, we studied the association between PD-1 and CD4+CD25high Treg in peripheral blood in transplant recipients. Methods:The expression levels of PD-1 between the healthy control group and KT group were compared by real-time RT-PCR and Flow cytometry. Real time RT-PCR was used for detection of PD-1 mRNA in transplant recipients after acute rejection. Immunohistochemistry was ultilized for clarifying the expression of PD-1. The interaction between PD-1 and CD4+CD25high Treg in immunogical tolerance was further investigated by MLR and flow cytometry; Using SPSS 16 statistics soft in analyzing clinical and experimental data.
Results:The expression levels of PD-1 in healthy control was 1.5±1.101, comparing with 4.221±1.106 in pre-transplant and 9.633±2.101 in 28days after transplantion. P values<0.01 were considered statistically significant. The expression level of PD-1 mRNA fluctuated with time, a significant decrease followed by a gradual increase after transplantation. The PD-1+CD3+T cell percentage fluctuation correlated with the PD-1 mRNA expression level. This study demonstrated that levels of PD-1 in peripheral blood may act as a biomarker for acute rejection. A significant relationship between the PD-1 mRNA and serum creatinine in patients with acute rejection was observed. And an inverse correlation between PD-1 mRNA and the time from transplantation to acute rejection was observed. Levels of Treg cells and PD-1+/Tregs were significantly increased in patients with acute rejection compared with DGF and stable renal function. To find how PD-1 to interact with Treg, MLR was utilized. Significant inhibition of induced CD4+CD25+highT cells was seen(from 27.4% to 19.1%). The percentage of CD69+CD4+CD25-Tcells increased from 25.1% to 41.2%.
Conclusion:PD-1 can be expressed in the peripheral blood in healthy group, with a significant lower level than that of renal transplantion groups. The expression level of PD-1 mRNA fluctuated with time, a significant increase followed by a gradual decrease after transplantation. PD-1+CD3+T cell percentage fluctuation correlated with the PD-1 mRNA expression level. This study demonstrates that levels of PD-1 in peripheral blood may act as a biomarker for acute rejection. A significant relationship between the PD-1 mRNA and serum creatinine in patients with acute rejection was observed. And an inverse correlation between PD-1 mRNA and the time from transplantation to acute rejection was observed. The number of CD4+CD25hlghTregs and the PD-1 expressed on it have a great increase in AR group. When inhibiting PD-1 pathway, Significant inhibition of induced CD4+CD25highT cells was seen(from 27.4% to 19.1%). The percentage of CD69+CD4+CD25-Tcells increased from 25.1% to 41.2%. This work demonstrated PD-1 pathway involved in the regulatory mechanism of CD4+CD25highTreg.
引文
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2. Fontenot JD, Rasmussen JP, Williams LM, et al. Regulatory T cell lineage specification by the fork-head transcription factor foxp3. Immunity,2005,22: 329-341.
3. Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol.2003,3(3):253-257.
4. Rubtsov Y. P, Rudensky AY. TGFbeta signalling in control of T-cell-mediated self-reactivity. Nat Rev Immunol.2007,7(6):443-453.
5. Von Boehmer H. Mechanisms of suppression by suppressor T cells. Nat I mmunol.2005,6(4):338-344.
6. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol.2003,4:330-336.
7. Allan SE, Broady R, Gregori S,et al. CD4+T-regulatory cells toward therapy for human diseases. Immunol Rev.2008,223:391-421.
8. Radziewicz H, Dunham RM, Grakoui A. PD-1 tempers Tregs in chronic HCV infection. J Clin Invest.2009,119 (3):450-3.
9. Haxhinasto S, Mathis D, Benoist C. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+cells. J Exp Med.2008,205:565-574.
10. Sauer S, Bruno L, Hertweck A, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci USA.2008,105: 7797-7802.
11. Battaglia M, Stabilini A, Migliavacca B, et al. Rapamycin promotes expansion of functional CD4+CD25+FOXP3+regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol.2006,177:8338-8347.
12. Strauss L, Whiteside TL, Knights A, et al. Selective survival of naturally occurring human CD4+CD25+Foxp3+regulatory T cells cultured with rapamycin. J Immunol.2007,178:320-329.
