钙调磷酸酶抑制剂对小鼠Th17细胞分化增殖的影响及其机制探讨
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摘要
钙调磷酸酶抑制剂对小鼠Thl7细胞分化增殖的影响及其机制探讨
目的
对许多终末期实体脏器疾病来说，器官移植是-个有效治疗手段。但是，尽管目前免疫抑制治疗取得了很大进展，移植排斥反应依然是影响受体长期存活的重要因素之-。th17细胞是2005年新发现的效应CD4_T细胞亚群，产生致炎细胞因子IL-17AF、IL6等，主要介导炎症反应、自身免疫病等的发生发展。文献报道，除th1细胞外，th17细胞也参与了移植排斥反应的进程；当th1细胞反应被抑制时，th17细胞可能发挥了更重要的作用。深入了解影响各亚群细胞分化增殖的因素有利于防治移植排斥反应。而钙调磷酸酶抑制剂作为目前移植临床最常用的免疫抑制剂，其与th17细胞的关系，迄今为止尚未阐明。因此，本课题通过人工建立th17极化环境培育出th17细胞，并建立小鼠颈部心脏移植模型，研究钙调磷酸酶抑制剂对小鼠th17细胞分化增殖的影响并探讨其机制；此外，通过体内实验研究th17细胞相关因子IL-17在小鼠心脏移植排斥反应中的表达及其意义。
方法
小鼠脾脏初始CD4~+CD25 T淋巴细胞使用抗CD3抗体及抗CD28抗体活化，1IGFBl及IL6等细胞因子诱导，促使其向th17细胞方向分化；施加不同剂量的钙调磷酸酶抑制剂如他克莫司或环孢素A进行干予页。使用流式细胞仪检测各组CD4’th17细胞亚群纯度，使用R_r_PCR及WesternBl0t检测各组Il_17mRNA相对量。建立小鼠颈部异位心脏移植模型，实验动物随机分组，分别为同系移植组，异系移植组，CA组及FK506组，观察各组供心存活时间；应用RT．PCR检测移植心脏IL-17mRNA、IFNv mRNA在移植术后2、4、6、8d的动态表达水平；病理切片了解发生排斥反应与否。
结果
本课题通过使用钙调磷酸酶抑制剂(他克莫司与环孢素A)，分别在体外环境和体内环境中进行干予页，发现th17细胞的分化增殖受到明显抑制；同时，小鼠心脏的急性排斥反应也得到了有效控制：钙调磷酸酶抑制剂抑制小鼠th17细胞亚群的分化增殖，且呈剂量依赖性。各组问差异有显著性(P<0．05)。此外，构建小鼠颈部异位心脏移植的急性排斥反应模型，观察th1、th17细胞因子在急性排斥反应不同阶段的表达情况。研究结果显示，Il，17参与了急性排斥反应的进程。在异系移植组(急性排斥反应组)中，术后第2天即可检测到ILl7 mRNA的表达，其表达量在术后第4d达丑高峰，随后逐渐下降，在术后第6d无表达。而th1细胞的主要细胞因子IFNv mRNA的表达则晚于IL-17 mRNA。这从侧面说明th17细胞和th1细胞在急性排斥反应的不同阶段分别发挥着重要作用。
结论
th17细胞在移植排斥反应的进程中起着重要作用，对IL-17的检测可以作为急性排斥反应早期诊断的予页见性指标。而钙调磷酸酶抑制剂除了可以抑制th1细胞外，对th17细胞的分化增殖和IL-17的释放也有着强大的抑制作用。以上研究发现，均有利于我们进-步了解移植排斥反应的进程和指导临床防治。本课题探讨了钙调磷酸酶抑制剂对小鼠th17细胞的影响：通过体外实验及体内实验发现，在钙调磷酸酶抑制剂存在的环境下，th17细胞亚群分化增殖明显减少；IL-17mRNA表达降低，且呈齐【量依赖性。这种现象需要新的机理进-步解释。经广泛阅读文献发现：Gomez—R0drigucz等在对T细胞受体信号通路及ITK蛋白的研究中提出：th17细胞内il基因的表达除了受RORm和S1_AT3转导的细胞因子刺激外，还要接受TCR信号通路钙调磷酸酶介导信号的刺激。th17细胞细胞因子IL-17A的表达与Ca2+内流和NFAR激活有关；反之，1ICR信号通路刺激减少或钙调磷酸酶受抑制优先减少了IL-17A的表达。由此推理得出结论，钙调磷酸酶抑制剂抑制th17细胞胞浆内的钙调磷酸酶，从而阻止NFA_rc的脱磷酸化和核内转移过程，进-步抑制il基因的转录活性，抑制Il，17A产生并减轻炎症进程，从另-途径抑制了排斥反应。钙调磷酸酶抑制剂可以抑制th17细胞亚群的分化增殖。本课题进-步阐明了钙调磷酸酶抑制剂发挥免疫抑制作用的机制，为临床上科学应用钙调磷酸酶抑制剂提供实验依据和理论基础。
Effects and Mechanisms of Calcineurin Inhibitor on Development of Murine Thl7 cellsObjective
Transplantation is the optimal treatment for many end-stage diseases in solid organs Despite progress in immuno suppression, allograft rejection is still a major challenge tc long-term survival of recipients and grafts. The immuno logic role of T helper type 17 cells a recently described CD4+ T-helper cell subset, has been implicated in a range o: autoimmune diseases and inflammatory responses previously believed to be mediated b) Thl. Studies have suggested the presence of both Thl and Thl7 cells during allograf rejection: along with Thl cells, Thl7 cells may also mediate allograft rejection, and neithe: subset is sufficient for the occurrence of rejection. When Thl cells are inhibited, Thl7 cells may have a more important role in allograft rejection. To prevent allograft rejection, it h necessary to understand the factors that affect development of T-cell subsets. Calcineurir inhibitor is a T-cell targetted immunosuppression drug that is widely used to preven allograft rejection, it exerts immunosuppression effects by inhibition of T-cell activation, ir particular, Thl cell. However, its pharmacologic effects on Thl7 cells have not been fiill> elucidated. To evaluate whether calcineurin inhibitor inhibits the activities of Thl7 cells cells were differentiated under Thl7 polarized conditions in the presence of increasing amounts of the calcineurin inhibitor such as tacrolimus and cyclosporine A. To establish heterotopic cardiac transplantation model in mice to provide an effective means fo] studying the effect and mechanism of calcineurin inhibitor on Thl7 cells. Besides, tc investigate the role of Thl 7 cells and their cytokines in cardiac allogrft rejection in mice.
