Kupffer 细胞调控Th17细胞分化及其在大鼠肝移植急性排斥反应中的作用研究
摘要
研究目的：
急性排斥反应是肝脏移植术后常见的严重并发症,也是导致慢性排斥和移植物失功的重要原因之一,研究肝脏移植后免疫调节的机制有助于为急性排斥反应提供新的治疗手段。辅助性T细胞17(T helper 17 cells, Th17)以表达IL-17而得名,是不同于Thl、Th2的CD4+T细胞新亚群,在自身免疫性疾病、机体抗感染、肿瘤发生和器官移植排斥中发挥重要作用。业已证明,转化生长因子-β(transforming growth factor beta, TGF-β)与IL-6联合作用能诱导原始CD4+T细胞分化为Th17细胞。而Kupffer细胞作为体内最大的定居型巨噬细胞群,在活化状态下既可吞噬肠道来源的病原菌以及内毒素,又可释放大量生物活性物质,具有强大的抗原递呈功能,为淋巴细胞的分化、增殖、成熟以及凋亡等提供各种调节信号。鉴于肝脏中Kupffer细胞在病理生理条件下分泌大量TGF-p与IL-6等细胞因子,我们认为此时形成的肝脏局部免疫微环境有利于Thl7细胞的分化和增殖,而Th17细胞可能在肝脏免疫性疾病及排斥反应中发挥重要作用。我们通过建立大鼠肝脏移植急性排斥模型,探讨Th17细胞在肝移植急性排斥反应中的作用及机制,同时利用氯化钆(gadolinium trichloride,GdCl3)抑制Kupffer细胞功能,观察其对移植排斥反应的作用及Th17细胞的影响,并通过体外实验进一步证实Kupffer细胞对Th17细胞分化的调控作用。
研究方-法：
实验动物采用近交系雄性Dark Agouti(DA)和Brown Norway(BN)大鼠,体重200-300g,改良Kamada法建立大鼠原位肝脏移植模型。实验分组:(A)异基因组：DA大鼠作为供体,BN大鼠作为受体；(B)GdCl3预处理组：DA大鼠作为供体,BN大鼠作为受体,供体术前24小时阴茎静脉注射GdCl3(10 mg/kg)；(C)同基因组：供受体均采用BN大鼠。每组各18对,6只观察生存期,其余于术后5天和10天处死,留取外周血和肝组织标本,分别检测肝功能、肝脏病理组织学分析,流式细胞术检测外周血和肝脏淋巴细胞Thl7细胞比例,使用荧光定量聚合酶链锁反应(polymerase chain reaction,PCR)、蛋白质印迹(Western blot)、免疫组化以及酶联免疫吸附(enzyme-linked immunosorbent assay,ELISA)法检测肝组织IL-17、IL-6、TGF-βmRNA和蛋白表达水平。在体外将通过原位胶原酶灌注结合离心淘洗法分离的大鼠Kupffer细胞与使用免疫磁珠法分选出的脾脏初始CD4+T淋巴细胞进行混合培养,然后经流式细胞术分析其淋巴细胞表型。
研究结果：
与同基因移植大鼠比较,异基因移植大鼠出现典型急性排斥反应改变,肝脏Kupffer细胞与淋巴细胞浸润明显,其中Th17细胞比例增高,同时肝内IL-8、髓过氧化物酶(myeloperoxidase,MPO)、TGF-β和IL-6表达水平明显上升。注射氯化钆的大鼠肝脏Kupffer细胞数量明显下降,急性排斥反应明显改善,生存时间延长,并且肝内与外周血Th17水平显著降低,同时肝内TGF-β和IL-6表达下降。可见氯化钆能够有效地抑制Kupffer细胞的免疫活性和Thl7细胞增殖,从而抑制大鼠同种异基因肝移植后急性排斥反应。分别分离急性排斥大鼠和同基因移植大鼠肝脏Kupffer细胞,与正常DA大鼠脾脏原始CD4+T细胞混合培养,流式细胞术检测发现前者Th17细胞比例也明显高于后者(30.8% vs 8.1%),ELISA检测发现急性排斥大鼠Kupffer细胞培养上清TGF-β和IL-6水平明显较同基因组高。
研究结论：
肝脏Kupffer细胞通过分泌TGF-β和IL-6等细胞因子诱导Th17细胞的分化,促进肝脏移植急性排斥反应的发生。
Objective:
Orthotopic liver transplantation (OLT) is applied as a valuable method for treating end-stage liver diseases. However, acute rejection is one of its most serious complication reported in～about 30% of liver transplants performed. T lymphocytes and Kupffer cells are the dominant cell types that are found to infiltrate the liver following transplantation. Consistent with these observations, CD4+ T cells have been proposed to play a crucial role in determining transplant rejection or tolerance. T helper (Th) 17, recently identified as a new subset of CD4+ T cells, has been discovered to implicate in transplant rejection. Data from animal experiments and clinical trials confirmed that Thl 7 cells have a role in allograft rejection of solid organs, which previously thought to be driven by Th1-mediated inflammation. Kupffer cells are macrophage that are present in liver and localize to portal area and within sinusoidal lumen. Kupffer cells have previously been implicated in the pathogenesis of hepatic allograft rejection based on their antigen presentation and cytokine production. As antigen presenting cells (APC) are associated with liver, Kupffer cells interact with lymphocytes to induce T-cell proliferation and cytokine synthesis. Furthermore, under pathophysiological conditions, Kupffer cells have been shown to secrete high levels of IL-6 and TGF-β, which are key factors for Th17 cell differentiation. Therefore, we wonder if it is possible that Kupffer cells induce Th17 cell differentiation via production of IL-6 and TGF-βto promote acute liver allograft rejection. To test this hypothesis, the role of Kupffer cells and Th17 cells in acute liver transplant rejection was investigated using a rat OLT model.
Methods:
A rat model of allogeneic liver transplantation from Dark Agouti (DA) to Brown Norway (BN) was established with or without pretreatment with gadoliniumchloride (GdCl3), and isogeneic liver transplantation (BN to BN) was used as a control. The expression of kupffer cells cell-derived Th17-related cytokines in liver and peripheral blood were determined by immunohistochemistry, flow cytometry or ELISA, and survival differences were compared between groups. Furthermore, Kupffer cells in liver grafts were isolated and cocultured with naive CD4+ T cells for 5 days, then T cells were collected and the frequency of Th17 differentiation was determined using flow cytometry.
Results:
Both Kupffer cells and Th17 cells were found to infiltrate into liver allografts accompanied by increase of IL-6 and TGF-βlevels. Pretreatment with GdCl3 attenuated intragraft-infiltration of Th17 cells as well as Kupffer cells, decreased IL-6 and TGF-βlevels in grafts, improved liver function and prolonged the survival time(16.33±0.96 days vs 11.50±0.99 days, p<0.01). In vitro, the Kupffer cells from allograft liver secreted significantly more IL-6, TGF-βand induced Th17 differentiation more effectively comparing with those from isograft (30.8% vs 8.1%).
Conclution:
Kupffer cells potentially function as inducers of Th17 cells by secreting IL-6 and TGF-β, and promote acute liver allograft rejection.
急性排斥反应是肝脏移植术后常见的严重并发症,也是导致慢性排斥和移植物失功的重要原因之一,研究肝脏移植后免疫调节的机制有助于为急性排斥反应提供新的治疗手段。辅助性T细胞17(T helper 17 cells, Th17)以表达IL-17而得名,是不同于Thl、Th2的CD4+T细胞新亚群,在自身免疫性疾病、机体抗感染、肿瘤发生和器官移植排斥中发挥重要作用。业已证明,转化生长因子-β(transforming growth factor beta, TGF-β)与IL-6联合作用能诱导原始CD4+T细胞分化为Th17细胞。而Kupffer细胞作为体内最大的定居型巨噬细胞群,在活化状态下既可吞噬肠道来源的病原菌以及内毒素,又可释放大量生物活性物质,具有强大的抗原递呈功能,为淋巴细胞的分化、增殖、成熟以及凋亡等提供各种调节信号。鉴于肝脏中Kupffer细胞在病理生理条件下分泌大量TGF-p与IL-6等细胞因子,我们认为此时形成的肝脏局部免疫微环境有利于Thl7细胞的分化和增殖,而Th17细胞可能在肝脏免疫性疾病及排斥反应中发挥重要作用。我们通过建立大鼠肝脏移植急性排斥模型,探讨Th17细胞在肝移植急性排斥反应中的作用及机制,同时利用氯化钆(gadolinium trichloride,GdCl3)抑制Kupffer细胞功能,观察其对移植排斥反应的作用及Th17细胞的影响,并通过体外实验进一步证实Kupffer细胞对Th17细胞分化的调控作用。
研究方-法：
实验动物采用近交系雄性Dark Agouti(DA)和Brown Norway(BN)大鼠,体重200-300g,改良Kamada法建立大鼠原位肝脏移植模型。实验分组:(A)异基因组：DA大鼠作为供体,BN大鼠作为受体；(B)GdCl3预处理组：DA大鼠作为供体,BN大鼠作为受体,供体术前24小时阴茎静脉注射GdCl3(10 mg/kg)；(C)同基因组：供受体均采用BN大鼠。每组各18对,6只观察生存期,其余于术后5天和10天处死,留取外周血和肝组织标本,分别检测肝功能、肝脏病理组织学分析,流式细胞术检测外周血和肝脏淋巴细胞Thl7细胞比例,使用荧光定量聚合酶链锁反应(polymerase chain reaction,PCR)、蛋白质印迹(Western blot)、免疫组化以及酶联免疫吸附(enzyme-linked immunosorbent assay,ELISA)法检测肝组织IL-17、IL-6、TGF-βmRNA和蛋白表达水平。在体外将通过原位胶原酶灌注结合离心淘洗法分离的大鼠Kupffer细胞与使用免疫磁珠法分选出的脾脏初始CD4+T淋巴细胞进行混合培养,然后经流式细胞术分析其淋巴细胞表型。
研究结果：
与同基因移植大鼠比较,异基因移植大鼠出现典型急性排斥反应改变,肝脏Kupffer细胞与淋巴细胞浸润明显,其中Th17细胞比例增高,同时肝内IL-8、髓过氧化物酶(myeloperoxidase,MPO)、TGF-β和IL-6表达水平明显上升。注射氯化钆的大鼠肝脏Kupffer细胞数量明显下降,急性排斥反应明显改善,生存时间延长,并且肝内与外周血Th17水平显著降低,同时肝内TGF-β和IL-6表达下降。可见氯化钆能够有效地抑制Kupffer细胞的免疫活性和Thl7细胞增殖,从而抑制大鼠同种异基因肝移植后急性排斥反应。分别分离急性排斥大鼠和同基因移植大鼠肝脏Kupffer细胞,与正常DA大鼠脾脏原始CD4+T细胞混合培养,流式细胞术检测发现前者Th17细胞比例也明显高于后者(30.8% vs 8.1%),ELISA检测发现急性排斥大鼠Kupffer细胞培养上清TGF-β和IL-6水平明显较同基因组高。
研究结论：
肝脏Kupffer细胞通过分泌TGF-β和IL-6等细胞因子诱导Th17细胞的分化,促进肝脏移植急性排斥反应的发生。
Objective:
Orthotopic liver transplantation (OLT) is applied as a valuable method for treating end-stage liver diseases. However, acute rejection is one of its most serious complication reported in～about 30% of liver transplants performed. T lymphocytes and Kupffer cells are the dominant cell types that are found to infiltrate the liver following transplantation. Consistent with these observations, CD4+ T cells have been proposed to play a crucial role in determining transplant rejection or tolerance. T helper (Th) 17, recently identified as a new subset of CD4+ T cells, has been discovered to implicate in transplant rejection. Data from animal experiments and clinical trials confirmed that Thl 7 cells have a role in allograft rejection of solid organs, which previously thought to be driven by Th1-mediated inflammation. Kupffer cells are macrophage that are present in liver and localize to portal area and within sinusoidal lumen. Kupffer cells have previously been implicated in the pathogenesis of hepatic allograft rejection based on their antigen presentation and cytokine production. As antigen presenting cells (APC) are associated with liver, Kupffer cells interact with lymphocytes to induce T-cell proliferation and cytokine synthesis. Furthermore, under pathophysiological conditions, Kupffer cells have been shown to secrete high levels of IL-6 and TGF-β, which are key factors for Th17 cell differentiation. Therefore, we wonder if it is possible that Kupffer cells induce Th17 cell differentiation via production of IL-6 and TGF-βto promote acute liver allograft rejection. To test this hypothesis, the role of Kupffer cells and Th17 cells in acute liver transplant rejection was investigated using a rat OLT model.
