IL-23、IL-17与移植免疫的相关性研究
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摘要
目的:探讨白介素23(IL-23)、白介素17(IL-17)在小鼠皮肤移植后不同免疫状态下外周循环血浆中及移植物组织病理的变化;了解IL-23、IL-17与调节T细胞(Treg cell)在不同免疫状态下的相互作用;探讨IL-23/IL-17通路在小鼠皮肤移植后的免疫调节作用。为临床移植后排斥反应的预防、诊断和治疗转归及免疫耐受提供理论指导。
方法:小鼠皮肤移植动物模型的建立(n=10):第1组、同种同基因移植组(BALB/c→BALB/c)、第2组、同种异基因移植组(C57BL/6→BALB/c),第3组、供体脾细胞输注组(C57BL/6→BALB/c)。观察三组不同时间移植皮瓣外观变化及镜下三组移植皮肤HE切片的病理改变;采用ELISA方法检测小鼠血浆IL-17、IL-23的浓度;RT-PCR反应检测移植皮肤及脾脏的IL-23mRNA、IL-17mRNA的表达;流式细胞仪检测脾脏Treg细胞百分比。
结果:三组小鼠移植后大体外观及HE染色镜下所见:同基因移植组小鼠移植皮术后皮片生长完好,无排斥反应发生;异基因小鼠移植皮出现典型的急性排斥反应;术前输注脾细胞异基因小鼠移植组,排斥反应明显减轻。
三组小鼠皮肤移植后,IL-17、IL-23及IL-23mRNA、IL-17mRNA术后第1天内均表达升高,差异无统计学意义(P＞0.05);随着移植时间的延长,2、3组IL-17、IL-23及IL-23mRNA、IL-17mRNA的表达明显升高,与第1组相比差异有统计学意义(P＜0.01);2与3组术后3、5、7天的IL-23、IL-23mRNA的表达与1组相比,差异有统计学意义(P＜0.05);2、3组相比无统计学意义(P＞0.05);三组术后第3、5、7天的IL-17、IL-17mRNA表达结果显示:1、3组与第2组之间相比差异均有统计学意义(P＜0.01)。1、3组之间无统计学差异(P＞0.05)。
流式细胞术检测显示:三组CD4~+FoxP3~+Treg细胞术后第1天占CD4~+T细胞的比例分别为(0.9±0.6)%、(0.7±0.5)%、(0.8±0.4)%,差异无统计学意义(P＞0.05)。在皮肤移植术后第7天,第3组CD4~+FoxP~(3+)Treg占CD~(4+)T细胞的比例高于2组,其分别为(5.1±2.8)%和(4.54±2.5)%,差别有统计学意义(P=0.00):Th17/CD4~+FoxP3~+Treg比值在第2组中的表达高于第3组差别有统计学意义(P=0.00)。
结论:
(1)、移植后早期发生急性排斥反应时,IL-23,IL-17及IL-23mRNA、IL-17mRNA处于高表达水平;无排斥反应条件下IL-23、IL-17及IL-23mRNA、IL-17mRNA早期升高,随着炎症减轻其数值降低,IL-23,IL-17可作为预测和纠正排斥反应发生的观察指标。
(2)、在急性排斥反应模型中IL-23与IL-17呈正相关性表达,IL-23作为IL-17的上游因子,对Th17细胞的成熟及其IL-17分泌有调控作用。抑制IL-23的分泌可降低IL-17的产生,可能降低排斥反应的发生。
(3)、受体输注供体脾细胞,可明显延长移植物的存活,其机制可能与IL-17的分泌降低CD4~+FoxP3~+Treg增多有关。
(4)、受体输注供体脾细胞可刺激Treg细胞生成,Thl7/CD4~+FoxP3~+Treg比值可能影响移植后的免疫状态。
Objective:To probe the changes of interleukin23(IL-23) and interleukinl 7(IL-17) in the peripheral circulation and the pathological tissues and organ after the skin transplantation in mice;to disscuss the interaction during IL-23,IL-17 and regulatory T cells under the situation of different immune state;to understand the effect of immulogical regulation of IL-23/IL-17 axis after the skin transplantation in mice and to provide the guidance of the theory for the prevention,diagnosis,treatment and immune tolerance of rejection after transplantation in clinic.