Methods
Murine naive CD4+CD25~ T cells were stimulated with plate-bound anti-CD3 and anti-CD28; then were induced by the cytokines such as TGFpl and IL-6, etc. Calcineurin inhibitor such as tacrolimus and cyclosporine A was added to the cells at the desired time point and desired concentrations. The subsets of CD4+Thl7 cells were examined by flow cytometry. The expression of IL-17 mRNA was assayed by RT-PCR and Western Blot. The heterotopic cardiac transplantation models were divided into 4 groups: isograft group, acute rejection group, CsA group and FK506 group. Mean survival time was measured. The mouse hearts in each group were harvested on the day 1, 2, 4, 6, and 8 post transplantation. The mRNA expression of IL-17 and IFNy was detected by RT-PCR.
Results
Calcineurin inhibitor inhibits the differentiation and proliferation of Thl7 cells in a dose-dependent manner. The differences among the groups are considered significant(P<0.05). In the acute rejection group, RT-PCR revealed that IL-17 mRNA was expressed earlier than IFNy, its expression was detected on the second day after transplantation, the expression quantity reached the peak on the postoperative day 4, the gradually reduced, and on the day 6 and 8, no expression was detectable.
Conclusion
Thl7 cells may play an important role in the development of allograft rejection, and IL-17 could serve as a predictive parameter for allograft rejection in the future. The present study investigated the effects of calcineurin inhibitor on Thl7 cells. Inhibition o: differentiation and proliferation of Thl7 cells was dose-dependent. Experssion of IL-1* mRNA was also inhibited. A new mechanism is necessary to explain this phenomenon Gomez-Rodriguez, et al. Observed that expression of the ill7a gene in Thl7 cells is particularly sensitive to the strength ofT-cell receptor signaling, requiring full activation o: Ca2+ mediated pathways in addition to cytokine signals requried for induction and activation of retinoic acid-related orphan receptor-yt and signal transducer and activator o: transcription-3. Expression ol IL-17A was rescued by pharmacologically induced Ca2" influx or activated NFATc; decreased T-cell receptor stimulation or calcineurin inhibitior preferentially reduced IL-17A expression. Expression of IL-17Ais specifically coupled tc T-cell receptor signaling via calcineurin-inhibited regulation of NFATc. In summary calcineurin inhibitor inhibits calcineurin in Thl7 cells, blocks dephosphorylation anc translocation of NFATc, and inhibits transcription of the ill7a gene, reducing expressior IL-17A and alleviating the process of inflammation, which in turn contributes tc suppression of allograft rejection. Fingding of the present study shed new light on the potential immuno suppres sive mechanisms of calcineurin inhibitor and presents anc experimental foundation and theoretical basis for clinical immunosupprission protocols.
目的
对许多终末期实体脏器疾病来说，器官移植是-个有效治疗手段。但是，尽管目前免疫抑制治疗取得了很大进展，移植排斥反应依然是影响受体长期存活的重要因素之-。th17细胞是2005年新发现的效应CD4_T细胞亚群，产生致炎细胞因子IL-17AF、IL6等，主要介导炎症反应、自身免疫病等的发生发展。文献报道，除th1细胞外，th17细胞也参与了移植排斥反应的进程；当th1细胞反应被抑制时，th17细胞可能发挥了更重要的作用。深入了解影响各亚群细胞分化增殖的因素有利于防治移植排斥反应。而钙调磷酸酶抑制剂作为目前移植临床最常用的免疫抑制剂，其与th17细胞的关系，迄今为止尚未阐明。因此，本课题通过人工建立th17极化环境培育出th17细胞，并建立小鼠颈部心脏移植模型，研究钙调磷酸酶抑制剂对小鼠th17细胞分化增殖的影响并探讨其机制；此外，通过体内实验研究th17细胞相关因子IL-17在小鼠心脏移植排斥反应中的表达及其意义。
方法
小鼠脾脏初始CD4~+CD25 T淋巴细胞使用抗CD3抗体及抗CD28抗体活化，1IGFBl及IL6等细胞因子诱导，促使其向th17细胞方向分化；施加不同剂量的钙调磷酸酶抑制剂如他克莫司或环孢素A进行干予页。使用流式细胞仪检测各组CD4’th17细胞亚群纯度，使用R_r_PCR及WesternBl0t检测各组Il_17mRNA相对量。建立小鼠颈部异位心脏移植模型，实验动物随机分组，分别为同系移植组，异系移植组，CA组及FK506组，观察各组供心存活时间；应用RT．PCR检测移植心脏IL-17mRNA、IFNv mRNA在移植术后2、4、6、8d的动态表达水平；病理切片了解发生排斥反应与否。
结果
本课题通过使用钙调磷酸酶抑制剂(他克莫司与环孢素A)，分别在体外环境和体内环境中进行干予页，发现th17细胞的分化增殖受到明显抑制；同时，小鼠心脏的急性排斥反应也得到了有效控制：钙调磷酸酶抑制剂抑制小鼠th17细胞亚群的分化增殖，且呈剂量依赖性。各组问差异有显著性(P<0．05)。此外，构建小鼠颈部异位心脏移植的急性排斥反应模型，观察th1、th17细胞因子在急性排斥反应不同阶段的表达情况。研究结果显示，Il，17参与了急性排斥反应的进程。在异系移植组(急性排斥反应组)中，术后第2天即可检测到ILl7 mRNA的表达，其表达量在术后第4d达丑高峰，随后逐渐下降，在术后第6d无表达。而th1细胞的主要细胞因子IFNv mRNA的表达则晚于IL-17 mRNA。这从侧面说明th17细胞和th1细胞在急性排斥反应的不同阶段分别发挥着重要作用。
结论
th17细胞在移植排斥反应的进程中起着重要作用，对IL-17的检测可以作为急性排斥反应早期诊断的予页见性指标。而钙调磷酸酶抑制剂除了可以抑制th1细胞外，对th17细胞的分化增殖和IL-17的释放也有着强大的抑制作用。以上研究发现，均有利于我们进-步了解移植排斥反应的进程和指导临床防治。本课题探讨了钙调磷酸酶抑制剂对小鼠th17细胞的影响：通过体外实验及体内实验发现，在钙调磷酸酶抑制剂存在的环境下，th17细胞亚群分化增殖明显减少；IL-17mRNA表达降低，且呈齐【量依赖性。这种现象需要新的机理进-步解释。经广泛阅读文献发现：Gomez—R0drigucz等在对T细胞受体信号通路及ITK蛋白的研究中提出：th17细胞内il基因的表达除了受RORm和S1_AT3转导的细胞因子刺激外，还要接受TCR信号通路钙调磷酸酶介导信号的刺激。th17细胞细胞因子IL-17A的表达与Ca2+内流和NFAR激活有关；反之，1ICR信号通路刺激减少或钙调磷酸酶受抑制优先减少了IL-17A的表达。由此推理得出结论，钙调磷酸酶抑制剂抑制th17细胞胞浆内的钙调磷酸酶，从而阻止NFA_rc的脱磷酸化和核内转移过程，进-步抑制il基因的转录活性，抑制Il，17A产生并减轻炎症进程，从另-途径抑制了排斥反应。钙调磷酸酶抑制剂可以抑制th17细胞亚群的分化增殖。本课题进-步阐明了钙调磷酸酶抑制剂发挥免疫抑制作用的机制，为临床上科学应用钙调磷酸酶抑制剂提供实验依据和理论基础。