Methods:
A rat model of allogeneic liver transplantation from Dark Agouti (DA) to Brown Norway (BN) was established with or without pretreatment with gadoliniumchloride (GdCl3), and isogeneic liver transplantation (BN to BN) was used as a control. The expression of kupffer cells cell-derived Th17-related cytokines in liver and peripheral blood were determined by immunohistochemistry, flow cytometry or ELISA, and survival differences were compared between groups. Furthermore, Kupffer cells in liver grafts were isolated and cocultured with naive CD4+ T cells for 5 days, then T cells were collected and the frequency of Th17 differentiation was determined using flow cytometry.
Results:
Both Kupffer cells and Th17 cells were found to infiltrate into liver allografts accompanied by increase of IL-6 and TGF-βlevels. Pretreatment with GdCl3 attenuated intragraft-infiltration of Th17 cells as well as Kupffer cells, decreased IL-6 and TGF-βlevels in grafts, improved liver function and prolonged the survival time(16.33±0.96 days vs 11.50±0.99 days, p<0.01). In vitro, the Kupffer cells from allograft liver secreted significantly more IL-6, TGF-βand induced Th17 differentiation more effectively comparing with those from isograft (30.8% vs 8.1%).
Conclution:
Kupffer cells potentially function as inducers of Th17 cells by secreting IL-6 and TGF-β, and promote acute liver allograft rejection.
引文
[1]Scientific Registry of Transplant Recipients. Available at:http://www.ustransplant. org/. Accessed September 11,2008.
[2]Reiner SL. Development in motion:helper T cells at work. Cell.2007; 129:33-36.
[3]Wadia PP, Tambur AR. Yin and yang of cytokine regulation in solid organ graft rejection and tolerance. Clin Lab Med.2008; 28:469-479.
[4]Bettelli E, Korn T, Kuchroo VK. Thl7:the third member of the effector T cell trilogy. Curr Opin Immunol.2007; 19:652-657.
[5]Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity. 2004; 21:467-476.
[6]Fossiez F, Djossou O, Chomarat P, et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med.1996; 183: 2593-2603.
[7]Tesmer LA, Lundy SK, Sarkar S, et al. Th17 cells in human disease. Immunol Rev. 2008; 223:87-113.
[8]Loong CC, Hsieh HG, Lui WY, et al. Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection. J Pathol.2002; 197:322-332.
[9]Vanaudenaerde BM, De Vleeschauwer SI, Vos R, et al. The role of the IL23/IL17 axis in bronchiolitis obliterans syndrome after lung transplantation. Am J Transplant.2008; 8:1911-1920.
[10]Chen H, Wang W, Xie H, et al. A pathogenic role of IL-17 at the early stage of corneal allograft rejection. Transpl Immunol.2009; 21:155-161.
[11]Yuan X, Paez-Cortez J, Schmitt-Knosalla I, et al. A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy. J Exp Med.2008; 205: 3133-3144.
[12]Antonysamy MA. Fanslow WC, Fu F, et al. Evidence for a role of IL-17 in organ allograft rejection:IL-17 promotes the functional differentiation of dendritic cell progenitors. J Immunol.1999; 162:577-584.
[13]Fabrega E, Lopez-Hoyos M. San Segundo D, et al. Changes in the serum levels of interleukin-17/interleukin-23 during acute rejection in liver transplantation. Liver Transpl.2009; 15:629-633.
[14]Kolios G, Valatas V, Kouroumalis E. Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol.2006; 12:7413-7420.
[15]Knolle PA, Gerken G. Local control of the immune response in the liver. Immunol Rev.2000; 174:21-34.
[16]Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature.2006; 441: 235-238.
[17]Veldhoen M, Hocking RJ, Flavell RA, et al. Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat Immunol.2006; 7:1151-1156.
[18]Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+T helper cells. Cell. 2006; 126:1121-1133.
[19]Bouwens L, Baekeland M, De Zanger R, et al. Quantitation, tissue distribution and proliferation kinetics of Kupffer cells in normal rat liver. Hepatology.1986; 6: 718-722.
[20]Sun Z, Wada T, Maemura K, et al. Hepatic allograft-derived Kupffer cells regulate T cell response in rats. Liver Transpl.2003; 9:489-497.
[21]Hanschen M, Zahler S, Krombach F, et al. Reciprocal activation between CD4(+) T cells and Kupffer cells during hepatic ischemia-reperfusion. Transplantation. 2008; 86:710-718.
[1]Xiang Z, Ma LL, Manicassamy S, et al. CD4+ T cells are sufficient to elicit allograft rejection and major histocompatibility complex class I molecule is required to induce recurrent autoimmune diabetes after pancreas transplantation in mice. Transplantation.2008; 85:1205-1211.
[2]Reiner SL. Development in motion:helper T cells at work. Cell.2007; 129:33-36.
[3]Wadia PP, Tambur AR. Yin and yang of cytokine regulation in solid organ graft rejection and tolerance. Clin Lab Med.2008; 28:469-479.
[4]Saiura A, Mataki C, Murakami T, et al. A comparison of gene expression in murine cardiac allografts and isografts by means DNA microarray analysis. Transplantation.2001; 72:320-329.
[5]Obata F, Yoshida K, Ohkubo M, et al. Contribution of CD4+ and CD8+T cells and interferon-gamma to the progress of chronic rejection of kidney allografts:the Th1 response mediates both acute and chronic rejection. Transpl Immunol.2005; 14: 21-25.
[6]Halloran PF, Miller LW, Urmson J, et al. IFN-gamma alters the pathology of graft rejection:protection from early necrosis. J Immunol.2001; 166:7072-7081.
[7]Miura M, El-Sawy T, Fairchild RL. Neutrophils mediate parenchymal tissue necrosis and accelerate the rejection of complete major histocompatibility complex-disparate cardiac allografts in the absence of interferon-gamma. Am J Pathol.2003; 162:509-519.
[8]Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol.2005; 6:1123-1132.
[9]Bettelli E, Korn T, Kuchroo VK. Th17:the third member of the effector T cell trilogy. Curr Opin Immunol.2007; 19:652-657.
[10]Tesmer LA, Lundy SK, Sarkar S, et al. Th17 cells in human disease. Immunol Rev. 2008; 223:87-113.
[11]Loong CC, Hsieh HG, Lui WY, et al. Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection. J Pathol.2002; 197:322-332.
[12]Vanaudenaerde BM, De Vleeschauwer SI, Vos R, et al. The role of the IL23/IL17 axis in bronchiolitis obliterans syndrome after lung transplantation. Am J Transplant.2008; 8:1911-1920.
[13]Chen H, Wang W, Xie H, et al. A pathogenic role of IL-17 at the early stage of corneal allograft rejection. Transpl Immunol.2009; 21:155-161.
[14]Yuan X, Paez-Cortez J, Schmitt-Knosalla I, et al. Anovel role of CD4 Thl7 cells in mediating cardiac allograft rejection and vasculopathy. J Exp Med.2008; 205: 3133-3144.
[15]Antonysamy MA, Fanslow WC, Fu F, et al. Evidence for a role of IL-17 in organ allograft rejection:IL-17 promotes the functional differentiation of dendritic cell progenitors. J Immunol.1999; 162:577-584.
[16]Fabrega E, Lopez-Hoyos M, San Segundo D, et al. Changes in the serum levels of interleukin-17/interleukin-23 during acute rejection in liver transplantation. Liver Transpl.2009; 15:629-633.
[17]Kamada N, Calne RY. Orthotopic liver transplantation in the rat. Technique using cuff for portal vein anastomosis and biliary drainage. Transplantation.1979; 28: 47-50.
[18]Banff schema for grading liver allograft rejection:an international consensus document. Hepatology.1997; 25:658-663.
[19]Weaver CT, Hatton RD, Mangan PR, et al. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol.2007; 25: 821-852.
[20]Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity. 2004; 21:467-476.
[21]Kishimoto T. The biology of interleukin-6. Blood.1989; 74:1-10.
[22]Kita Y, Iwaki Y, Demetris AJ, et al. Evaluation of sequential serum interleukin-6 levels in liver allograft recipients. Transplantation.1994; 57:1037-1041.
[23]Warle MC, Metselaar HJ, Hop WC, et al. Early differentiation between rejection and infection in liver transplant patients by serum and biliary cytokine patterns. Transplantation.2003; 75:146-151.
[24]Chen L, Ahmed E, Wang T, et al. TLR signals promote IL-6/IL-17-dependent transplant rejection. J Immunol.2009:182:6217-6225.
[25]Laan M, Cui ZH, Hoshino H, et al. Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways. J Immunol.1999; 162:2347-2352.
[26]Prause O, Laan M,. Lotvall J, et al..Pharmacological modulation of interleukin-17-induced GCP-2-, GRO-alpha-and interleukin-8 release in human bronchial epithelial cells. Eur J Pharmacol.2003; 462:193-198.
[27]Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature.2006; 441: 235-238.
[28]Mangan PR, Harrington LE, O'Quinn DB, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature.2006; 441:231-234.
[29]Li MO, Wan YY, Sanjabi S, et al. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol.2006; 24:99-146.
[30]Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+CD25-naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med.2003; 198:1875-1886.
[31]Malik R, Selden C, Hodgson H. The role of non-parenchymal cells in liver growth. Semin Cell Dev Biol.2002; 13:425-431.
[32]Yasumi Y, Takikawa Y. Endo R, et al. Interleukin-17 as a new marker of severity of acute hepatic injury. Hepatology Research.2007; 37:248-254.
[33]Zhang JY, Zhang Z, Lin F, et al. Interleukin-17-Producing CD4(+) T Cells Increase with Severity of Liver Damage in Patients with Chronic Hepatitis B. Hepatology. 2010; 51:81-91.
[34]Lan RYZ, Salunga TL, Tsuneyama K, et al. Hepatic IL-17 responses in human and murine primary biliary cirrhosis. Journal of Autoimmunity.2009; 32:43-51.