13. Thomson AW, Turnquist HR, Raimondi G. Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol.2009,9:324-337.
14. Parsa AT, Bruno L, Hertweck A, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007,13:84-88.
15. Vadivel N, Trikudanathan S, Chandraker A. Transplant tolerance through costimulation blockade—are we there yet? Front Biosci,2007,12:2935-46.
16. Muthukumar T, Dadhania D, Ding R, et al. Messenger RNA for FOXP3 in the urine of renal-allograft recipients. N Engl J Med 2005; 353:2342-2351.
17. Krupnick AS, Gelman AE, Barchet W, et al. Murine vascular endothelium activates and induces the generation of allogeneic CD4+25+Foxp3+regulatory T cells. J Immunol.2005,175(10):6265-70
18. Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature.2006,439(7007):682-7
19. Dolganiuc A, Paek E, Kodys K, et al. Myeloid dendritic cells of patients with chronic HCV infection induce proliferation of regulatory T lymphocytes. Gastroenterology.2008,135(6):2119-27
20. Jacobs JF, Idema AJ, Bol KF, et al. Regulatory T cells and the PD-L1/PD-1 pathway mediate immune suppression in malignant human brain tumors. Neuro Oncol.2009,11(4):394-402
21. Wang W, Lau R, Yu D, et al. PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+CD25(Hi) regulatory T cells. Int Immunol.2009,21(9):1065-77.
22. Francisco LM, Salinas VH, Brown KE, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009,206(13):3015-29.
1. Momin S, Flores S, Angel B B, et al. Interactions between programmed death 1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms in type 1 diabetes. Diabetes Res Clin Pract,2009,83(3):289-94.
2. Liang SC, Latchman YE, Buhlmann JE, et al. Regulation of PD-1, PD-L1 and PD-L2 expression during normal and autoimmune responses. Eur J Immunol, 2003,33(10):270622716.
3. Zhang X, Schwartz JC, Guo XL, et al. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity,2004,20(3):3372347.
4.Fife BF, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev,2008,224:166-82.
5. Carter L, Fouser LA, Jussif J, et al. PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+T cells and is overcome by IL-2. Eur J Immunol,2002, 32(3):6342643.
6. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol,2001,2(3):261-268.
7. Subudhi SK, Zhou P, Yerian LM, et al. Local expression of B7-H1 promotes organ-specific autoimmunity and transplant rejection. J Clin Invest,2004,113 (5): 6942700.
8. Nishimura H, Nose M, Hiai H, et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif carrying immunoreceptor. Immunity,1999,11(2):1412151.
9. Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science,2001,291 (502):3192322.
10. Latchman YE, Liang SC, Wu Y, et al. PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells. Proc Natl Acad Sci USA,2004,101 (29):10691-10696.
11. Matsumoto K, Inoue H, Nakano T, et al. B7-DC regulates asthmatic response by an IFN-gamma-dependent mechanism. J Immunol,2004,172:253022541.
12. Ansari MJ, Salama AD, Chitnis T, et al. The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med,2003,198:63269.
13. Loke P, Allison JP. PD-L1 and PD-L2 are differentially regulated by Thl and Th2 cells. Proc Natl Acad Sci USA,2003,100 (9):5336-5341.
14. Clarkson MR, Sayegh MH. T-cell costimulatory pathways in allograft rejection and tolerance. Transplantation,2005,80:555-63
15. Vadivel N, Trikudanathan S, Chandraker A. Transplant tolerance through costimulation blockade—are we there yet? Front Biosci,2007,12:2935-46
16. Kean LS, Gangappa S, Pearson TC, Larsen CP. Transplant tolerance in nonhuman primates:progress, current challenges and unmet needs. Am J Transplant,2006,6:884-93
17. Schilbach K, Schick J, Wehrmann M,et al. PD-1-PD-L1 pathway is involved in suppressing alloreactivity of heart infiltrating T cells during murine gvhd across minor histocompatibility antigen barriers. Transplantation.2007,84(2):214-22.