Effects and Mechanisms of Calcineurin Inhibitor on Development of Murine Thl7 cellsObjective
Transplantation is the optimal treatment for many end-stage diseases in solid organs Despite progress in immuno suppression, allograft rejection is still a major challenge tc long-term survival of recipients and grafts. The immuno logic role of T helper type 17 cells a recently described CD4+ T-helper cell subset, has been implicated in a range o: autoimmune diseases and inflammatory responses previously believed to be mediated b) Thl. Studies have suggested the presence of both Thl and Thl7 cells during allograf rejection: along with Thl cells, Thl7 cells may also mediate allograft rejection, and neithe: subset is sufficient for the occurrence of rejection. When Thl cells are inhibited, Thl7 cells may have a more important role in allograft rejection. To prevent allograft rejection, it h necessary to understand the factors that affect development of T-cell subsets. Calcineurir inhibitor is a T-cell targetted immunosuppression drug that is widely used to preven allograft rejection, it exerts immunosuppression effects by inhibition of T-cell activation, ir particular, Thl cell. However, its pharmacologic effects on Thl7 cells have not been fiill> elucidated. To evaluate whether calcineurin inhibitor inhibits the activities of Thl7 cells cells were differentiated under Thl7 polarized conditions in the presence of increasing amounts of the calcineurin inhibitor such as tacrolimus and cyclosporine A. To establish heterotopic cardiac transplantation model in mice to provide an effective means fo] studying the effect and mechanism of calcineurin inhibitor on Thl7 cells. Besides, tc investigate the role of Thl 7 cells and their cytokines in cardiac allogrft rejection in mice.
Methods
Murine naive CD4+CD25~ T cells were stimulated with plate-bound anti-CD3 and anti-CD28; then were induced by the cytokines such as TGFpl and IL-6, etc. Calcineurin inhibitor such as tacrolimus and cyclosporine A was added to the cells at the desired time point and desired concentrations. The subsets of CD4+Thl7 cells were examined by flow cytometry. The expression of IL-17 mRNA was assayed by RT-PCR and Western Blot. The heterotopic cardiac transplantation models were divided into 4 groups: isograft group, acute rejection group, CsA group and FK506 group. Mean survival time was measured. The mouse hearts in each group were harvested on the day 1, 2, 4, 6, and 8 post transplantation. The mRNA expression of IL-17 and IFNy was detected by RT-PCR.
Results
Calcineurin inhibitor inhibits the differentiation and proliferation of Thl7 cells in a dose-dependent manner. The differences among the groups are considered significant(P<0.05). In the acute rejection group, RT-PCR revealed that IL-17 mRNA was expressed earlier than IFNy, its expression was detected on the second day after transplantation, the expression quantity reached the peak on the postoperative day 4, the gradually reduced, and on the day 6 and 8, no expression was detectable.
Conclusion
Thl7 cells may play an important role in the development of allograft rejection, and IL-17 could serve as a predictive parameter for allograft rejection in the future. The present study investigated the effects of calcineurin inhibitor on Thl7 cells. Inhibition o: differentiation and proliferation of Thl7 cells was dose-dependent. Experssion of IL-1* mRNA was also inhibited. A new mechanism is necessary to explain this phenomenon Gomez-Rodriguez, et al. Observed that expression of the ill7a gene in Thl7 cells is particularly sensitive to the strength ofT-cell receptor signaling, requiring full activation o: Ca2+ mediated pathways in addition to cytokine signals requried for induction and activation of retinoic acid-related orphan receptor-yt and signal transducer and activator o: transcription-3. Expression ol IL-17A was rescued by pharmacologically induced Ca2" influx or activated NFATc; decreased T-cell receptor stimulation or calcineurin inhibitior preferentially reduced IL-17A expression. Expression of IL-17Ais specifically coupled tc T-cell receptor signaling via calcineurin-inhibited regulation of NFATc. In summary calcineurin inhibitor inhibits calcineurin in Thl7 cells, blocks dephosphorylation anc translocation of NFATc, and inhibits transcription of the ill7a gene, reducing expressior IL-17A and alleviating the process of inflammation, which in turn contributes tc suppression of allograft rejection. Fingding of the present study shed new light on the potential immuno suppres sive mechanisms of calcineurin inhibitor and presents anc experimental foundation and theoretical basis for clinical immunosupprission protocols.