[35]Lemmers A, Moreno C, Gustot T, et al. The Interleukin-17 Pathway Is Involved in Human Alcoholic Liver Disease. Hepatology.2009; 49:646-657.
[36]Rutitzky LI, Bazzone L. Shainheit MG, et al. IL-23 is required for the development of severe egg-induced immunopathology in schistosomiasis and for lesional expression of IL-17. Journal of Immunology.2008; 180:2486-2495.
[37]Zhang JP, Yan J, Xu J, et al. Increased intratumoral IL-17-producing cells survival in hepatocellular carcinoma correlate with poor patients. Journal of Hepatology. 2009; 50:980-989.
[38]Stritesky GL, Yeh N, Kaplan MH. IL-23 promotes maintenance but not commitment to the Th17 lineage. J Immunol.2008; 181:5948-5955.
[39]Nurieva R, Yang XO, Martinez G, et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature.2007; 448:480-483.
[40]Ivanov, Ⅱ, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006; 126:1121-1133.
[1]Bouwens L, Baekeland M, De Zanger R, et al. Quantitation, tissue distribution and proliferation kinetics of Kupffer cells in normal rat liver. Hepatology.1986; 6: 718-722.
[2]Winwood PJ, Arthur MJ. Kupffer cells:their activation and role in animal models of liver injury and human liver disease. Semin Liver Dis.1993; 13:50-59.
[3]Kolios G, Valatas V. Kouroumalis E. Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol.2006; 12:7413-7420.
[4]Savier E, Lemasters JJ, Thurman RG. Kupffer cells participate in rejection following liver transplantation in the rat. Transpl Int.1994; 7 Suppl 1:S183-186.
[5]von Frankenberg M, Golling M, Mehrabi A, et al. Donor pretreatment with gadolinium chloride improves early graft function and survival after porcine liver transplantation. Transpl Int.2003; 16:806-813.
[6]Imamura H, Laberge S, Brault A, et al. Immunogenic role of Kupffer cells in a rat model of acute liver allograft rejection. Liver Transpl Surg.1995; 1:389-394.
[7]Chen Y, Liu ZJ, Liang SY, et al. Role of Kupffer cells in the induction of tolerance of orthotopic liver transplantation in rats. Liver Transplantation.2008; 14: 823-836.
[8]Sun ZL, Wada T, Maemura K, et al. Hepatic allograft-derived Kupffer cells regulate T cell response in rats. Liver Transplantation.2003; 9:489-497.
[9]Lee CM, Yeoh GC, Olynyk JK. Differential effects of gadolinium chloride on Kupffer cells in vivo and in vitro. Int J Biochem Cell Biol.2004; 36:481-488.
[10]Ferreira J, Tapia G, Videla LA. Effects of the Kupffer cell inactivator gadolinium chloride on rat liver oxygen uptake and content of mitochondrial cytochromes. FEBS Lett.1998; 426:263-265.
[11]Kamada N. Genetics of liver graft rejection in the rat. Experimental Liver Transplantation. Boca Raton, FL, CRC Press,1988, pp 55-66
[12]Demetris AJ, Qian S, Sun H, et al. Early events in liver allograft rejection. Delineation of sites of simultaneous intragraft and recipient lymphoid tissue sensitization. Am J Pathol.1991; 138:609-618.
[13]Kamada N, Calne RY Orthotopic liver transplantation in the rat. Technique using cuff for portal vein anastomosis and biliary drainage. Transplantation.1979; 28: 47-50.
[14]Banff schema for grading liver allograft rejection:an international consensus document. Hepatology.1997; 25:658-663.
[15]Pirenne J, Gunson B, Khaleef H, et al. Influence of ischemia-reperfusion injury on rejection after liver transplantation. Transplant Proc.1997; 29:366-367.
[16]Winwood PJ, Arthur MJ. Kupffer cells:their activation and role in animal models of liver injury and human liver disease. Semin Liver Dis.1993; 13:50-59.
[17]Hanschen M, Zahler S, Krombach F. et al. Reciprocal activation between CD4+ T cells and Kupffer cells during hepatic ischemia-reperfusion. Transplantation.2008; 86:710-718.
[18]Giakoustidis DE, Iliadis S, Tsantilas D, et al. Blockade of Kupffer cells by gadolinium chloride reduces lipid peroxidation and protects liver from ischemia/reperfusion injury. Hepatogastroenterology.2003; 50:1587-1592.
[19]Shiratori Y, Kiriyama H, Fukushi Y, et al. Modulation of Ischemia-Reperfusion-Induced Hepatic-Injury by Kupffer Cells. Digestive Diseases and Sciences.1994; 39:1265-1272.
[20]Rogoff TM, Lipsky PE. Role of the Kupffer cells in local and systemic immune responses. Gastroenterology.1981; 80:854-860.
[21]Settaf A, Milton AD, Spencer SC, et al. Donor class I and class II major histocompatibility complex antigen expression following liver allografting in rejecting and nonrejecting rat strain combinations. Transplantation.1988; 46: 32-40.
[22]Gouw AS, Houthoff HJ, Huitema S, et al. Expression of major histocompatibility complex antigens and replacement of donor cells by recipient ones in human liver grafts. Transplantation.1987; 43:291-296.
[23]Kwekkeboom J, Kuijpers MA, Bruyneel B, et al. Expression of CD80 on Kupffer cells is enhanced in cadaveric liver transplants. Clin Exp Immunol.2003; 132: 345-351.
[24]Lohse AW, Knolle PA, Bilo K, et al. Antigen-presenting function and B7 expression of murine sinusoidal endothelial cells and Kupffer cells. Gastroenterology.1996; 110:1175-1181.
[25]Xiang Z, Ma LL, Manicassamy S, et al. CD4+ T cells are sufficient to elicit allograft rejection and major histocompatibility complex class I molecule is required to induce recurrent autoimmune diabetes after pancreas transplantation in mice. Transplantation.2008; 85:1205-1211.
[26]Reiner SL. Development in motion:helper T cells at work. Cell.2007; 129:33-36.
[27]Wadia PP, Tambur AR. Yin and yang of cytokine regulation in solid organ graft rejection and tolerance. Clin Lab Med.2008; 28:469-479.
[28]Cavaillon JM. Cytokines and macrophages. Biomed Pharmacother.1994; 48: 445-453.
[29]Krohn N, Kapoor S, Enami Y, et al. Hepatocyte transplantation-induced liver inflammation is driven by cytokines-chemokines associated with neutrophils and Kupffer cells. Gastroenterology.2009; 136:1806-1817.
[30]Nagaki M, Moriwaki H. Implication of cytokines:Roles of tumor necrosis factor-alpha in liver injury. Hepatol Res.2008; 38:S19-S28.
[31]Hardonk MJ, Dijkhuis FWJ, Hulstaert CE, et al. Heterogeneity of Rat-Liver and Spleen Macrophages in Gadolinium Chloride-Induced Elimination and Repopulation. Journal of Leukocyte Biology.1992; 52:296-302.
[32]Sun Z, Wada T, Uchikura K, et al. Role of Fas/Fasl in Kupffer cell-dependent deletion of alloantigen activated T cells following liver transplantation. Transplant Proc.2001; 33:279-282.
[33]Miyagawa-Hayashino A, Tsuruyama T, Egawa H, et al. FasL expression in hepatic antigen-presenting cells and phagocytosis of apoptotic T cells by FasL+Kupffer cells are indicators of rejection activity in human liver allografts. Am J Pathol. 2007; 171:1499-1508.
[1]Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol.2005; 6:1123-1132.
[2]Bettelli E, Korn T, Kuchroo VK. Th17:the third member of the effector T cell trilogy. Curr Opin Immunol.2007; 19:652-657.
[3]Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector Thl7 and regulatory cells. Nature.2006; 441: 235-238.
[4]Khayrullina T, Yen JH, Jing H, et al. In vitro differentiation of dendritic cells in the presence of prostaglandin E2 alters the IL-12/IL-23 balance and promotes differentiation of Th17 cells. J Immunol.2008; 181:721-735.
[5]Wang Q, Liu C, Zhu F, et al. Reoxygenation of hypoxia-differentiated dentritic cells induces Thl and Th17 cell differentiation. Mol Immunol.2010; 47:922-931.
[6]Bouwens L, De Bleser P, Vanderkerken K, et al. Liver cell heterogeneity:functions of non-parenchymal cells.1992; 46:155-168.
[7]Bouwens L, Baekeland M, De Zanger R, et al. Quantitation, tissue distribution and proliferation kinetics of Kupffer cells in normal rat liver. Hepatology.1986; 6: 718-722.
[8]Decker K. The response of liver macrophages to inflammatory stimulation. Keio J Med.1998; 47:1-9.
[9]Sun Z, Wada T, Maemura K, et al. Hepatic allograft-derived Kupffer cells regulate T cell response in rats. Liver Transpl.2003; 9:489-497.
[10]Hanschen M, Zahler S. Krombach F, et al. Reciprocal activation between CD4+T cells and Kupffer cells during hepatic ischemia-reperfusion. Transplantation.2008; 86:710-718.
[11]Morita A, Itoh Y, Toyama T, et al. Activated Kupffer cells play an important role in intra-hepatic Thl-associated necro-inflammation in Concanavalin A-induced hepatic injury in mice. Hepatol Res.2003; 27:143-50.
[12]Wiegard C, Frenzel C, Herkel.J, et al. Murine liver antigen presenting cells control suppressor activity of CD4+CD25+ regulatory T cells. Hepatology.2005; 42: 193-199.
[13]Ge X, Nowak G, Ericzon BG, et al. Liver sinusoidal endothelial cell function in rejected and spontaneously accepted rat liver allografts. Transpl Int.2008; 21: 49-56.
[14]Jiang G, Yang HR, Wang L, et al. Hepatic stellate cells preferentially expand allogeneic CD4+ CD25+ FoxP3+ regulatory T cells in an IL-2-dependent manner. Transplantation.2008; 86:1492-1502.
[15]Dienes HP, Drebber U. Pathology of immune-mediated liver injury. Dig Dis.2010; 28:57-62.
[16]Sumpter TL, Lunz JG,3rd, Castellaneta A, et al. Dendritic cell immunobiology in relation to liver transplant outcome. Front Biosci (Elite Ed).2009; 1:99-114.
[17]Kamada N, Calne RY. Orthotopic liver transplantation in the rat. Technique using cuff for portal vein anastomosis and biliary drainage. Transplantation.1979; 28: 47-50.
[18]Kawada N, Seki S, Inoue M, et al. Effect of antioxidants, resveratrol, quercetin, and N-acetylcysteine, on the functions of cultured rat hepatic stellate cells and Kupffer cells. Hepatology.1998; 27:1265-1274.
[19]Luettig B, Pape L, Bode U, et al. Naive and memory T lymphocytes migrate in comparable numbers through normal rat liver:activated T cells accumulate in the periportal field. J Immunol.1999; 163:4300-4307.
[20]Lee CM, Yeoh GC, Olynyk JK. Differential effects of gadolinium chloride on Kupffer cells in vivo and in vitro. Int J Biochem Cell Biol.2004; 36:481-488.