18. Sandner SE, Clarkson MR, Salama AD, Sanchez-Fueyo A, Domenig C, et al. Role of the programmed death-1 pathway in regulation of alloimmune responses in vivo. J Immunol,2005,174:3408-15
19. Tao R, Wang L, Han R, Wang T, Ye Q, et al. Differential effects of B and T lymphocyte attenuator and programmed death-1 on acceptance of partially versus fully MHC-mismatched cardiac allografts. J Immunol,2005,175:5774-82
20. Ozkaynak E,Wang L, Goodearl A, McDonald K, Qin S, et al. Programmed death-1 targeting can promote allograft survival. J Immunol,2002,169:6546-53
21. Ito T, Ueno T, Clarkson MR, Yuan X, Jurewicz MM, et al. Analysis of the role of negative T cell costimulatory pathways in CD4 and CD8 T cell-mediated alloimmune responses in vivo. J Immunol,2005,174:6648-56
22. Selenko-Gebauer N, Majdic O, Szekeres A, Hofler G, Guthann E, et al. B7-H1 (programmed death-1 ligand) on dendritic cells is involved in the induction and maintenance of T cell anergy. J Immunol,2003,170:3637-44
23.Abe M, Wang Z, de Creus A, Thomson AW.2005. Plasmacytoid dendritic cell precursors induce allogeneic T-cell hyporesponsiveness and prolong heart graft survival. Am J Transplant.2005,5:1808-19
24. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008,26:677-704.
25. Tanaka K, Albin MJ, Yuan X, Yamaura K, Habicht A, et al.2007. PD-L1 is required for peripheral transplantation tolerance and protection from chronic allograft rejection. J Immunol,2007,179:5204-10
26. Blazar BR, Carreno BM, Panoskaltsis-Mortari A, Carter L, Iwai Y, et al. Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-y-dependent mechanism. J Immunol,2003, 171:1272-77
27. Choop R, Wahl P, Le Hir M, et al. Suppressed T-cell activation by IFN-gamma-induced expression of PD-L1 on renal tubular epithelial cells. Nephrol Dial Transplant,2004,19 (11):2713-2720
28.吴雄飞,丁涵露,张建国,等。急性排斥反应时移植肾组织中程序性死亡配体-1及其受体的表达。中华器官移植杂志,2005,26(9)：536-538
29. Kitazawa Y, Fujino M, Wang Q, Kimura H, Azuma M, et al. Involvement of the programmed death-1/programmed death-1 ligand pathway in CD4+CD25+ regulatory T-cell activity to suppress alloimmune responses. Transplantation, 2007,83:774-82
30. Okazaki T, Honjo T. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol,2006,27 (4):195-201.
31. Keir ME, Liang SC, Guleria I, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med,2006,203 (4):883-895.
32. Yamazaki T, Akiba H, Koyanagi A, et al. Blockade of B7-H1 on macrophages suppresses CD4+T cell proliferation by augmenting IFN-gamma-induced nitric oxide production. J Immunol,2005,175 (3):1586-1592.
2. Thomson AW, Turnquist HR, Raimondi G. Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol,2009,9:324-337.
3. Liang SC, Latchman YE, Buhlmann JE, et al. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol, 2003,33(10):2706-16.
4. Zhang X, Schwartz JC, Guo XL, et al. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity,2004,20(3):3372347.
5. Liang SC, Latchman YE, Buhlmann JE, et al. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol, 2003,33:2706-16.
6. Ansari MJ, Salama AD, Chitnis T, et al. The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med,2003,198:63-69.
7. Wang J, Yoshida T, Nakaki F, et al. Establishment of NOD-Pdcd1-/-mice as an efficient animal model of type Ⅰ diabetes. Proc Natl Acad Sci USA.2008, 102:11823-28
8. Keir ME, Liang SC, Guleria I, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J. Exp. Med.2006,203:883-95.
9. Baecher-Allan C, Brown JA, Freeman GJ, et al. CD4+CD25+ regulatory cells from human peripheral blood express very high levels of CD25 ex vivo. Novartis Found. Symp.2003,252:67-88.
10. Krupnick AS, Gelman AE, Barchet W, et al. Murine vascular endotheliumactivates and induces the generation of allogeneic CD4+25+Foxp3+ regulatory T cells. J. Immunol.2005,175:6265-70.