引文
[1] Park H,Li Z,Yang XO,et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immuno 1,2005,6(11):1133-1141.
[2] Harrington LE,Hatton RD,Mangan PR,et al. Interleukin 17-producing CD4+effector Tcells develop via a lineage distinct from the T helper type 1 and 2 lineages. NatImmuno 1,2005,6(11):1123-1132.
[3] Bettelli E,Carrier Y,Gao W,et al. Reciprocal developmental pathways for the generationof pathogenic effector TH17 and regulatory T cells. Nature,2006,441(7090):235-238.
[4] Wahl SM,Wen J,Moutsopoulos N. TGF-beta:a mobile purveyor of immune privilege.Immunol Rev,2006,213:213-227.
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[8] Stumhofer JS,Laurence A,Wilson EH,et al. Interleukin 27 negatively regulates thedevelopment of interleukin 17-producing T helper cells during chronic inflammation of thecentral nervous system. NatImmunol,2006,7(9):937-945.
[9] Batten M,Li J,Yi S,et al. Interleukin 27 limits autoimmune encephalomyelitis bysuppressing the development of interleukin 17-producing T cells. NatImmunol,2006,7(9):929-936.
[10] Bettelli E,Oukka M,Kuchroo VK. T(H)-17 cells in the circle of immunity andautoimmunity. Nat Immuno 1,2007,8(4) :345-350.
[11] Miura M,EL-Sawy T,Fairchild RL. Neutrophils mediate parenchymal tissue necrosis
and accelerate the rejection of complete major histocompatibility complex-disparatecardiac allografts in the absence of interferon-gamma. Am J Pathol,2003,162(2) :509-519.
[12] Yuan X,Paez-Cortez J,Schmitt-Knosalla I,et al. A novel role of CD4 Thl7 cells irmediating cardiac allograft rejection and vasculopathy. J ExfMed,2008,205(13):3133-3144.
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[16] Antonysamy MA,Fanslow WC,Fu F,et al. Evidence for a role of IL-17 in orgarallograft fejection:IL-17 promotes the fimctional differentiation of dendritic eelprogenitors. J Immunol,1999,162(l):577-584.
[17] Tang JL,Subbotin VM,Antonysamy MA,et al. Interleukin-17 antagonism inhibitsacute but not chronic vascular rejection. Transplantation,2001,72(2):348-350.
[18] Hsieh HG,Loong CC,Lui WY,et al. IL-17 expression as a possible predictiveparameter for subclinical renal allograft rejection. Transpl Int,2001,14(5):287-298.
[19] Loong CC,Hsien HG,Lui WY, et al. Evidence for the early involvement of interleukir17 in human and experimental renal allograft rejection. J Pathol,2002,197(3):322-332.
[20] Liu XK,Clements JL,Gaffen SL. Signaling through the murine T cell receptor inducesIL-17 production in the absence of costimulation,IL-23 or dendritic cells. Mo!Cells,2005,20(3):339-347.
[21] Cho ML,Ju JH,Kim KW,et al. Cyclosporine A inhibits IL-15-induced IL-1"production in CD4+ T cells via down-regulation of PI3K/Akt and NF-kappaB. Immuno!Lett,2007,108(l):88-96.
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[1] Park H,Li Z,Yang XO,et al. A distinct lineage of CD4 T cells regulates tissueinflammation by producing interleukin 17. Nat Immuno 1,2005,6(11):1133-1141.
[2] Harrington LE,Hatton RD,Mangan PR,et al. Interleukin 17-producing CD4+effector Tcells develop via a lineage distinct from the T helper type 1 and 2 lineages. NatImmuno 1,2005,6(11):1123-1132.
[3] Bettelli E,Carrier Y,Gao W,et al. Reciprocal developmental pathways for the generationof pathogenic effector TH17 and regulatory T cells. Nature,2006,441(7090):235-238.
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[1]朱晓星，杨康，吴蔚。近交系小鼠不同品系颈部心脏移植。现代生物医学进展，2008，8(1)：56—58。
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[1] Park H,Li Z,Yang XO,et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immuno 1,2005,6(11): 1133-1141.
[2] Harrington LE,Hatton RD,Mangan PR,et al. Interleukin 17-producing CD4+ effector 1cells develop via a lineage distinct from the T helper type 1 and 2 lineages. NaImmuno 1,2005,6(11):1123-1132.
[3] Bettelli E,Carrier Y,Gao W,et al. Reciprocal developmental pathways for the generatiorof pathogenic effector TH17 and regulatory T cells. Nature,2006,441(7090):235-238.
[4] Wahl SM,Wen J,Moutsopoulos N. TGF-beta:a mobile purveyor of immune privilegeImmunol Rev,2006,213:213-227.
[5] Veldhoen M,Hocking RJ,Atkins CJ,et al. TGFbeta in the context of an inflammatorycytokine milieu supports de novo differentiation of IL-17-producing T cellsImmunity,2006,24(2):179-189.
[6] O'Garra A,Stockinger B,Veldhoen M. Differentiation of human T(H)-17 cells doe;require TGF-beta! Nat Immunol,2008,9(6):588-590.
[7] Mangan PR,Harrington LE,O'Quinn DB,et al. Transforming growth factor-beta inducesdevelopment ofthe T(H)17 lineage. Nature,2006,441(7090):231-234.
[8] Laurence A,OShea JJ. T(H)17-differentiation:of mice and men. NaImmunol,2007,8(9):903-905.
[9] Li M0,Wan YY, Flavell RA. T cell-produced transforming growth iactor-betal controlsT cell tolerance and regulates Thl-and Thl7-cell differentiationImmunity,2007,26(5):579-591.
[10] Zhou L,Lopes JE,Chong MM,et al. TGF-beta-induced Foxp3 inhibits T(H)17 eeldifferentiation by antagonizing RORgammat Junction. Nature,2008,453(7192):236-240.