[21]Gorelik L, Flavell RA. Transforming growth factor-beta in T-cell biology. Nat Rev Immunol.2002; 2:46-53.
[22]Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+CD25-naive T cells to CD4+CD25+regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med.2003; 198:1875-1886.
[23]Li MO, Wan YY, Sanjabi S, et al. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol.2006; 24:99-146.
[24]Malik R, Selden C, Hodgson H. The role of non-parenchymal cells in liver growth. Semin Cell Dev Biol.2002; 13:425-431.
[25]Kita Y, Iwaki Y, Demetris AJ, et al. Evaluation of sequential serum interleukin-6 levels in liver allograft recipients. Transplantation.1994; 57:1037-1041.
[26]Warle MC, Metselaar HJ, Hop WC, et al. Early differentiation between rejection and infection in liver transplant patients by serum and biliary cytokine patterns. Transplantation.2003; 75:146-151.
[27]Yang XO, Panopoulos A D, Nurieva R et al. STATS ragulales cytokine mediated generation of inflammatorv help T cells. J Biol Chem.2007; 282:358-363.
[28]Zhou L, IvaJlov II, Spolskj R et al. IL-6 programs T(H)-17 cell diffrentiation by. promoting sequential engagenment of the IL-21 andIL-23 pathways. J. nat lmunol. 2007; 8:967-974.
[29]Graham JM. Fractionation of hepatic nonparenchymal cells. Scientific World Journal.2002; 2:1347-1350.
[30]Hardonk MJ, Dijkhuis FWJ, Hulstaert CE, et al. Heterogeneity of Rat-Liver and Spleen Macrophages in Gadolinium Chloride-Induced Elimination and Repopulation. Journal of Leukocyte Biology.1992; 52:296-302.
[31]Kolios G, Valatas V, Kouroumalis E. Role of Kupffer cells in the pathogenesis of liver disease. World Journal of Gastroenterology.2006; 12:7413-7420.
[32]Otto C, Kauczok J, Martens N, et al. Mechanisms of tolerance induction after rat liver transplantation:intrahepatic CD4(+) T cells produce different cytokines during rejection and tolerance in response to stimulation. J Gastrointest Surg.2002; 6:455-463.
[1]Lechler RI, Sykes M, Thomson AW, et al. Organ transplantation--how much of the promise has been realized? Nat Med.2005; 11:605-613.
[2]Xiang Z, Ma LL, Manicassamy S, et al. CD4+ T cells are sufficient to elicit allograft rejection and major histocompatibility complex class Ⅰ molecule is required to induce recurrent autoimmune diabetes after pancreas transplantation in mice. Transplantation.2008; 85:1205-1211.
[3]Nelms K, Keegan AD, Zamorano J, et al. The IL-4 receptor:signaling mechanisms and biologic functions. Annu Rev Immunol.1999; 17:701-738.
[4]Gately MK, Renzetti LM, Magram J, et al. The interleukin-12/interleukin-12-receptor system:role in normal and pathologic immune responses. Annu Rev Immunol.1998; 16:495-521.
[5]Szabo SJ, Kim ST, Costa GL, et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell.2000; 100:655-669.
[6]Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell.1997; 89:587-596.
[7]Wadia PP, Tambur AR. Yin and yang of cytokine regulation in solid organ graft rejection and tolerance. Clin Lab Med.2008; 28:469-479.
[8]Tesmer L A, Lundy S K, Sarkar S, et al. Th17 cells in human disease. Immunol Rev.2008; 223:87-113.
[9]Constantinescu CS, Wysocka M, Hilliard B, et al. Antibodies against IL-12 prevent superantigen-induced and spontaneous relapses of experimental autoimmune encephalomyelitis. J Immunol.1998; 161:5097-5104.
[10]Leonard JP, Waldburger KE, Goldman SJ. Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin-12. Journal of experimential medicine.1995; 181:381-386.
[11]Segal BM, Shevach EM. The innate immune system controls susceptibility to experimental allergic encephalomyelitis (EAE) by regulating the interleukin (IL)-12/IL-10 balance. Faseb Journal.1998; 12:A1099-A1099.
[12]Cua D J, Sherlock J, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature.2003; 421: 744-748.
[13]Oppmann B, Lesley R, Blom B et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000; 13:715-25.
[14]Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenie T cell population that induces autoimmune inflammation. Exp Med.2005; 201:233-240.
[15]Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a liesge distinct from the T helper type 1 and lineages. Nat Immunol.2005; 6:1123-1132.
[16]Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulares tissue inflammation by producing interleukin 17. Nat Immunol.2005; 6:1133-1141.
[17]Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med.2005; 201: 233-240.
[18]Thakker P, Leach MW. Kuang W, et al. IL-23 is critical in the induction but not in the effector phase of experimental autoimmune encephalomyelitis. J Immunol. 2007; 178:2589-2598.
[19]Veldhoen M. Hocking RJ, Flavell RA, et al. Signals medated by transforming growth factor beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat Immunol.2006; 7:1151-1156.
[20]Paul R. Mangan, Laurie E. Harrington, Darrell B. O'Quinn, et al. Transforming growth factor-b induces development of the TH17 lineage, Nat Immunol.2006; 441-449.
[21]Veldhoen M, Hocking RJ, Atkins CJ, et al. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity.2006; 24:179-189.
[22]Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+CD25-naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med.2003; 198:1875-1886.
[23]Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector Th17 and regulatory cells. Nature.2006; 441: 235-238.
[24]Nurieva R, Yang XO, Martinez G, et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature.2007; 448:480-483
[25]Wan S, Xia C, Morel L. IL-6 produced by dendritic cells from lupus-prone mice inhibits CD4+CD25+T cell regulatory functions. J Immunol.2007; 178:271-279.
[26]Kimura A, Naka T, Kishimoto T. et al. IL-6-dependent and-independent pathways in the development of interleukin 17-producing T helper cells. Proc Natl Acad Sci USA.2007; 104:12099-12104.
,[27] Nambu A, Nakae S. IL-1 and Allergy. Allergol Int.2010; 59:125.-135.
[28]Benwell RK, Lee DR. Essential and synergistic roles of IL1 and IL6 in human Thl7 differentiation directed by TLR ligand-activated dendritic cells. Clin Immunol.2010; 134:178-187.
[29]Korn T, Bettelli E, Gao W, et al. IL-21 initiates an alternate pathway to induce proinflammatory Th17 cells. Nature.2007; 448:484-487..
[30]Ivanov II, McKenzie BS, Zhou L et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 2006; 126:1121-33.
[31]Eberl G, Littman DR. Thymic origin of intestinal alphabeta T cells revealed by fate mapping of ROR gammat+cells. Science.2004; 305:248-251.
[32]Yang XO, Panopoulos AD, Nurieva R et al. STAT3 ragulales cytokine mediated generation of inflammatorv help T cells. J Biol Chem.2007; 282:358-363.
[33]Zhou L, IvaJlov II, Spolskj R et al. IL-6 programs T(H)-17 cell diffrentiation by promoting sequential engagenment of the IL-21 andIL-23 pathways. J. nat lmunol. 2007; 8:967-974.
[34]Harrington LE, Hatton RD, Mangan PR. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol.2005; 6:1123-1132.
[35]Laurence A, Tato C M, Davidson T S, et al. Interleukin-2 Signaling via STAT5 Constrains T Helper 17 Cell Generation. Immunity.2007; 26:371-381.
[36]Batten M, Li J, Yi S, et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat Immuno. 2006; 7:929-936.
[37]Kleinschek MA, Owyang AM, Joyce-Shaikh B, et al. IL-25 regulates Thl7 function in autoimmune inflammation. JEM.2007; 204:161-170.
[38]Moseley TA, Haudenschild DR, Rose L, et al. Interleukin-17 family and IL-17 receptors. Cytokine growth Factor Rev.2003; 14:155-174.
[39]Ferretti S, Bonneau O, Dubois GR, et al. IL-17, produced by lymphocytes and neutrophils, is necessary for lipopolysaccharide-induced airway neutrophilia:IL-15 as a possible trigger. J Immunol.2003; 170:2106-2112.
[40]Lockhart E, Green AM, Flynn J L. IL-17 production is dominated by gammadelta T cells rather than CD4 T cells during Mycobacterium tuberculosis infection. J Immunol.2006; 177:4662-4669.
[41]Shin HC, Benbernou N, Esnault S, et al. Expression of IL-17 in human memory CD45RO+ T lymphocytes and its regulation by protein kinase A pathway. Cytokine.1999; 11:257-266.
[42]Molet S, Hamid Q, Davoine F et al. IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J Allergy Clin Immunol. 2001; 108:430-438.
[43]Zhou Q, Desta T, Fenton M, et al. Cytokine profiling of macrophages exposed to Porphyromonas gingivalis. its lipopolysaccharide, or its FimA protein. Infect Immun.2005; 73:935-943.
[44]Ye P, Garvey PB, Zhang P, et al. Interleukin-17 and lung host defense against Klebsiella pneumoniae infection. Am J Respir Cell Mol Biol,2001;25:335-340.
[45]Khader SA, Cooper AM. IL-23 and IL-17 in tuberculosis. Cytokine,2008,.41: 79-83
[46]Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity. 2004; 21:467-476.
[47]Hata K, Andoh A, Shimada M, et al. IL-17 stimulates inflammatory responses via NF-kappaB and MAP kinase pathways in human colonic myofibroblasts. Am J Physiol Gastrointest Liver Physiol.2002; 282:G1035-1044.
[48]Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity, 2004; 21:467-476
[49]Kawaguchi M, Kokubu F, Kuga H, et al. Modulation of bronchial epithelial cells by IL-17. J Allergy Clin Immunol.2001; 108:804-809.
[50]Chang SH, Dong C.A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses. Cell research.2007; 17:435-440.
[51]Li H, Chen J, Huang A, et al. Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 cytokine family. Proc Natl Acad Sci U S A.2000; 97:773-778.
[52]Zenewicz LA, Yancopoulos GD, Valenzuela DM, et al. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity.2007; 27; 177:26-35.
[53]Ramadori G, Meyer zum Buschenfelde KH. The acute phase reaction and its mediators. II:Alpha tumor necrosis factor and interleukin-6. Z Gastroenterol.1990; 28:14-21.
[54]Xiang Z, Ma LL, Manicassamy S, et al. CD4+ T cells are sufficient to elicit allograft rejection and major histocompatibility complex class I molecule is required to induce recurrent autoimmune diabetes after pancreas transplantation in mice. Transplantation.2008; 85:1205-1211.
[55]Zelenika D, Adams E, Humm S, et al. The role of CD4+ T-cell subsets in determining transplantation rejection or tolerance. Immunol Rev.2001; 182: 164-179.
[56]Saiura A, Mataki C, Murakami T, et al. A comparison of gene expression in murine cardiac allografts and isografts by means DNA microarray analysis. Transplantation.2001; 72:320-329.
[57]Obata F, Yoshida K, Ohkubo M, et al. Contribution of CD4+ and CD8+ T cells and interferon-gamma to the progress of chronic rejection of kidney allografts:the Th1 response mediates both acute and chronic rejection. Transpl Immunol.2005; 14: 21-25.
[58]Halloran PF, Miller LW, Urmson J, et al. IFN-gamma alters the pathology of graft rejection:protection from early necrosis.J Immunol.2001; 166:7072-7081.