Method:The construction of animal model of skin transplantation in mice(n=10): groupl,isotransplantation(BALB/c→BALB/c);group2,allotransplantation (C57BL/6→BALB/c);group3,the donor spleenocytes were transfused to the recipient before transplantation(C57BL/6→BALB/c).To observe the three groups appearance changes of the transplanted skin and the pathological sections difference with Hematoxylin-eosine(HE) at different timing;to detect the concentration of IL-17,IL-23 in blood serum with ELISA method,IL-23mRNA,IL-17mRNA with R-T-PCR and Tregs in spleen with Flow cytometry.
Result:With the observation and sections of H.E:the transplanted skin is well in the isotransplantation group without acute rejection,the typical acute rejection was occurred in the allotransplantation group and the rejection was significantly reduce in the group of preoperative infusion of allogeneic spleen cells in mice.There is no statistical significance in three groups among IL-17,IL-23,IL-23mRNA and IL-17mRNA at the first day after skin transplantation in mice(P＞0.05);to compare group2,group 3 with the groupl,there is statistical significance with the expressions of IL-23,IL-23mRNA at the 3,5,7 day(P＜0.01) and at the same time there is no statistical significance between 2rd and 3th group(P＞0.05);with the expressions of IL-17,IL-17mRNA,there is also significant difference between group2 and group1 or 3,and no statistical significance between 1 and 3 group at 3,5,7day after skin transplantation(P＜0.01).
The percentage of CD4~+FoxP3+Treg account for CD4+T of the three groups is (0.9±0.6)%,(0.7±0.5)%,(0.8±0.4)%respectively at 1 day after transplantation and no statistical significance of three groups(P＞0.05).At the 7 day,the percentage of 3 group is higer than that of 2 group,(5.1±2.8)%,(4.54±2.5)%respectively with statistically significant(p=0.00);the relative value of Th17/CD4~+FoxP3+Treg in the 2 group is higer than that in the 3 group(p=0.00).
Conclusion:
1.Early post-transplant acute rejection occurs,expression of IL-23,IL-17 and IL-23mRNA,IL-17mRNA is in high-level;under conditions of no rejection and immune tolerance,IL-23,IL-17 and IL-23mRNA,IL-17mRNA rise in early stage,reducing its value as reduced inflammation,IL-23,IL-17 could serve as a preditor of acute rejection and prognostic indicator.
2.In the acute rejection model,IL-23 and IL-17 expression was positively correlated.As the upper reaches of the IL-17 factor,IL-23 regulates Th17 cell growth and its secretion of IL-17.Inhibition of IL-23 may reduce IL-17 production,which might decrease the incidence of rejection.
3.Infusion of donor spleen cells,can induce immune tolerance in skin allograft recipient mice.The mechanism may be related to the reduction of IL-17 and the increase of CD4+FoxP3+Tregs.
4.Infusion of donor spleen cells may stimulate the generation of CD4+FoxP3+ Tregs in skin allograft recipient mice.Th17/CD4+FoxP3+Treg ratio may affect the immune system after transplantation.