11. Velu V, Kannanganat S, Ibegbu C, et al. Elevated expression levels of inhibitory receptor programmed death 1 on simian immunodeficiency virus-specific CD8 T cells during chronic infection but not after vaccination. J Virol.2007,81(11):5819-28.
12. Petrovas C, Casazza JP, Brenchley JM, et al. PD-1 is a regulator of virus-specific CD8+ T cell survival inHIV infection. J. Exp. Med.2006, 203:2281-92.
13. Day CL, Kaufmann DE, Kiepiela P, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature.2006, 443:350-54.
14. Trautmann L, Janbazian L,ChomontN, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat. Med. 2006,12:1198-202.
15. Urbani S, Amadei B, Tola D, et al. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J. Virol.2006, 80:11398-403.
16. D'Souza M, Fontenot AP, Mack DG, et al. Programmed-death 1 expression on HIV-specific CD4+ T cells is driven by viral replication and associated with T cell dysfunction. J. Immunol.2007,179:1979-87.
17. Truong W, Hancock WW, Anderson CC, et al. Co-inhibitory T-cell signaling in islet allograft rejection and tolerance. Cell Transplant,2006,15(2): 105-119.
18. Chuan C, Shirong L, Zhicheng S, et al. Effect of combined application of external cyclosporine A and CTLA-4 Ig on the survival of ratauricle allograft. National Natural Science Foundation of China.2002,16(4):281-283
19. Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol.2004,4:336-347.
20. Greenwald RJ, Freeman GJ, SharpeAH. The B7 family revisited. Ann Rev Immunol.2005,23:515-548.
21. Clarkson MR, Sayegh MH. T-cell costimulatory pathways in allograft rejection and tolerance. Transplantation.2005,80:555-563.
22. Brown JA, Dorfman DM, Ma FR, et al. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J. Immunol.2003,170:1257-66.
1. Momin S, Flores S, Angel B B, et al. Interactions between programmed death 1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms in type 1 diabetes. Diabetes Res Clin Pract.2009,83(3):289-94.
2. Okazaki T, Honjo T. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol,2006,27 (4):195-201.
3. Fife BF, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev.2008,224:166-82.
4. Truong W, Hancock WW, Anderson CC, et al. Co-inhibitory T-cell signaling in islet allograft rejection and tolerance. Cell Transplant.2006,15(2): 105-119.
5. Chuan C, Shirong L, Zhicheng S, et al. Effect of combined application of external cyclosporine A and CTLA-4 Ig on the survival of ratauricle allograft. National Natural Science Foundation of China.2002,16(4):281-283
6. Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol.2004,4:336-347.
7. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Ann Rev Immunol.2005,23:515-548.
8. Muthukumar T, Dadhania D, Ding R, et al. Messenger RNA for FOXP3 in the urine of renal-allograft recipients. N Engl J Med 2005; 353:2342-2351.
9. Kitazawa Y, Fujino M, Wang Q, et al. Involvement of the programmed deathl /programmed death-1 ligand pathway in CD4+CD25+ regulatory T cell activity to suppress alloimmune responses. Transplantation.2007,83:774-782.
10. Alakulppi NS, Kyllonen LE, Partanen J, et al. Diagnosis of acute renal allograft rejection by analyzing whole blood mRNA expression of lymphocyte marker molecules. Transplantation.2007,83:791-798.
11. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol.2008,26:677-704.
12. Tanaka K, Albin MJ, Yuan X, Yamaura K, Habicht A, et al. PD-L1 is required for peripheral transplantation tolerance and protection from chronic allograft rejection. J Immunol.2007,179:5204-10.
13. Blazar BR, Carreno BM, Panoskaltsis-Mortari A, et al. Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-y dependent mechanism. J Immunol.2003,171:1272-77.
1. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev.2010,236:219-42.
2. Fontenot JD, Rasmussen JP, Williams LM, et al. Regulatory T cell lineage specification by the fork-head transcription factor foxp3. Immunity,2005,22: 329-341.
3. Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol.2003,3(3):253-257.