[59]Miura M, El-Sawy T, Fairchild RL. Neutrophils mediate parenchymal tissue necrosis and accelerate the rejection of complete major histocompatibility complex-disparate cardiac allografts in the absence of interferon-gamma.Am J Pathol.2003; 162:509-519.
[60]Li XC, Zheng XX, Strom TB. T-cell growth factors in allograft rejection and tolerance. Transplant Proc 1999; 31:342-343.
[61]Smith XG, Bolton EM, Ruchatz H, et al. Selective blockade of IL-15 by soluble IL-15 receptor alpha-chain enhances cardiac allograft survival. J Immunol 2000; 165:3444-3450.
[62]Gorbacheva V, Fan R, Li X, et al. Interleukin-17 promotes early allograft inflammation. Am J Pathol.2010; 177:1265-1273.
[63]Tang JL, Subbotin VM, Antonysamy MA, et al. Interleukin-17 antagonism inhibits acute but not chronic vascular rejection. Transplantation.2001; 72:348-350.
[64]Antonysamy MA, Fanslow WC, Fu F, et al. Evidence for a role of IL-17 in organ allograft rejection:IL-17 promotes the functional differentiation of dendritic cell progenitors. J Immunol.1999; 162:577-584.
[65]Hsieh HG, Loong CC, Lui WY, et al. IL-17 expression as a possible predictive parameter for subclinical renal allograft rejection. Transpl Int.2001; 14:287-298.
[66]Loong CC, Hsieh HG, Lui WY, et al. Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection. J Pathol.2002; 197:322-332.
[67]Verleden GM, Vos R, Vanaudenaerde BM, et al. Interleukin-17 and neutrophils are increased in BAL fluid during acute lung rejection. Chest.2007; 131:1988-1989;.
[68]Yoshida S, Haque A, Mizobuchi T, et al. Anti-type V collagen lymphocytes that express IL-17 and IL-23 induce rejection pathology in fresh and well-healed lung transplants.Am J Transplant.2006; 6:724-735.
[69]Chen H, Wang W, Xie H, et al.A pathogenic role of IL-17 at the early stage of corneal allograft rejection. Transpl Immunol.2009; 21:155-161.
[70]Fabrega E, Lopez-Hoyos M, San Segundo D, et al. Changes in the serum levels of interleukin-17/interleukin-23 during acute rejection in liver transplantation. Liver Transpl.2009; 15:629-633.
[71]Tang JL, Subbotin VM, Antonysamy MA, et al. Interleukin-17 antagonism inhibits acute but not chronic vascular rejection. Transplantation.2001; 72:348-350.
[72]Paul LC. New insights in chronic allograft rejection.Curr Opin Urol.2002; 12: 89-93.
[73]Yuan X, Paez-Cortez J, Schmitt-Knosalla I, et al. A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy. J Exp Med.2008; 205: 3133-3144.
[74]Itoh S, Nakae S, Axtell RC, et al. IL-17 contributes to the development of chronic rejection in a murine heart transplant model. J Clin Immunol.2010; 30:235-240.
[75]Divella C, Rossini M, Loverre A, et al. Immunohistochemical characterization of glomerular and tubulointerstitial infiltrates in renal transplant patients with chronic allograft dysfunction. Nephrol Dial Transplant.2010; 25:4071-4077.
[76]San Segundo D, Lopez-Hoyos M, Fernandez-Fresnedo G, et al. T(H)17 versus Treg cells in renal transplant candidates:effect of a previous transplant. Transplant Proc. 2008; 40:2885-2888.
[77]Wuyts WA, Vanaudenaerde BM, Dupont LJ, et al. Interleukin-17--induced interleukin-8 release in human airway smooth muscle cells:role for mitogen-activated kinases and nuclear factor-kappaB. J Heart Lung Transplant. 2005; 24:875-881.
[78]Vanaudenaerde BM, Wuyts WA, Dupont LJ, et al. Interleukin-17 stimulates release of interleukin-8 by human airway smooth muscle cells in vitro:a potential role for interleukin-17 and airway smooth muscle cells in bronchiolitis obliterans syndrome. J Heart Lung Transplant.2003; 22:1280-1283.
[79]Dor FJ, Gollackner B, Cooper DK.Can spleen transplantation induce tolerance? A review of the literature. Transpl Int.2003; 16:451-460.
[80]Higgins MJ, Blackall DP. Transfusion-associated graft-versus-host disease:a serious residual risk of blood transfusion.Curr Hematol Rep.2005; 4:470-476.
[81]Andres AM, Santamaria ML, Ramos E, et al. Graft-vs-host disease after small bowel transplantation in children. J Pediatr Surg.2010; 45:330-336.
[82]Xue F, Chen W, Wang XG, et al.Establishment of an acute graft-versus-host disease model following liver transplantation in donor-dominant one-way major histocompatibility complex matching rats.Transplant Proc.2009; 41:1914-1920.
[83]Kato T, Yazawa K, Madono K, et al.Acute graft-versus-host-disease in kidney transplantation:case report and review of literature. Transplant Proc.2009; 41: 3949-3952.
[84]Ichiki Y, Bowlus CL, Shimoda S, et al. T cell immunity and graft-versus-host disease (GVHD). Autoimmun Rev.2006; 5:1-9.
[85]Choi S, Reddy P.Graft-versus-host disease. Panminerva Med.2010;52(2):111-24.
[86]Jaksch M, Mattsson J.The pathophysiology of acute graft-versus-host disease. Scand J Immunol.2005; 61:398-409.
[87]Krenger W, Ferrara JL. Graft-versus-host disease and the Th1/Th2 paradigm. Immunol Res.1996; 15:50-73.
[88]Yang YG, Dey BR, Sergio JJ, et al. Donor-derived interferon gamma is required for inhibition of acute graft-versus-host disease by interleukin 12. J Clin Invest 1998; 102:2126-2135.
[89]Yang YG, Qi J, Wang MG, et al. Donor-derived interferon gamma separates graft-versus-leukemia effects and graft-versus-host disease induced by donor CD8 T cells. Blood 2002; 99:4207-4215.
[90]Burman AC, Banovic TD, Kuns RD, et al. IFN{gamma} differentially controls the development of idiopathic pneumonia syndrome and GVHD of the gastrointestinal tract. Blood 2007; 110:1064-1072.
[91]Yi T, Chen Y, Wang L, et al. Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease.Blood.2009; 114:3101-3112.
[92]Yi T, Zhao D, Lin CL, et al. Absence of donor Th17 leads to augmented Thl differentiation and exacerbated acute graft-versus-host disease. Blood.2008; CD4+112:2101-2110.
[93]Kappel LW, Goldberg GL, King CG, et al. IL-17 contributes to CD4-mediated graft-versus-host disease.Blood.2009; 113:945-952.
[94]Ratajczak P, Janin A, Peffault de Latour R, et al. Th17/Treg ratio in human graft-versus-host disease. Blood.2010; 116:1165-1171.
[95]Carlson MJ, West ML, Coghill JM, et al. In vitro-differentiated TH17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations.Blood.2009; 113:1365-1374.
[2]Reiner SL. Development in motion:helper T cells at work. Cell.2007; 129:33-36.
[3]Wadia PP, Tambur AR. Yin and yang of cytokine regulation in solid organ graft rejection and tolerance. Clin Lab Med.2008; 28:469-479.
[4]Bettelli E, Korn T, Kuchroo VK. Thl7:the third member of the effector T cell trilogy. Curr Opin Immunol.2007; 19:652-657.
[5]Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity. 2004; 21:467-476.
[6]Fossiez F, Djossou O, Chomarat P, et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med.1996; 183: 2593-2603.
[7]Tesmer LA, Lundy SK, Sarkar S, et al. Th17 cells in human disease. Immunol Rev. 2008; 223:87-113.
[8]Loong CC, Hsieh HG, Lui WY, et al. Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection. J Pathol.2002; 197:322-332.
[9]Vanaudenaerde BM, De Vleeschauwer SI, Vos R, et al. The role of the IL23/IL17 axis in bronchiolitis obliterans syndrome after lung transplantation. Am J Transplant.2008; 8:1911-1920.
[10]Chen H, Wang W, Xie H, et al. A pathogenic role of IL-17 at the early stage of corneal allograft rejection. Transpl Immunol.2009; 21:155-161.
[11]Yuan X, Paez-Cortez J, Schmitt-Knosalla I, et al. A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy. J Exp Med.2008; 205: 3133-3144.
[12]Antonysamy MA. Fanslow WC, Fu F, et al. Evidence for a role of IL-17 in organ allograft rejection:IL-17 promotes the functional differentiation of dendritic cell progenitors. J Immunol.1999; 162:577-584.
[13]Fabrega E, Lopez-Hoyos M. San Segundo D, et al. Changes in the serum levels of interleukin-17/interleukin-23 during acute rejection in liver transplantation. Liver Transpl.2009; 15:629-633.
[14]Kolios G, Valatas V, Kouroumalis E. Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol.2006; 12:7413-7420.
[15]Knolle PA, Gerken G. Local control of the immune response in the liver. Immunol Rev.2000; 174:21-34.
[16]Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature.2006; 441: 235-238.
[17]Veldhoen M, Hocking RJ, Flavell RA, et al. Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat Immunol.2006; 7:1151-1156.
[18]Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+T helper cells. Cell. 2006; 126:1121-1133.
[19]Bouwens L, Baekeland M, De Zanger R, et al. Quantitation, tissue distribution and proliferation kinetics of Kupffer cells in normal rat liver. Hepatology.1986; 6: 718-722.
[20]Sun Z, Wada T, Maemura K, et al. Hepatic allograft-derived Kupffer cells regulate T cell response in rats. Liver Transpl.2003; 9:489-497.
[21]Hanschen M, Zahler S, Krombach F, et al. Reciprocal activation between CD4(+) T cells and Kupffer cells during hepatic ischemia-reperfusion. Transplantation. 2008; 86:710-718.
[1]Xiang Z, Ma LL, Manicassamy S, et al. CD4+ T cells are sufficient to elicit allograft rejection and major histocompatibility complex class I molecule is required to induce recurrent autoimmune diabetes after pancreas transplantation in mice. Transplantation.2008; 85:1205-1211.
[2]Reiner SL. Development in motion:helper T cells at work. Cell.2007; 129:33-36.
[3]Wadia PP, Tambur AR. Yin and yang of cytokine regulation in solid organ graft rejection and tolerance. Clin Lab Med.2008; 28:469-479.
[4]Saiura A, Mataki C, Murakami T, et al. A comparison of gene expression in murine cardiac allografts and isografts by means DNA microarray analysis. Transplantation.2001; 72:320-329.
[5]Obata F, Yoshida K, Ohkubo M, et al. Contribution of CD4+ and CD8+T cells and interferon-gamma to the progress of chronic rejection of kidney allografts:the Th1 response mediates both acute and chronic rejection. Transpl Immunol.2005; 14: 21-25.
[6]Halloran PF, Miller LW, Urmson J, et al. IFN-gamma alters the pathology of graft rejection:protection from early necrosis. J Immunol.2001; 166:7072-7081.