方法:小鼠皮肤移植动物模型的建立(n=10):第1组、同种同基因移植组(BALB/c→BALB/c)、第2组、同种异基因移植组(C57BL/6→BALB/c),第3组、供体脾细胞输注组(C57BL/6→BALB/c)。观察三组不同时间移植皮瓣外观变化及镜下三组移植皮肤HE切片的病理改变;采用ELISA方法检测小鼠血浆IL-17、IL-23的浓度;RT-PCR反应检测移植皮肤及脾脏的IL-23mRNA、IL-17mRNA的表达;流式细胞仪检测脾脏Treg细胞百分比。
结果:三组小鼠移植后大体外观及HE染色镜下所见:同基因移植组小鼠移植皮术后皮片生长完好,无排斥反应发生;异基因小鼠移植皮出现典型的急性排斥反应;术前输注脾细胞异基因小鼠移植组,排斥反应明显减轻。
三组小鼠皮肤移植后,IL-17、IL-23及IL-23mRNA、IL-17mRNA术后第1天内均表达升高,差异无统计学意义(P＞0.05);随着移植时间的延长,2、3组IL-17、IL-23及IL-23mRNA、IL-17mRNA的表达明显升高,与第1组相比差异有统计学意义(P＜0.01);2与3组术后3、5、7天的IL-23、IL-23mRNA的表达与1组相比,差异有统计学意义(P＜0.05);2、3组相比无统计学意义(P＞0.05);三组术后第3、5、7天的IL-17、IL-17mRNA表达结果显示:1、3组与第2组之间相比差异均有统计学意义(P＜0.01)。1、3组之间无统计学差异(P＞0.05)。
流式细胞术检测显示:三组CD4~+FoxP3~+Treg细胞术后第1天占CD4~+T细胞的比例分别为(0.9±0.6)%、(0.7±0.5)%、(0.8±0.4)%,差异无统计学意义(P＞0.05)。在皮肤移植术后第7天,第3组CD4~+FoxP~(3+)Treg占CD~(4+)T细胞的比例高于2组,其分别为(5.1±2.8)%和(4.54±2.5)%,差别有统计学意义(P=0.00):Th17/CD4~+FoxP3~+Treg比值在第2组中的表达高于第3组差别有统计学意义(P=0.00)。
结论:
(1)、移植后早期发生急性排斥反应时,IL-23,IL-17及IL-23mRNA、IL-17mRNA处于高表达水平;无排斥反应条件下IL-23、IL-17及IL-23mRNA、IL-17mRNA早期升高,随着炎症减轻其数值降低,IL-23,IL-17可作为预测和纠正排斥反应发生的观察指标。
(2)、在急性排斥反应模型中IL-23与IL-17呈正相关性表达,IL-23作为IL-17的上游因子,对Th17细胞的成熟及其IL-17分泌有调控作用。抑制IL-23的分泌可降低IL-17的产生,可能降低排斥反应的发生。
(3)、受体输注供体脾细胞,可明显延长移植物的存活,其机制可能与IL-17的分泌降低CD4~+FoxP3~+Treg增多有关。
(4)、受体输注供体脾细胞可刺激Treg细胞生成,Thl7/CD4~+FoxP3~+Treg比值可能影响移植后的免疫状态。
Objective:To probe the changes of interleukin23(IL-23) and interleukinl 7(IL-17) in the peripheral circulation and the pathological tissues and organ after the skin transplantation in mice;to disscuss the interaction during IL-23,IL-17 and regulatory T cells under the situation of different immune state;to understand the effect of immulogical regulation of IL-23/IL-17 axis after the skin transplantation in mice and to provide the guidance of the theory for the prevention,diagnosis,treatment and immune tolerance of rejection after transplantation in clinic.
Method:The construction of animal model of skin transplantation in mice(n=10): groupl,isotransplantation(BALB/c→BALB/c);group2,allotransplantation (C57BL/6→BALB/c);group3,the donor spleenocytes were transfused to the recipient before transplantation(C57BL/6→BALB/c).To observe the three groups appearance changes of the transplanted skin and the pathological sections difference with Hematoxylin-eosine(HE) at different timing;to detect the concentration of IL-17,IL-23 in blood serum with ELISA method,IL-23mRNA,IL-17mRNA with R-T-PCR and Tregs in spleen with Flow cytometry.
Result:With the observation and sections of H.E:the transplanted skin is well in the isotransplantation group without acute rejection,the typical acute rejection was occurred in the allotransplantation group and the rejection was significantly reduce in the group of preoperative infusion of allogeneic spleen cells in mice.There is no statistical significance in three groups among IL-17,IL-23,IL-23mRNA and IL-17mRNA at the first day after skin transplantation in mice(P＞0.05);to compare group2,group 3 with the groupl,there is statistical significance with the expressions of IL-23,IL-23mRNA at the 3,5,7 day(P＜0.01) and at the same time there is no statistical significance between 2rd and 3th group(P＞0.05);with the expressions of IL-17,IL-17mRNA,there is also significant difference between group2 and group1 or 3,and no statistical significance between 1 and 3 group at 3,5,7day after skin transplantation(P＜0.01).