[11] Ivanov II,Mckenzie BS,Zhou L,et al. The orphan nuclear receptor RORgammadirects the differentiation program of proinflammatory IL-17+ T helper cells.Cell,2006,126(6):1121-1133.
[12] Starnes T,Broxmeyer HE,Robertson MJ,et al. Cutting edge:IL-17D,a novel member ofthe IL-17 family, stimulates cytokine production and inhibits hemopoiesis. JImmunol,2002,169(2):642-646.
[13] Briistle A,Heink S,Huber M,et al. The development of inflammatory T(H)-17 cellsrequires interferon-regulatory factor 4. Nat Immunol,2007,8(9):958-966.
[14] Weaver CT,Harrington LE,Mangan PR,et al. Thl7:an effector CD4 T cell lineage withregulatory T cell ties. Immunity,2006,24(6):677-688.
[15] Zhou LJvanov II,Spolski R,et al. IL-6 programs T(H)-17 cell differentiation bypromoting sequential engagement of the IL-21 and IL-23 pathways. NatImmuno 1,2007,8(9) :967-974.
[16] Deenick EK,Tangye SG. Autoimmunity:IL-21:A new player in Thl7-celldifferentiation. Immunol Cell Biol,2007,85(7):503-505.
[17] Korn T,Bettelli E,Gao W.,et al. IL-21 initiates an alternative pathway to induceproinflammatory T(H)17 cells. Nature,2007,448(7152):484-487.
[18] Nurieva R,Yang XO,Martinez G,et al. Essential autocrine regulation by IL-21 in thegeneration of inflammatory T cells. Nature,2007,448(7152):480-483.
[19] Laurence A,Tato CM,Davidson TS,et al. Interleukin-2 signaling via STAT5 constrainsT helper 17 cell generation. Immunity,2007,26(3):371-381.
[20] Stumhofer JS,Laurence A,Wilson EH,et al. Interleukin 27 negatively regulates thedevelopment of interleukin 17-producing T helper cells during chronic inflammation of thecentral nervous system. NatImmunol,2006,7(9):937-945.
[21] Batten M,Li J,Yi S,et al. Interleukin 27 limits autoimmune encephalomyelitis bysuppressing the development of interleukin 17-producing T cells. NatImmunol,2006,7(9):929-936.
[22] Bettelli E,Oukka M,Kuchroo VK. T(H)-17 cells in the circle of immunity andautoimmunity. Nat Immuno 1,2007,8(4) :345-350.
[23] Liu XK,Clements JL,Gaffen SL. Signaling through the murine T cell receptor inducesIL-17 production in the absence of costimulation,IL-23 or dendritic cells. Mo!Cells,2005,20(3):339-347.
[24] Moseley TA,Haudenschild DR,Rose L,et al. Interleukin-17 family and IL-17 receptorsCytokine Growth Factor Rev. 2003,14(2):155-174.
[25] Lubberts E,Koenders MI,van den Berg WB. The role of T-cell interleukin-17 irconducting destructive arthritis :lessons from animal models. Arthritis ResTher,2005,7(l):29-37.
[26] Weaver CT,Hatton RD,Mangan PR,et al. IL-17 family cytokines and the expandingdiversity of effector T cell lineages. Annu Rev Immunol,2007,25:821-852.
[27] Ferretti S,Bonneau O,Dubois GR,et al. IL-17,produced by lymphocytes andneutrophils,is necessary for lipopolysaccharide-induced airway neutrophilia:IL-15 as i.possible trigger. JImmunol,2003,170(4):2106-2112.
[28] Nakae S,Nambu A,Sudo K,et al. Suppression of immune induction olcollagen-induced arthritis in IL-17-deficient mice. J Immunol,2003,171(11):6173-6177.
[29] Tan W,Huang W,Zhong Q,et al. IL-17 receptor knockout mice have enhancedmyelotoxicity and impaired hemopoietic recovery following gamma irradiation. .Immunol,2006,176(10):6186-6193.
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[31] Yuan X,Paez-Cortez J,Schmitt-Knosalla I,et al. A novel role of CD4 Thl7 cells irmediating cardiac allograft rejection and vasculopathy. J ExfMed,2008,205(13):3133-3144.
[32] Chen Y,Wood KJ. Interleukin-23 and TH17 cells in transplantation immunity:does23+17 equal rejection? Transplantation,2007,84(9):1071-1074.
[33] Rao DA,Tracey KJ,Pober JS. IL-lalpha and IL-lbeta are endogenous mediatorslinking cell injury to the adaptive alloimmune response.Immunol,2007,179(10):6536-6546.
[34] Van Kooten C,Boonstra JG,Paape ME,et al. Interleukin-17 activates human renalepithelial cells in vitro and is expressed during renal allograft rejection. J Am SocNephrol,1998,9(8):1526-1534.
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[1] Morales JM, Wramner L, Kreis H, et al. Sirolimus does not exhibit nephrotoxicitycompared to cyclosporine in renal transplant recipients. Am J Transplant, 2002, 2(5):436-442.
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[2] Harrington LE,Hatton RD,Mangan PR,et al. Interleukin 17-producing CD4+effector Tcells develop via a lineage distinct from the T helper type 1 and 2 lineages. NatImmuno 1,2005,6(11):1123-1132.
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[4] Wahl SM,Wen J,Moutsopoulos N. TGF-beta:a mobile purveyor of immune privilege.Immunol Rev,2006,213:213-227.
[5] Li M0,Wan YY, Flavell RA. T cell-produced transforming growth factor-betal controlsT cell tolerance and regulates Th 1 -and Th 17-cell differentiation.Immunity,2007,26(5):579-591.
[6] Laurence A,Tato CM,Davidson TS,et al. Interleukin-2 signaling via STAT5 constrains Thelper 17 cell generation. Immunity,2007,26(3):371-381.
[7] Veldhoen M,Hocking RJ,Atkins CJ,et al. TGFbeta in the context of an inflammatorycytokine milieu supports de novo differentiation of IL-17-producing T cells.Immunity,2006,24(2): 179-189.