4. Rubtsov Y. P, Rudensky AY. TGFbeta signalling in control of T-cell-mediated self-reactivity. Nat Rev Immunol.2007,7(6):443-453.
5. Von Boehmer H. Mechanisms of suppression by suppressor T cells. Nat I mmunol.2005,6(4):338-344.
6. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol.2003,4:330-336.
7. Allan SE, Broady R, Gregori S,et al. CD4+T-regulatory cells toward therapy for human diseases. Immunol Rev.2008,223:391-421.
8. Radziewicz H, Dunham RM, Grakoui A. PD-1 tempers Tregs in chronic HCV infection. J Clin Invest.2009,119 (3):450-3.
9. Haxhinasto S, Mathis D, Benoist C. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+cells. J Exp Med.2008,205:565-574.
10. Sauer S, Bruno L, Hertweck A, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci USA.2008,105: 7797-7802.
11. Battaglia M, Stabilini A, Migliavacca B, et al. Rapamycin promotes expansion of functional CD4+CD25+FOXP3+regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol.2006,177:8338-8347.
12. Strauss L, Whiteside TL, Knights A, et al. Selective survival of naturally occurring human CD4+CD25+Foxp3+regulatory T cells cultured with rapamycin. J Immunol.2007,178:320-329.
13. Thomson AW, Turnquist HR, Raimondi G. Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol.2009,9:324-337.
14. Parsa AT, Bruno L, Hertweck A, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007,13:84-88.
15. Vadivel N, Trikudanathan S, Chandraker A. Transplant tolerance through costimulation blockade—are we there yet? Front Biosci,2007,12:2935-46.
16. Muthukumar T, Dadhania D, Ding R, et al. Messenger RNA for FOXP3 in the urine of renal-allograft recipients. N Engl J Med 2005; 353:2342-2351.
17. Krupnick AS, Gelman AE, Barchet W, et al. Murine vascular endothelium activates and induces the generation of allogeneic CD4+25+Foxp3+regulatory T cells. J Immunol.2005,175(10):6265-70
18. Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature.2006,439(7007):682-7
19. Dolganiuc A, Paek E, Kodys K, et al. Myeloid dendritic cells of patients with chronic HCV infection induce proliferation of regulatory T lymphocytes. Gastroenterology.2008,135(6):2119-27
20. Jacobs JF, Idema AJ, Bol KF, et al. Regulatory T cells and the PD-L1/PD-1 pathway mediate immune suppression in malignant human brain tumors. Neuro Oncol.2009,11(4):394-402
21. Wang W, Lau R, Yu D, et al. PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+CD25(Hi) regulatory T cells. Int Immunol.2009,21(9):1065-77.
22. Francisco LM, Salinas VH, Brown KE, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009,206(13):3015-29.
1. Momin S, Flores S, Angel B B, et al. Interactions between programmed death 1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms in type 1 diabetes. Diabetes Res Clin Pract,2009,83(3):289-94.
2. Liang SC, Latchman YE, Buhlmann JE, et al. Regulation of PD-1, PD-L1 and PD-L2 expression during normal and autoimmune responses. Eur J Immunol, 2003,33(10):270622716.
3. Zhang X, Schwartz JC, Guo XL, et al. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity,2004,20(3):3372347.
4.Fife BF, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev,2008,224:166-82.
5. Carter L, Fouser LA, Jussif J, et al. PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+T cells and is overcome by IL-2. Eur J Immunol,2002, 32(3):6342643.
6. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol,2001,2(3):261-268.
7. Subudhi SK, Zhou P, Yerian LM, et al. Local expression of B7-H1 promotes organ-specific autoimmunity and transplant rejection. J Clin Invest,2004,113 (5): 6942700.
8. Nishimura H, Nose M, Hiai H, et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif carrying immunoreceptor. Immunity,1999,11(2):1412151.
9. Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science,2001,291 (502):3192322.
10. Latchman YE, Liang SC, Wu Y, et al. PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells. Proc Natl Acad Sci USA,2004,101 (29):10691-10696.
11. Matsumoto K, Inoue H, Nakano T, et al. B7-DC regulates asthmatic response by an IFN-gamma-dependent mechanism. J Immunol,2004,172:253022541.