The percentage of CD4~+FoxP3+Treg account for CD4+T of the three groups is (0.9±0.6)%,(0.7±0.5)%,(0.8±0.4)%respectively at 1 day after transplantation and no statistical significance of three groups(P＞0.05).At the 7 day,the percentage of 3 group is higer than that of 2 group,(5.1±2.8)%,(4.54±2.5)%respectively with statistically significant(p=0.00);the relative value of Th17/CD4~+FoxP3+Treg in the 2 group is higer than that in the 3 group(p=0.00).
Conclusion:
1.Early post-transplant acute rejection occurs,expression of IL-23,IL-17 and IL-23mRNA,IL-17mRNA is in high-level;under conditions of no rejection and immune tolerance,IL-23,IL-17 and IL-23mRNA,IL-17mRNA rise in early stage,reducing its value as reduced inflammation,IL-23,IL-17 could serve as a preditor of acute rejection and prognostic indicator.
2.In the acute rejection model,IL-23 and IL-17 expression was positively correlated.As the upper reaches of the IL-17 factor,IL-23 regulates Th17 cell growth and its secretion of IL-17.Inhibition of IL-23 may reduce IL-17 production,which might decrease the incidence of rejection.
3.Infusion of donor spleen cells,can induce immune tolerance in skin allograft recipient mice.The mechanism may be related to the reduction of IL-17 and the increase of CD4+FoxP3+Tregs.
4.Infusion of donor spleen cells may stimulate the generation of CD4+FoxP3+ Tregs in skin allograft recipient mice.Th17/CD4+FoxP3+Treg ratio may affect the immune system after transplantation.
引文
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[21]Schnurr M,Toy T,Shin A,et al.Extracellular nucleotide signaling by P2 receptors inhibits IL-12 and enhances IL-23 expression in human dendritic cells:a novel role for the cAMP pathway.Blood 2005,105:1582-1589
[22]Schulz O,Edwards AD,Schito M,et al.CD40 triggering of heterodimeric IL-12 p70 production by dendritic cells in vivo requires a microbial priming signal.Immunity 2000,13:453-462
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[28]Veckman V,Miettinen M,Pirhonen J,et al.Streptococcus pyogenes and Lactobacillus rhamnosus differentially induce maturation and production of Th1-type cytokines and chemokines in human monocyte-derived dendritic cells.J.Leukoc.Biol.2004,75:764-771
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[34]Matusevicius D,Kivis(a|¨)kk P,He B,et al.Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis.Mult.Scler.1999,5:101-104
[35]Kotake S,UdagawaN,Takahashi N,et al.IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis.J.Clin.Invest.1999,103:1345-1352
[36]Li J,Li D,Tan Z.The expression of interleukin-17,interferon-gamma,and macrophage inflammatory protein-3 alpha mRNA in patients with psoriasis vulgaris.J Huazhong Univ Sci Technolog Med Sci.2004,24:294-296
[37]Afkarian M,Sedy JR,Yang J,et al.T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4C T cells.Nat.Immunol.2002,3:549-557
[38]Lovett-Racke AE,Rocchini AE,Choy J,et al.Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes.Immunity.2004,21,719-731
[39]Lugo-Villarino G,Maldonado-Lopez R,Possemato R,et al.T-bet is required for optimal production of IFN-gamma and antigen-specific T cell activation by dendritic cells.Proc.Natl.Acad.Sci.U.S.A.2003,100:7749-7754
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[57]Jianping Li,Eleonora Simeoni,Sylvain Fleury,et al Gene transfer of soluble interleukin-17 receptor prolongs cardiac allograft survival in a rat model.European Journal of Cardio-thoracic Surgery 2006,29:779—783
2、Halloran,P.,T.Batiuk,N.Goes,et al.An overview of the cytokines in transplantation.Transplant Sci.1993,3:69.
3、Paul,L.C.Growth factors in chronic rejection.Transplant Sci.1993,3:113.
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5、Kupiec-Weglinski,J.W.,T.Sablinski,W.W.Hancock,et al.Modulation of accelerated rejection of cardiac allografts in sensitized rats by anti-interleukin-2 receptor monoclonal antibody and cyclosporine therapy.Transplantation 1991,51:300.
6、Imagawa,D.K.,J.M.Millis,P.Seu,et al.The role of tumor necrosis factor in allograft rejection.Ⅲ.Evidence that anti-TNF antibody therapy prolongs allograft survival in rats with acute rejection.Transplantation 1991,51:57.