[7]Miura M, El-Sawy T, Fairchild RL. Neutrophils mediate parenchymal tissue necrosis and accelerate the rejection of complete major histocompatibility complex-disparate cardiac allografts in the absence of interferon-gamma. Am J Pathol.2003; 162:509-519.
[8]Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol.2005; 6:1123-1132.
[9]Bettelli E, Korn T, Kuchroo VK. Th17:the third member of the effector T cell trilogy. Curr Opin Immunol.2007; 19:652-657.
[10]Tesmer LA, Lundy SK, Sarkar S, et al. Th17 cells in human disease. Immunol Rev. 2008; 223:87-113.
[11]Loong CC, Hsieh HG, Lui WY, et al. Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection. J Pathol.2002; 197:322-332.
[12]Vanaudenaerde BM, De Vleeschauwer SI, Vos R, et al. The role of the IL23/IL17 axis in bronchiolitis obliterans syndrome after lung transplantation. Am J Transplant.2008; 8:1911-1920.
[13]Chen H, Wang W, Xie H, et al. A pathogenic role of IL-17 at the early stage of corneal allograft rejection. Transpl Immunol.2009; 21:155-161.
[14]Yuan X, Paez-Cortez J, Schmitt-Knosalla I, et al. Anovel role of CD4 Thl7 cells in mediating cardiac allograft rejection and vasculopathy. J Exp Med.2008; 205: 3133-3144.
[15]Antonysamy MA, Fanslow WC, Fu F, et al. Evidence for a role of IL-17 in organ allograft rejection:IL-17 promotes the functional differentiation of dendritic cell progenitors. J Immunol.1999; 162:577-584.
[16]Fabrega E, Lopez-Hoyos M, San Segundo D, et al. Changes in the serum levels of interleukin-17/interleukin-23 during acute rejection in liver transplantation. Liver Transpl.2009; 15:629-633.
[17]Kamada N, Calne RY. Orthotopic liver transplantation in the rat. Technique using cuff for portal vein anastomosis and biliary drainage. Transplantation.1979; 28: 47-50.
[18]Banff schema for grading liver allograft rejection:an international consensus document. Hepatology.1997; 25:658-663.
[19]Weaver CT, Hatton RD, Mangan PR, et al. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol.2007; 25: 821-852.
[20]Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity. 2004; 21:467-476.
[21]Kishimoto T. The biology of interleukin-6. Blood.1989; 74:1-10.
[22]Kita Y, Iwaki Y, Demetris AJ, et al. Evaluation of sequential serum interleukin-6 levels in liver allograft recipients. Transplantation.1994; 57:1037-1041.
[23]Warle MC, Metselaar HJ, Hop WC, et al. Early differentiation between rejection and infection in liver transplant patients by serum and biliary cytokine patterns. Transplantation.2003; 75:146-151.
[24]Chen L, Ahmed E, Wang T, et al. TLR signals promote IL-6/IL-17-dependent transplant rejection. J Immunol.2009:182:6217-6225.
[25]Laan M, Cui ZH, Hoshino H, et al. Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways. J Immunol.1999; 162:2347-2352.
[26]Prause O, Laan M,. Lotvall J, et al..Pharmacological modulation of interleukin-17-induced GCP-2-, GRO-alpha-and interleukin-8 release in human bronchial epithelial cells. Eur J Pharmacol.2003; 462:193-198.
[27]Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature.2006; 441: 235-238.
[28]Mangan PR, Harrington LE, O'Quinn DB, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature.2006; 441:231-234.
[29]Li MO, Wan YY, Sanjabi S, et al. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol.2006; 24:99-146.
[30]Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+CD25-naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med.2003; 198:1875-1886.
[31]Malik R, Selden C, Hodgson H. The role of non-parenchymal cells in liver growth. Semin Cell Dev Biol.2002; 13:425-431.
[32]Yasumi Y, Takikawa Y. Endo R, et al. Interleukin-17 as a new marker of severity of acute hepatic injury. Hepatology Research.2007; 37:248-254.
[33]Zhang JY, Zhang Z, Lin F, et al. Interleukin-17-Producing CD4(+) T Cells Increase with Severity of Liver Damage in Patients with Chronic Hepatitis B. Hepatology. 2010; 51:81-91.
[34]Lan RYZ, Salunga TL, Tsuneyama K, et al. Hepatic IL-17 responses in human and murine primary biliary cirrhosis. Journal of Autoimmunity.2009; 32:43-51.
[35]Lemmers A, Moreno C, Gustot T, et al. The Interleukin-17 Pathway Is Involved in Human Alcoholic Liver Disease. Hepatology.2009; 49:646-657.
[36]Rutitzky LI, Bazzone L. Shainheit MG, et al. IL-23 is required for the development of severe egg-induced immunopathology in schistosomiasis and for lesional expression of IL-17. Journal of Immunology.2008; 180:2486-2495.
[37]Zhang JP, Yan J, Xu J, et al. Increased intratumoral IL-17-producing cells survival in hepatocellular carcinoma correlate with poor patients. Journal of Hepatology. 2009; 50:980-989.
[38]Stritesky GL, Yeh N, Kaplan MH. IL-23 promotes maintenance but not commitment to the Th17 lineage. J Immunol.2008; 181:5948-5955.
[39]Nurieva R, Yang XO, Martinez G, et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature.2007; 448:480-483.
[40]Ivanov, Ⅱ, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006; 126:1121-1133.
[1]Bouwens L, Baekeland M, De Zanger R, et al. Quantitation, tissue distribution and proliferation kinetics of Kupffer cells in normal rat liver. Hepatology.1986; 6: 718-722.
[2]Winwood PJ, Arthur MJ. Kupffer cells:their activation and role in animal models of liver injury and human liver disease. Semin Liver Dis.1993; 13:50-59.
[3]Kolios G, Valatas V. Kouroumalis E. Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol.2006; 12:7413-7420.
[4]Savier E, Lemasters JJ, Thurman RG. Kupffer cells participate in rejection following liver transplantation in the rat. Transpl Int.1994; 7 Suppl 1:S183-186.
[5]von Frankenberg M, Golling M, Mehrabi A, et al. Donor pretreatment with gadolinium chloride improves early graft function and survival after porcine liver transplantation. Transpl Int.2003; 16:806-813.
[6]Imamura H, Laberge S, Brault A, et al. Immunogenic role of Kupffer cells in a rat model of acute liver allograft rejection. Liver Transpl Surg.1995; 1:389-394.
[7]Chen Y, Liu ZJ, Liang SY, et al. Role of Kupffer cells in the induction of tolerance of orthotopic liver transplantation in rats. Liver Transplantation.2008; 14: 823-836.
[8]Sun ZL, Wada T, Maemura K, et al. Hepatic allograft-derived Kupffer cells regulate T cell response in rats. Liver Transplantation.2003; 9:489-497.
[9]Lee CM, Yeoh GC, Olynyk JK. Differential effects of gadolinium chloride on Kupffer cells in vivo and in vitro. Int J Biochem Cell Biol.2004; 36:481-488.
[10]Ferreira J, Tapia G, Videla LA. Effects of the Kupffer cell inactivator gadolinium chloride on rat liver oxygen uptake and content of mitochondrial cytochromes. FEBS Lett.1998; 426:263-265.
[11]Kamada N. Genetics of liver graft rejection in the rat. Experimental Liver Transplantation. Boca Raton, FL, CRC Press,1988, pp 55-66
[12]Demetris AJ, Qian S, Sun H, et al. Early events in liver allograft rejection. Delineation of sites of simultaneous intragraft and recipient lymphoid tissue sensitization. Am J Pathol.1991; 138:609-618.
[13]Kamada N, Calne RY Orthotopic liver transplantation in the rat. Technique using cuff for portal vein anastomosis and biliary drainage. Transplantation.1979; 28: 47-50.
[14]Banff schema for grading liver allograft rejection:an international consensus document. Hepatology.1997; 25:658-663.
[15]Pirenne J, Gunson B, Khaleef H, et al. Influence of ischemia-reperfusion injury on rejection after liver transplantation. Transplant Proc.1997; 29:366-367.
[16]Winwood PJ, Arthur MJ. Kupffer cells:their activation and role in animal models of liver injury and human liver disease. Semin Liver Dis.1993; 13:50-59.
[17]Hanschen M, Zahler S, Krombach F. et al. Reciprocal activation between CD4+ T cells and Kupffer cells during hepatic ischemia-reperfusion. Transplantation.2008; 86:710-718.
[18]Giakoustidis DE, Iliadis S, Tsantilas D, et al. Blockade of Kupffer cells by gadolinium chloride reduces lipid peroxidation and protects liver from ischemia/reperfusion injury. Hepatogastroenterology.2003; 50:1587-1592.
[19]Shiratori Y, Kiriyama H, Fukushi Y, et al. Modulation of Ischemia-Reperfusion-Induced Hepatic-Injury by Kupffer Cells. Digestive Diseases and Sciences.1994; 39:1265-1272.
[20]Rogoff TM, Lipsky PE. Role of the Kupffer cells in local and systemic immune responses. Gastroenterology.1981; 80:854-860.
[21]Settaf A, Milton AD, Spencer SC, et al. Donor class I and class II major histocompatibility complex antigen expression following liver allografting in rejecting and nonrejecting rat strain combinations. Transplantation.1988; 46: 32-40.
[22]Gouw AS, Houthoff HJ, Huitema S, et al. Expression of major histocompatibility complex antigens and replacement of donor cells by recipient ones in human liver grafts. Transplantation.1987; 43:291-296.
[23]Kwekkeboom J, Kuijpers MA, Bruyneel B, et al. Expression of CD80 on Kupffer cells is enhanced in cadaveric liver transplants. Clin Exp Immunol.2003; 132: 345-351.
[24]Lohse AW, Knolle PA, Bilo K, et al. Antigen-presenting function and B7 expression of murine sinusoidal endothelial cells and Kupffer cells. Gastroenterology.1996; 110:1175-1181.
[25]Xiang Z, Ma LL, Manicassamy S, et al. CD4+ T cells are sufficient to elicit allograft rejection and major histocompatibility complex class I molecule is required to induce recurrent autoimmune diabetes after pancreas transplantation in mice. Transplantation.2008; 85:1205-1211.
[26]Reiner SL. Development in motion:helper T cells at work. Cell.2007; 129:33-36.
[27]Wadia PP, Tambur AR. Yin and yang of cytokine regulation in solid organ graft rejection and tolerance. Clin Lab Med.2008; 28:469-479.
[28]Cavaillon JM. Cytokines and macrophages. Biomed Pharmacother.1994; 48: 445-453.
[29]Krohn N, Kapoor S, Enami Y, et al. Hepatocyte transplantation-induced liver inflammation is driven by cytokines-chemokines associated with neutrophils and Kupffer cells. Gastroenterology.2009; 136:1806-1817.
[30]Nagaki M, Moriwaki H. Implication of cytokines:Roles of tumor necrosis factor-alpha in liver injury. Hepatol Res.2008; 38:S19-S28.
[31]Hardonk MJ, Dijkhuis FWJ, Hulstaert CE, et al. Heterogeneity of Rat-Liver and Spleen Macrophages in Gadolinium Chloride-Induced Elimination and Repopulation. Journal of Leukocyte Biology.1992; 52:296-302.