[8] Stumhofer JS,Laurence A,Wilson EH,et al. Interleukin 27 negatively regulates thedevelopment of interleukin 17-producing T helper cells during chronic inflammation of thecentral nervous system. NatImmunol,2006,7(9):937-945.
[9] Batten M,Li J,Yi S,et al. Interleukin 27 limits autoimmune encephalomyelitis bysuppressing the development of interleukin 17-producing T cells. NatImmunol,2006,7(9):929-936.
[10] Bettelli E,Oukka M,Kuchroo VK. T(H)-17 cells in the circle of immunity andautoimmunity. Nat Immuno 1,2007,8(4) :345-350.
[11] Miura M,EL-Sawy T,Fairchild RL. Neutrophils mediate parenchymal tissue necrosis
and accelerate the rejection of complete major histocompatibility complex-disparatecardiac allografts in the absence of interferon-gamma. Am J Pathol,2003,162(2) :509-519.
[12] Yuan X,Paez-Cortez J,Schmitt-Knosalla I,et al. A novel role of CD4 Thl7 cells irmediating cardiac allograft rejection and vasculopathy. J ExfMed,2008,205(13):3133-3144.
[13] Chen Y,Wood KJ. Interleukin-23 and TH17 cells in transplantation immunity:does23+17 equal rejection? Transplantation,2007,84(9):1071-1074.
[14] Rao DA,Tracey KJ,Pober JS. IL-lalpha and IL-lbeta are endogenous mediatorslinking cell injury to the adaptive alloimmune response. JImmunol,2007,179(10):6536-6546.
[15] Van Kooten C,Boonstra JG,Paape ME,et al. Interleukin-17 activates human renaepithelial cells in vitro and is expressed during renal allograft rejection. J Am SotNephrol,1998,9(8):1526-1534.
[16] Antonysamy MA,Fanslow WC,Fu F,et al. Evidence for a role of IL-17 in orgarallograft fejection:IL-17 promotes the fimctional differentiation of dendritic eelprogenitors. J Immunol,1999,162(l):577-584.
[17] Tang JL,Subbotin VM,Antonysamy MA,et al. Interleukin-17 antagonism inhibitsacute but not chronic vascular rejection. Transplantation,2001,72(2):348-350.
[18] Hsieh HG,Loong CC,Lui WY,et al. IL-17 expression as a possible predictiveparameter for subclinical renal allograft rejection. Transpl Int,2001,14(5):287-298.
[19] Loong CC,Hsien HG,Lui WY, et al. Evidence for the early involvement of interleukir17 in human and experimental renal allograft rejection. J Pathol,2002,197(3):322-332.
[20] Liu XK,Clements JL,Gaffen SL. Signaling through the murine T cell receptor inducesIL-17 production in the absence of costimulation,IL-23 or dendritic cells. Mo!Cells,2005,20(3):339-347.
[21] Cho ML,Ju JH,Kim KW,et al. Cyclosporine A inhibits IL-15-induced IL-1"production in CD4+ T cells via down-regulation of PI3K/Akt and NF-kappaB. Immuno!Lett,2007,108(l):88-96.
[22] Lowes MA,Kikuchi T,Fuentes-Duculan J,et al. Psoriasis vulgaris lesions contain discrete populations of Thl andThl7 Tcells. J Invest Dermatol,2008,128(5):1207-1211. [23] Kopf H,de la Rosa GM,Howard OM,et al. Rapamycin inhibits differentiation of Thl7 cells and promotes generation of FoxP3+ T regulatory cells. Int Immunopharmacol,2007,7(13):1819-1824.
[1] Park H,Li Z,Yang XO,et al. A distinct lineage of CD4 T cells regulates tissueinflammation by producing interleukin 17. Nat Immuno 1,2005,6(11):1133-1141.
[2] Harrington LE,Hatton RD,Mangan PR,et al. Interleukin 17-producing CD4+effector Tcells develop via a lineage distinct from the T helper type 1 and 2 lineages. NatImmuno 1,2005,6(11):1123-1132.
[3] Bettelli E,Carrier Y,Gao W,et al. Reciprocal developmental pathways for the generationof pathogenic effector TH17 and regulatory T cells. Nature,2006,441(7090):235-238.
[4] Wahl SM,Wen J,Moutsopoulos N. TGF-beta:a mobile purveyor of immune privilege.Immunol Rev,2006,213:213-227.
[5] Veldhoen M,Hocking RJ,Atkins CJ,et al. TGFbeta in the context of an inflammatorycytokine milieu supports de novo differentiation of IL-17-producing T cells.Immunity,2006,24(2): 179-189.
[6] O'Garra A,Stockinger B,Veldhoen M. Differentiation of human T(H)-17 cells doesrequire TGF-beta! Natlmmunol,2008,9(6):588-590.
[7] Mangan PR,Harrington LE,OQuinn DB,et al. Transforming growth factor-beta inducesdevelopment of the T(H)17 lineage. Nature, 20 06,441 (7090) :231-234.
[8] Laurence A,OShea JJ. T(H)17-differentiation:of mice and men. NatImmunol,2007,8(9):903-905.
[9] Li M0,Wan YY, Flavell RA. T cell-produced transforming growth factor-betal controlsT cell tolerance and regulates Th 1 -and Th 17-cell differentiation.Immunity,2007,26(5):579-591.
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[14] Weaver CT,Harrington LE,Mangan PR,et al. Thl7:an effector CD4 T cell lineage witrregulatory T cell ties. Immunity,2006,24(6):677-688.
[15] Zhou LJvanov II,Spolski R,et al. IL-6 programs T(H)-17 cell differentiation b)promoting sequential engagement of the IL-21 and IL-23 pathways. NaImmunol,2007,8(9):967-974.
[16] Deenick EK,Tangye SG. Autoimmunity:IL-21:A new player in Thl7-celdifferentiation. Immunol Cell Biol,2007,85(7):503-505.
[17] Korn T,Bettelli E,Gao W.,et al. IL-21 initiates an alternative pathway to inductproinflammatory T(H)17 cells. Nature,2007,448(7152):484-487.