12. Ansari MJ, Salama AD, Chitnis T, et al. The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med,2003,198:63269.
13. Loke P, Allison JP. PD-L1 and PD-L2 are differentially regulated by Thl and Th2 cells. Proc Natl Acad Sci USA,2003,100 (9):5336-5341.
14. Clarkson MR, Sayegh MH. T-cell costimulatory pathways in allograft rejection and tolerance. Transplantation,2005,80:555-63
15. Vadivel N, Trikudanathan S, Chandraker A. Transplant tolerance through costimulation blockade—are we there yet? Front Biosci,2007,12:2935-46
16. Kean LS, Gangappa S, Pearson TC, Larsen CP. Transplant tolerance in nonhuman primates:progress, current challenges and unmet needs. Am J Transplant,2006,6:884-93
17. Schilbach K, Schick J, Wehrmann M,et al. PD-1-PD-L1 pathway is involved in suppressing alloreactivity of heart infiltrating T cells during murine gvhd across minor histocompatibility antigen barriers. Transplantation.2007,84(2):214-22.
18. Sandner SE, Clarkson MR, Salama AD, Sanchez-Fueyo A, Domenig C, et al. Role of the programmed death-1 pathway in regulation of alloimmune responses in vivo. J Immunol,2005,174:3408-15
19. Tao R, Wang L, Han R, Wang T, Ye Q, et al. Differential effects of B and T lymphocyte attenuator and programmed death-1 on acceptance of partially versus fully MHC-mismatched cardiac allografts. J Immunol,2005,175:5774-82
20. Ozkaynak E,Wang L, Goodearl A, McDonald K, Qin S, et al. Programmed death-1 targeting can promote allograft survival. J Immunol,2002,169:6546-53
21. Ito T, Ueno T, Clarkson MR, Yuan X, Jurewicz MM, et al. Analysis of the role of negative T cell costimulatory pathways in CD4 and CD8 T cell-mediated alloimmune responses in vivo. J Immunol,2005,174:6648-56
22. Selenko-Gebauer N, Majdic O, Szekeres A, Hofler G, Guthann E, et al. B7-H1 (programmed death-1 ligand) on dendritic cells is involved in the induction and maintenance of T cell anergy. J Immunol,2003,170:3637-44
23.Abe M, Wang Z, de Creus A, Thomson AW.2005. Plasmacytoid dendritic cell precursors induce allogeneic T-cell hyporesponsiveness and prolong heart graft survival. Am J Transplant.2005,5:1808-19
24. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008,26:677-704.
25. Tanaka K, Albin MJ, Yuan X, Yamaura K, Habicht A, et al.2007. PD-L1 is required for peripheral transplantation tolerance and protection from chronic allograft rejection. J Immunol,2007,179:5204-10
26. Blazar BR, Carreno BM, Panoskaltsis-Mortari A, Carter L, Iwai Y, et al. Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-y-dependent mechanism. J Immunol,2003, 171:1272-77
27. Choop R, Wahl P, Le Hir M, et al. Suppressed T-cell activation by IFN-gamma-induced expression of PD-L1 on renal tubular epithelial cells. Nephrol Dial Transplant,2004,19 (11):2713-2720
28.吴雄飞,丁涵露,张建国,等。急性排斥反应时移植肾组织中程序性死亡配体-1及其受体的表达。中华器官移植杂志,2005,26(9)：536-538
29. Kitazawa Y, Fujino M, Wang Q, Kimura H, Azuma M, et al. Involvement of the programmed death-1/programmed death-1 ligand pathway in CD4+CD25+ regulatory T-cell activity to suppress alloimmune responses. Transplantation, 2007,83:774-82
30. Okazaki T, Honjo T. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol,2006,27 (4):195-201.
31. Keir ME, Liang SC, Guleria I, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med,2006,203 (4):883-895.
32. Yamazaki T, Akiba H, Koyanagi A, et al. Blockade of B7-H1 on macrophages suppresses CD4+T cell proliferation by augmenting IFN-gamma-induced nitric oxide production. J Immunol,2005,175 (3):1586-1592.