[32]Sun Z, Wada T, Uchikura K, et al. Role of Fas/Fasl in Kupffer cell-dependent deletion of alloantigen activated T cells following liver transplantation. Transplant Proc.2001; 33:279-282.
[33]Miyagawa-Hayashino A, Tsuruyama T, Egawa H, et al. FasL expression in hepatic antigen-presenting cells and phagocytosis of apoptotic T cells by FasL+Kupffer cells are indicators of rejection activity in human liver allografts. Am J Pathol. 2007; 171:1499-1508.
[1]Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol.2005; 6:1123-1132.
[2]Bettelli E, Korn T, Kuchroo VK. Th17:the third member of the effector T cell trilogy. Curr Opin Immunol.2007; 19:652-657.
[3]Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector Thl7 and regulatory cells. Nature.2006; 441: 235-238.
[4]Khayrullina T, Yen JH, Jing H, et al. In vitro differentiation of dendritic cells in the presence of prostaglandin E2 alters the IL-12/IL-23 balance and promotes differentiation of Th17 cells. J Immunol.2008; 181:721-735.
[5]Wang Q, Liu C, Zhu F, et al. Reoxygenation of hypoxia-differentiated dentritic cells induces Thl and Th17 cell differentiation. Mol Immunol.2010; 47:922-931.
[6]Bouwens L, De Bleser P, Vanderkerken K, et al. Liver cell heterogeneity:functions of non-parenchymal cells.1992; 46:155-168.
[7]Bouwens L, Baekeland M, De Zanger R, et al. Quantitation, tissue distribution and proliferation kinetics of Kupffer cells in normal rat liver. Hepatology.1986; 6: 718-722.
[8]Decker K. The response of liver macrophages to inflammatory stimulation. Keio J Med.1998; 47:1-9.
[9]Sun Z, Wada T, Maemura K, et al. Hepatic allograft-derived Kupffer cells regulate T cell response in rats. Liver Transpl.2003; 9:489-497.
[10]Hanschen M, Zahler S. Krombach F, et al. Reciprocal activation between CD4+T cells and Kupffer cells during hepatic ischemia-reperfusion. Transplantation.2008; 86:710-718.
[11]Morita A, Itoh Y, Toyama T, et al. Activated Kupffer cells play an important role in intra-hepatic Thl-associated necro-inflammation in Concanavalin A-induced hepatic injury in mice. Hepatol Res.2003; 27:143-50.
[12]Wiegard C, Frenzel C, Herkel.J, et al. Murine liver antigen presenting cells control suppressor activity of CD4+CD25+ regulatory T cells. Hepatology.2005; 42: 193-199.
[13]Ge X, Nowak G, Ericzon BG, et al. Liver sinusoidal endothelial cell function in rejected and spontaneously accepted rat liver allografts. Transpl Int.2008; 21: 49-56.
[14]Jiang G, Yang HR, Wang L, et al. Hepatic stellate cells preferentially expand allogeneic CD4+ CD25+ FoxP3+ regulatory T cells in an IL-2-dependent manner. Transplantation.2008; 86:1492-1502.
[15]Dienes HP, Drebber U. Pathology of immune-mediated liver injury. Dig Dis.2010; 28:57-62.
[16]Sumpter TL, Lunz JG,3rd, Castellaneta A, et al. Dendritic cell immunobiology in relation to liver transplant outcome. Front Biosci (Elite Ed).2009; 1:99-114.
[17]Kamada N, Calne RY. Orthotopic liver transplantation in the rat. Technique using cuff for portal vein anastomosis and biliary drainage. Transplantation.1979; 28: 47-50.
[18]Kawada N, Seki S, Inoue M, et al. Effect of antioxidants, resveratrol, quercetin, and N-acetylcysteine, on the functions of cultured rat hepatic stellate cells and Kupffer cells. Hepatology.1998; 27:1265-1274.
[19]Luettig B, Pape L, Bode U, et al. Naive and memory T lymphocytes migrate in comparable numbers through normal rat liver:activated T cells accumulate in the periportal field. J Immunol.1999; 163:4300-4307.
[20]Lee CM, Yeoh GC, Olynyk JK. Differential effects of gadolinium chloride on Kupffer cells in vivo and in vitro. Int J Biochem Cell Biol.2004; 36:481-488.
[21]Gorelik L, Flavell RA. Transforming growth factor-beta in T-cell biology. Nat Rev Immunol.2002; 2:46-53.
[22]Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+CD25-naive T cells to CD4+CD25+regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med.2003; 198:1875-1886.
[23]Li MO, Wan YY, Sanjabi S, et al. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol.2006; 24:99-146.
[24]Malik R, Selden C, Hodgson H. The role of non-parenchymal cells in liver growth. Semin Cell Dev Biol.2002; 13:425-431.
[25]Kita Y, Iwaki Y, Demetris AJ, et al. Evaluation of sequential serum interleukin-6 levels in liver allograft recipients. Transplantation.1994; 57:1037-1041.
[26]Warle MC, Metselaar HJ, Hop WC, et al. Early differentiation between rejection and infection in liver transplant patients by serum and biliary cytokine patterns. Transplantation.2003; 75:146-151.
[27]Yang XO, Panopoulos A D, Nurieva R et al. STATS ragulales cytokine mediated generation of inflammatorv help T cells. J Biol Chem.2007; 282:358-363.
[28]Zhou L, IvaJlov II, Spolskj R et al. IL-6 programs T(H)-17 cell diffrentiation by. promoting sequential engagenment of the IL-21 andIL-23 pathways. J. nat lmunol. 2007; 8:967-974.
[29]Graham JM. Fractionation of hepatic nonparenchymal cells. Scientific World Journal.2002; 2:1347-1350.
[30]Hardonk MJ, Dijkhuis FWJ, Hulstaert CE, et al. Heterogeneity of Rat-Liver and Spleen Macrophages in Gadolinium Chloride-Induced Elimination and Repopulation. Journal of Leukocyte Biology.1992; 52:296-302.
[31]Kolios G, Valatas V, Kouroumalis E. Role of Kupffer cells in the pathogenesis of liver disease. World Journal of Gastroenterology.2006; 12:7413-7420.
[32]Otto C, Kauczok J, Martens N, et al. Mechanisms of tolerance induction after rat liver transplantation:intrahepatic CD4(+) T cells produce different cytokines during rejection and tolerance in response to stimulation. J Gastrointest Surg.2002; 6:455-463.
[1]Lechler RI, Sykes M, Thomson AW, et al. Organ transplantation--how much of the promise has been realized? Nat Med.2005; 11:605-613.
[2]Xiang Z, Ma LL, Manicassamy S, et al. CD4+ T cells are sufficient to elicit allograft rejection and major histocompatibility complex class Ⅰ molecule is required to induce recurrent autoimmune diabetes after pancreas transplantation in mice. Transplantation.2008; 85:1205-1211.
[3]Nelms K, Keegan AD, Zamorano J, et al. The IL-4 receptor:signaling mechanisms and biologic functions. Annu Rev Immunol.1999; 17:701-738.
[4]Gately MK, Renzetti LM, Magram J, et al. The interleukin-12/interleukin-12-receptor system:role in normal and pathologic immune responses. Annu Rev Immunol.1998; 16:495-521.
[5]Szabo SJ, Kim ST, Costa GL, et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell.2000; 100:655-669.
[6]Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell.1997; 89:587-596.
[7]Wadia PP, Tambur AR. Yin and yang of cytokine regulation in solid organ graft rejection and tolerance. Clin Lab Med.2008; 28:469-479.
[8]Tesmer L A, Lundy S K, Sarkar S, et al. Th17 cells in human disease. Immunol Rev.2008; 223:87-113.
[9]Constantinescu CS, Wysocka M, Hilliard B, et al. Antibodies against IL-12 prevent superantigen-induced and spontaneous relapses of experimental autoimmune encephalomyelitis. J Immunol.1998; 161:5097-5104.
[10]Leonard JP, Waldburger KE, Goldman SJ. Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin-12. Journal of experimential medicine.1995; 181:381-386.
[11]Segal BM, Shevach EM. The innate immune system controls susceptibility to experimental allergic encephalomyelitis (EAE) by regulating the interleukin (IL)-12/IL-10 balance. Faseb Journal.1998; 12:A1099-A1099.
[12]Cua D J, Sherlock J, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature.2003; 421: 744-748.
[13]Oppmann B, Lesley R, Blom B et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000; 13:715-25.
[14]Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenie T cell population that induces autoimmune inflammation. Exp Med.2005; 201:233-240.
[15]Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a liesge distinct from the T helper type 1 and lineages. Nat Immunol.2005; 6:1123-1132.
[16]Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulares tissue inflammation by producing interleukin 17. Nat Immunol.2005; 6:1133-1141.
[17]Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med.2005; 201: 233-240.
[18]Thakker P, Leach MW. Kuang W, et al. IL-23 is critical in the induction but not in the effector phase of experimental autoimmune encephalomyelitis. J Immunol. 2007; 178:2589-2598.
[19]Veldhoen M. Hocking RJ, Flavell RA, et al. Signals medated by transforming growth factor beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat Immunol.2006; 7:1151-1156.
[20]Paul R. Mangan, Laurie E. Harrington, Darrell B. O'Quinn, et al. Transforming growth factor-b induces development of the TH17 lineage, Nat Immunol.2006; 441-449.
[21]Veldhoen M, Hocking RJ, Atkins CJ, et al. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity.2006; 24:179-189.
[22]Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+CD25-naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med.2003; 198:1875-1886.
[23]Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector Th17 and regulatory cells. Nature.2006; 441: 235-238.
[24]Nurieva R, Yang XO, Martinez G, et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature.2007; 448:480-483
[25]Wan S, Xia C, Morel L. IL-6 produced by dendritic cells from lupus-prone mice inhibits CD4+CD25+T cell regulatory functions. J Immunol.2007; 178:271-279.
[26]Kimura A, Naka T, Kishimoto T. et al. IL-6-dependent and-independent pathways in the development of interleukin 17-producing T helper cells. Proc Natl Acad Sci USA.2007; 104:12099-12104.
,[27] Nambu A, Nakae S. IL-1 and Allergy. Allergol Int.2010; 59:125.-135.
[28]Benwell RK, Lee DR. Essential and synergistic roles of IL1 and IL6 in human Thl7 differentiation directed by TLR ligand-activated dendritic cells. Clin Immunol.2010; 134:178-187.
[29]Korn T, Bettelli E, Gao W, et al. IL-21 initiates an alternate pathway to induce proinflammatory Th17 cells. Nature.2007; 448:484-487..
[30]Ivanov II, McKenzie BS, Zhou L et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 2006; 126:1121-33.
[31]Eberl G, Littman DR. Thymic origin of intestinal alphabeta T cells revealed by fate mapping of ROR gammat+cells. Science.2004; 305:248-251.
[32]Yang XO, Panopoulos AD, Nurieva R et al. STAT3 ragulales cytokine mediated generation of inflammatorv help T cells. J Biol Chem.2007; 282:358-363.
[33]Zhou L, IvaJlov II, Spolskj R et al. IL-6 programs T(H)-17 cell diffrentiation by promoting sequential engagenment of the IL-21 andIL-23 pathways. J. nat lmunol. 2007; 8:967-974.
[34]Harrington LE, Hatton RD, Mangan PR. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol.2005; 6:1123-1132.