[18] Nurieva R,Yang XO,Martinez G,et al. Essential autocrine regulation by IL-21 in thtgeneration of inflammatory T cells. Nature,2007,448(7152):480-483.
[19] Laurence A,Tato CM,Davidson TS,et al. Interleukin-2 signaling via STAT5 constrainsT helper 17 cell generation. Immunity,2007,26(3):371-381.
[20] Stumhofer JS,Laurence A,Wilson EH,et al. Interleukin 27 negatively regulates thtdevelopment of interleukin 17-producing T helper cells during chronic inflammation of thtcentral nervous system. Nat Immunol,2006,7(9):937-945.
[21] Batten M,Li J,Yi S,et al. Interleukin 27 limits autoimmune encephalomyelitis b)suppressing the development of interleukin 17-producing T cells. NaImmunol,2006,7(9):929-936.
[22] Bettelli E,Oukka M,Kuchroo VK. T(H)-17 cells in the circle of immunity ancautoimmunity. Nat Immuno 1,2007,8(4) :345-350.
[23] Liu XK,Clements JL,Gaffen SL. Signaling through the murine T cell receptor inducesIL-17 production in the absence of costimulation,IL-23 or dendritic cells. MolCells,2005,20(3):339-347.
[24] Moseley TA,Haudenschild DR,Rose L,et al. Interleukin-17 family and IL-17 receptors.Cytokine Growth Factor Rev. 2003,14(2):155-174.
[25] Lubberts E,Koenders MI,van den Berg WB. The role of T-cell interleukin-17 inconducting destructive arthritis :lessons from animal models. Arthritis ResTher,2005,7(l):29-37.
[26] Weaver CT,Hatton RD,Mangan PR,et al. IL-17 family cytokines and the expandingdiversity of effector T cell lineages. Annu Rev Immunol,2007,25:821-852.
[27] Ferretti S,Bonneau O,Dubois GR,et al. IL-17,produced by lymphocytes andneutrophils,is necessary for lipopolysaccharide-induced airway neutrophilia:IL-15 as apossible trigger. JImmunol,2003,170(4):2106-2112.
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[1]朱晓星，杨康，吴蔚。近交系小鼠不同品系颈部心脏移植。现代生物医学进展，2008，8(1)：56—58。
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[1] Mcgeachy MJ, Cua DJ. Thl7 cell differentiation: the long and winding road. Immunity,2008,28(4): 445453.
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[1] Park H,Li Z,Yang XO,et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immuno 1,2005,6(11): 1133-1141.
[2] Harrington LE,Hatton RD,Mangan PR,et al. Interleukin 17-producing CD4+ effector 1cells develop via a lineage distinct from the T helper type 1 and 2 lineages. NaImmuno 1,2005,6(11):1123-1132.
[3] Bettelli E,Carrier Y,Gao W,et al. Reciprocal developmental pathways for the generatiorof pathogenic effector TH17 and regulatory T cells. Nature,2006,441(7090):235-238.
[4] Wahl SM,Wen J,Moutsopoulos N. TGF-beta:a mobile purveyor of immune privilegeImmunol Rev,2006,213:213-227.
[5] Veldhoen M,Hocking RJ,Atkins CJ,et al. TGFbeta in the context of an inflammatorycytokine milieu supports de novo differentiation of IL-17-producing T cellsImmunity,2006,24(2):179-189.
[6] O'Garra A,Stockinger B,Veldhoen M. Differentiation of human T(H)-17 cells doe;require TGF-beta! Nat Immunol,2008,9(6):588-590.
[7] Mangan PR,Harrington LE,O'Quinn DB,et al. Transforming growth factor-beta inducesdevelopment ofthe T(H)17 lineage. Nature,2006,441(7090):231-234.
[8] Laurence A,OShea JJ. T(H)17-differentiation:of mice and men. NaImmunol,2007,8(9):903-905.
[9] Li M0,Wan YY, Flavell RA. T cell-produced transforming growth iactor-betal controlsT cell tolerance and regulates Thl-and Thl7-cell differentiationImmunity,2007,26(5):579-591.
[10] Zhou L,Lopes JE,Chong MM,et al. TGF-beta-induced Foxp3 inhibits T(H)17 eeldifferentiation by antagonizing RORgammat Junction. Nature,2008,453(7192):236-240.
[11] Ivanov II,Mckenzie BS,Zhou L,et al. The orphan nuclear receptor RORgammadirects the differentiation program of proinflammatory IL-17+ T helper cells.Cell,2006,126(6):1121-1133.
[12] Starnes T,Broxmeyer HE,Robertson MJ,et al. Cutting edge:IL-17D,a novel member ofthe IL-17 family, stimulates cytokine production and inhibits hemopoiesis. JImmunol,2002,169(2):642-646.
[13] Briistle A,Heink S,Huber M,et al. The development of inflammatory T(H)-17 cellsrequires interferon-regulatory factor 4. Nat Immunol,2007,8(9):958-966.
[14] Weaver CT,Harrington LE,Mangan PR,et al. Thl7:an effector CD4 T cell lineage withregulatory T cell ties. Immunity,2006,24(6):677-688.
[15] Zhou LJvanov II,Spolski R,et al. IL-6 programs T(H)-17 cell differentiation bypromoting sequential engagement of the IL-21 and IL-23 pathways. NatImmuno 1,2007,8(9) :967-974.
[16] Deenick EK,Tangye SG. Autoimmunity:IL-21:A new player in Thl7-celldifferentiation. Immunol Cell Biol,2007,85(7):503-505.
[17] Korn T,Bettelli E,Gao W.,et al. IL-21 initiates an alternative pathway to induceproinflammatory T(H)17 cells. Nature,2007,448(7152):484-487.
[18] Nurieva R,Yang XO,Martinez G,et al. Essential autocrine regulation by IL-21 in thegeneration of inflammatory T cells. Nature,2007,448(7152):480-483.
[19] Laurence A,Tato CM,Davidson TS,et al. Interleukin-2 signaling via STAT5 constrainsT helper 17 cell generation. Immunity,2007,26(3):371-381.