[35]Laurence A, Tato C M, Davidson T S, et al. Interleukin-2 Signaling via STAT5 Constrains T Helper 17 Cell Generation. Immunity.2007; 26:371-381.
[36]Batten M, Li J, Yi S, et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat Immuno. 2006; 7:929-936.
[37]Kleinschek MA, Owyang AM, Joyce-Shaikh B, et al. IL-25 regulates Thl7 function in autoimmune inflammation. JEM.2007; 204:161-170.
[38]Moseley TA, Haudenschild DR, Rose L, et al. Interleukin-17 family and IL-17 receptors. Cytokine growth Factor Rev.2003; 14:155-174.
[39]Ferretti S, Bonneau O, Dubois GR, et al. IL-17, produced by lymphocytes and neutrophils, is necessary for lipopolysaccharide-induced airway neutrophilia:IL-15 as a possible trigger. J Immunol.2003; 170:2106-2112.
[40]Lockhart E, Green AM, Flynn J L. IL-17 production is dominated by gammadelta T cells rather than CD4 T cells during Mycobacterium tuberculosis infection. J Immunol.2006; 177:4662-4669.
[41]Shin HC, Benbernou N, Esnault S, et al. Expression of IL-17 in human memory CD45RO+ T lymphocytes and its regulation by protein kinase A pathway. Cytokine.1999; 11:257-266.
[42]Molet S, Hamid Q, Davoine F et al. IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J Allergy Clin Immunol. 2001; 108:430-438.
[43]Zhou Q, Desta T, Fenton M, et al. Cytokine profiling of macrophages exposed to Porphyromonas gingivalis. its lipopolysaccharide, or its FimA protein. Infect Immun.2005; 73:935-943.
[44]Ye P, Garvey PB, Zhang P, et al. Interleukin-17 and lung host defense against Klebsiella pneumoniae infection. Am J Respir Cell Mol Biol,2001;25:335-340.
[45]Khader SA, Cooper AM. IL-23 and IL-17 in tuberculosis. Cytokine,2008,.41: 79-83
[46]Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity. 2004; 21:467-476.
[47]Hata K, Andoh A, Shimada M, et al. IL-17 stimulates inflammatory responses via NF-kappaB and MAP kinase pathways in human colonic myofibroblasts. Am J Physiol Gastrointest Liver Physiol.2002; 282:G1035-1044.
[48]Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity, 2004; 21:467-476
[49]Kawaguchi M, Kokubu F, Kuga H, et al. Modulation of bronchial epithelial cells by IL-17. J Allergy Clin Immunol.2001; 108:804-809.
[50]Chang SH, Dong C.A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses. Cell research.2007; 17:435-440.
[51]Li H, Chen J, Huang A, et al. Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 cytokine family. Proc Natl Acad Sci U S A.2000; 97:773-778.
[52]Zenewicz LA, Yancopoulos GD, Valenzuela DM, et al. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity.2007; 27; 177:26-35.
[53]Ramadori G, Meyer zum Buschenfelde KH. The acute phase reaction and its mediators. II:Alpha tumor necrosis factor and interleukin-6. Z Gastroenterol.1990; 28:14-21.
[54]Xiang Z, Ma LL, Manicassamy S, et al. CD4+ T cells are sufficient to elicit allograft rejection and major histocompatibility complex class I molecule is required to induce recurrent autoimmune diabetes after pancreas transplantation in mice. Transplantation.2008; 85:1205-1211.
[55]Zelenika D, Adams E, Humm S, et al. The role of CD4+ T-cell subsets in determining transplantation rejection or tolerance. Immunol Rev.2001; 182: 164-179.
[56]Saiura A, Mataki C, Murakami T, et al. A comparison of gene expression in murine cardiac allografts and isografts by means DNA microarray analysis. Transplantation.2001; 72:320-329.
[57]Obata F, Yoshida K, Ohkubo M, et al. Contribution of CD4+ and CD8+ T cells and interferon-gamma to the progress of chronic rejection of kidney allografts:the Th1 response mediates both acute and chronic rejection. Transpl Immunol.2005; 14: 21-25.
[58]Halloran PF, Miller LW, Urmson J, et al. IFN-gamma alters the pathology of graft rejection:protection from early necrosis.J Immunol.2001; 166:7072-7081.
[59]Miura M, El-Sawy T, Fairchild RL. Neutrophils mediate parenchymal tissue necrosis and accelerate the rejection of complete major histocompatibility complex-disparate cardiac allografts in the absence of interferon-gamma.Am J Pathol.2003; 162:509-519.
[60]Li XC, Zheng XX, Strom TB. T-cell growth factors in allograft rejection and tolerance. Transplant Proc 1999; 31:342-343.
[61]Smith XG, Bolton EM, Ruchatz H, et al. Selective blockade of IL-15 by soluble IL-15 receptor alpha-chain enhances cardiac allograft survival. J Immunol 2000; 165:3444-3450.
[62]Gorbacheva V, Fan R, Li X, et al. Interleukin-17 promotes early allograft inflammation. Am J Pathol.2010; 177:1265-1273.
[63]Tang JL, Subbotin VM, Antonysamy MA, et al. Interleukin-17 antagonism inhibits acute but not chronic vascular rejection. Transplantation.2001; 72:348-350.
[64]Antonysamy MA, Fanslow WC, Fu F, et al. Evidence for a role of IL-17 in organ allograft rejection:IL-17 promotes the functional differentiation of dendritic cell progenitors. J Immunol.1999; 162:577-584.
[65]Hsieh HG, Loong CC, Lui WY, et al. IL-17 expression as a possible predictive parameter for subclinical renal allograft rejection. Transpl Int.2001; 14:287-298.
[66]Loong CC, Hsieh HG, Lui WY, et al. Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection. J Pathol.2002; 197:322-332.
[67]Verleden GM, Vos R, Vanaudenaerde BM, et al. Interleukin-17 and neutrophils are increased in BAL fluid during acute lung rejection. Chest.2007; 131:1988-1989;.
[68]Yoshida S, Haque A, Mizobuchi T, et al. Anti-type V collagen lymphocytes that express IL-17 and IL-23 induce rejection pathology in fresh and well-healed lung transplants.Am J Transplant.2006; 6:724-735.
[69]Chen H, Wang W, Xie H, et al.A pathogenic role of IL-17 at the early stage of corneal allograft rejection. Transpl Immunol.2009; 21:155-161.
[70]Fabrega E, Lopez-Hoyos M, San Segundo D, et al. Changes in the serum levels of interleukin-17/interleukin-23 during acute rejection in liver transplantation. Liver Transpl.2009; 15:629-633.
[71]Tang JL, Subbotin VM, Antonysamy MA, et al. Interleukin-17 antagonism inhibits acute but not chronic vascular rejection. Transplantation.2001; 72:348-350.
[72]Paul LC. New insights in chronic allograft rejection.Curr Opin Urol.2002; 12: 89-93.
[73]Yuan X, Paez-Cortez J, Schmitt-Knosalla I, et al. A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy. J Exp Med.2008; 205: 3133-3144.
[74]Itoh S, Nakae S, Axtell RC, et al. IL-17 contributes to the development of chronic rejection in a murine heart transplant model. J Clin Immunol.2010; 30:235-240.
[75]Divella C, Rossini M, Loverre A, et al. Immunohistochemical characterization of glomerular and tubulointerstitial infiltrates in renal transplant patients with chronic allograft dysfunction. Nephrol Dial Transplant.2010; 25:4071-4077.
[76]San Segundo D, Lopez-Hoyos M, Fernandez-Fresnedo G, et al. T(H)17 versus Treg cells in renal transplant candidates:effect of a previous transplant. Transplant Proc. 2008; 40:2885-2888.
[77]Wuyts WA, Vanaudenaerde BM, Dupont LJ, et al. Interleukin-17--induced interleukin-8 release in human airway smooth muscle cells:role for mitogen-activated kinases and nuclear factor-kappaB. J Heart Lung Transplant. 2005; 24:875-881.
[78]Vanaudenaerde BM, Wuyts WA, Dupont LJ, et al. Interleukin-17 stimulates release of interleukin-8 by human airway smooth muscle cells in vitro:a potential role for interleukin-17 and airway smooth muscle cells in bronchiolitis obliterans syndrome. J Heart Lung Transplant.2003; 22:1280-1283.
[79]Dor FJ, Gollackner B, Cooper DK.Can spleen transplantation induce tolerance? A review of the literature. Transpl Int.2003; 16:451-460.
[80]Higgins MJ, Blackall DP. Transfusion-associated graft-versus-host disease:a serious residual risk of blood transfusion.Curr Hematol Rep.2005; 4:470-476.
[81]Andres AM, Santamaria ML, Ramos E, et al. Graft-vs-host disease after small bowel transplantation in children. J Pediatr Surg.2010; 45:330-336.
[82]Xue F, Chen W, Wang XG, et al.Establishment of an acute graft-versus-host disease model following liver transplantation in donor-dominant one-way major histocompatibility complex matching rats.Transplant Proc.2009; 41:1914-1920.
[83]Kato T, Yazawa K, Madono K, et al.Acute graft-versus-host-disease in kidney transplantation:case report and review of literature. Transplant Proc.2009; 41: 3949-3952.
[84]Ichiki Y, Bowlus CL, Shimoda S, et al. T cell immunity and graft-versus-host disease (GVHD). Autoimmun Rev.2006; 5:1-9.
[85]Choi S, Reddy P.Graft-versus-host disease. Panminerva Med.2010;52(2):111-24.
[86]Jaksch M, Mattsson J.The pathophysiology of acute graft-versus-host disease. Scand J Immunol.2005; 61:398-409.
[87]Krenger W, Ferrara JL. Graft-versus-host disease and the Th1/Th2 paradigm. Immunol Res.1996; 15:50-73.
[88]Yang YG, Dey BR, Sergio JJ, et al. Donor-derived interferon gamma is required for inhibition of acute graft-versus-host disease by interleukin 12. J Clin Invest 1998; 102:2126-2135.
[89]Yang YG, Qi J, Wang MG, et al. Donor-derived interferon gamma separates graft-versus-leukemia effects and graft-versus-host disease induced by donor CD8 T cells. Blood 2002; 99:4207-4215.
[90]Burman AC, Banovic TD, Kuns RD, et al. IFN{gamma} differentially controls the development of idiopathic pneumonia syndrome and GVHD of the gastrointestinal tract. Blood 2007; 110:1064-1072.
[91]Yi T, Chen Y, Wang L, et al. Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease.Blood.2009; 114:3101-3112.
[92]Yi T, Zhao D, Lin CL, et al. Absence of donor Th17 leads to augmented Thl differentiation and exacerbated acute graft-versus-host disease. Blood.2008; CD4+112:2101-2110.
[93]Kappel LW, Goldberg GL, King CG, et al. IL-17 contributes to CD4-mediated graft-versus-host disease.Blood.2009; 113:945-952.
[94]Ratajczak P, Janin A, Peffault de Latour R, et al. Th17/Treg ratio in human graft-versus-host disease. Blood.2010; 116:1165-1171.
[95]Carlson MJ, West ML, Coghill JM, et al. In vitro-differentiated TH17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations.Blood.2009; 113:1365-1374.