[20] Stumhofer JS,Laurence A,Wilson EH,et al. Interleukin 27 negatively regulates thedevelopment of interleukin 17-producing T helper cells during chronic inflammation of thecentral nervous system. NatImmunol,2006,7(9):937-945.
[21] Batten M,Li J,Yi S,et al. Interleukin 27 limits autoimmune encephalomyelitis bysuppressing the development of interleukin 17-producing T cells. NatImmunol,2006,7(9):929-936.
[22] Bettelli E,Oukka M,Kuchroo VK. T(H)-17 cells in the circle of immunity andautoimmunity. Nat Immuno 1,2007,8(4) :345-350.
[23] Liu XK,Clements JL,Gaffen SL. Signaling through the murine T cell receptor inducesIL-17 production in the absence of costimulation,IL-23 or dendritic cells. Mo!Cells,2005,20(3):339-347.
[24] Moseley TA,Haudenschild DR,Rose L,et al. Interleukin-17 family and IL-17 receptorsCytokine Growth Factor Rev. 2003,14(2):155-174.
[25] Lubberts E,Koenders MI,van den Berg WB. The role of T-cell interleukin-17 irconducting destructive arthritis :lessons from animal models. Arthritis ResTher,2005,7(l):29-37.
[26] Weaver CT,Hatton RD,Mangan PR,et al. IL-17 family cytokines and the expandingdiversity of effector T cell lineages. Annu Rev Immunol,2007,25:821-852.
[27] Ferretti S,Bonneau O,Dubois GR,et al. IL-17,produced by lymphocytes andneutrophils,is necessary for lipopolysaccharide-induced airway neutrophilia:IL-15 as i.possible trigger. JImmunol,2003,170(4):2106-2112.
[28] Nakae S,Nambu A,Sudo K,et al. Suppression of immune induction olcollagen-induced arthritis in IL-17-deficient mice. J Immunol,2003,171(11):6173-6177.
[29] Tan W,Huang W,Zhong Q,et al. IL-17 receptor knockout mice have enhancedmyelotoxicity and impaired hemopoietic recovery following gamma irradiation. .Immunol,2006,176(10):6186-6193.
[30] Miura M,EL-Sawy T,Fairchild RL. Neutrophils mediate parenchymal tissue necrosisand accelerate the rejection of complete major histocompatibility complex-disparatecardiac allografts in the absence of interferon-gamma. Am J Pathol,2003,162(2) :509-519.
[31] Yuan X,Paez-Cortez J,Schmitt-Knosalla I,et al. A novel role of CD4 Thl7 cells irmediating cardiac allograft rejection and vasculopathy. J ExfMed,2008,205(13):3133-3144.
[32] Chen Y,Wood KJ. Interleukin-23 and TH17 cells in transplantation immunity:does23+17 equal rejection? Transplantation,2007,84(9):1071-1074.
[33] Rao DA,Tracey KJ,Pober JS. IL-lalpha and IL-lbeta are endogenous mediatorslinking cell injury to the adaptive alloimmune response.Immunol,2007,179(10):6536-6546.
[34] Van Kooten C,Boonstra JG,Paape ME,et al. Interleukin-17 activates human renalepithelial cells in vitro and is expressed during renal allograft rejection. J Am SocNephrol,1998,9(8):1526-1534.
[35] Antonysamy MA,Fanslow WC,Fu F,et al. Evidence for a role of IL-17 in organallograft fejection:IL-17 promotes the functional differentiation of dendritic cellprogenitors. J Immunol,1999,162(l):577-584.
[36] Tang JL,Subbotin VM,Antonysamy MA,et al. Interleukin-17 antagonism inhibitsacute but not chronic vascular rejection. Transplantation,2001,72(2):348-350.
[37] Hsieh HG,Loong CC,Lui WY,et al. IL-17 expression as a possible predictiveparameter for subclinical renal allograft rejection. Transpl Int,2001,14(5):287-298.
[38] Loong CC,Hsieh HG,Lui WY, et al. Evidence for the early involvement of interleukin17 in human and experimental renal allograft rejection. J Pathol,2002,197(3):322-332.
[39] Vanaudenaerde BM,Dupont LJ,Wuyts WA,et al. The role of interleukin-17 duringacute rejection after lung transplantation. Eur Respir J,2006,27(4):779-787.
[40] Cho ML,Ju JH,Kim KW,et al. Cyclosporine A inhibits IL-15-induced IL-17production in CD4+ T cells via down-regulation of PI3K/Akt and NF-kappaB. ImmunolLett,2007,108(l):88-96.
[41] Lowes MA,Kikuchi T,Fuentes-Duculan J,et al. Psoriasis vulgaris lesions containdiscrete populations of Thl andThl7 Tcells. J Invest Dermatol,2008,128(5):1207-1211.
[42] Kopf H,de la Rosa GM,Howard OM,et al. Rapamycin inhibits differentiation of Thl7cells and promotes generation of FoxP3+ T regulatory cells. IntImmunopharmacol,2007,7(13):1819-1824.
[43] Evans HG,Suddason TJackson I,et al. Optimal induction of T helper 17 cells inhumans requires T cell receptor ligation in the context of Toll-like receptor-activatedmonocytes. ProcNatlAcad SciU S A,2007,104(43):17034-17039.
[44] O'Connor RA,Malpass KH,Anderton SM. The inflamed central nervous system drivesthe activation and rapid proliferation of Foxp3+ regulatory T cells. JImmunol,2007,179(2):958-966.
[45] Lohr J,Knoechel B,Wang JJ,et al. Role of IL-17 and regulatory T lymphocytes in i.systemic autoimmune disease. J Exp Med,2006,203(13):2785-2791.
[46] Koenen HJ,Smeets RL,Vink PM,et al. Human CD25highFoxp3pos regulatory T cellsdifferentiate into IL-17-producing cells. Blood,2008,112(6):2340-2352.
[1] Morales JM, Wramner L, Kreis H, et al. Sirolimus does not exhibit nephrotoxicitycompared to cyclosporine in renal transplant recipients. Am J Transplant, 2002, 2(5):436-442.
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