7、Landolfo,S.,F.Cofano,M.Giovarelli,et al.Inhibition of interferon-g may suppress allograft reactivity by T lymphocytes in vitro and in vivo.Science 1985,229:176.
8、Maliszewski,C.R.,P.J.Morrissey,W.C.Fanslow,et al.Delayed allograft rejection in mice transgenic for a soluble form of the IL-4 receptor.Cell.Immunol.1992,143:434.
9、Williamson,E.,P.Garside,J.A.Bradley,et al.Neutralizing IL-12 during induction of murine acute graft-versus-host disease polarizes the cytokine profile toward a Th2-type alloimmune response and confers long term protection from disease.J.Immunol.1997,159:1208.
10、Pugh-Humphreys,R.G.P.,A.W.Thomson,et al.Cytokines and their receptors as potential therapeutic targets.In The Cytokine Handbook,3rd Ed.A.W.Thomson,ed.Academic Press,San Diego,1998,p.885.
11、Yao,Z.,W.C.Fanslow,M.F.Seldin,et al.Herpesvirus saimiri encodes a new cytokine,IL-17,which binds to a novel cytokine receptor.Immunity 1995,3:811.
12、Jovanovic,D.V.,J.A.Di Battista,J.Martel-Pelletier,et al.IL-17 stimulates the production and expression of proinflammatory cytokines,IL-1b and TNF-a,by human macrophages.J.Immunol.1998,160:3513.
13、Mary A.Antonysamy,William C.et al Evidence for a Role of IL-17 in Organ Allograft Rejection:IL-17 Promotes the Functional Differentiation of Dendritic Cell Progenitors 1 The Journal of Immunology,1999,162:577-584.
14、Che-Chuan Loong,Hsian-Guey Hsieh,Wing-Yiu Lui,et al Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection.J Pathol 2002,197:322-332.
15、Jianping Li,Eleonora Simeoni,Sylvain Fleury,et al Gene transfer of soluble interleukin-17 receptor prolongs cardiac allograft survival in a rat model.European Journal of Cardio-thoracic Surgery 2006,29:779—783
16、Mosmann TR,Cherwinski H,Bond MW,et al.Two types of murine helper T cell clone.I.Definition according to profiles of lymphokine activities and secreted proteins.J.Immunol.1986,136:2348-2357
17、Mosmann,T.R.and Coffman,R.L.TH1 and TH2 cells:different patterns of lymphokine secretion lead to different functional properties.Annu.Rev.Immunol.1989,7:145-173
18、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
19、Rouvier E,Luciani MF,Mattei MG,et al.CTLA-8,cloned from an activated T cell,bearing AU-rich messenger RNA instability sequences,and homologous to a herpesvirus saimiri gene.J.Immunol.1993,150:5445-5456
20、Matusevicius D,Kivis(a|¨)kk P,He B,et al.Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis.Mult.Scler.1999,5:101-104
21、otake S,Udagawa N,Takahashi N,et al.IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis.J.Clin.Invest.1999,103:1345-1352
22、Li J,Li D,Tan Z.The expression of interleukin-17,interferon-gamma,and macrophage inflammatory protein-3 alpha mRNA in patients with psoriasis vulgaris.J Huazhong Univ Sci Technolog Med Sci.2004,24:294-296
23、Jefford M,Schnurr M,Toy T,et al.Functional comparison of DCs generated in vivo with Flt3 ligand or in vitro from blood monocytes:differential regulation of function by specific classes of physiologic stimuli.Blood 2003,102:1753-1763
24、Smits HH,van Beelen AJ,Hessle C,et al.Commensal Gram-negative bacteria prime human dendritic cells for enhanced IL-23 and IL-27 expression and enhanced Thl development.Eur.J.Immunol.2004,34:1371-1380
25、Krajina T,Leithauser F,Moller P,et al.Colonic lamina propria dendritic cells in mice with CD4C T cell-induced colitis.Eur.J.Immunol.2003,33:1073-1083
26、Oppmann B,Lesley R,Blom B,et al.Novel p1 protein engages IL-12p40 to form a cytokine,IL-23,with biological activities similar as well as distinct from IL-12.Immunity 2000,13:715-725
27、Happel KI,Zheng M,Young E,et al.Cutting edge:roles of Toll-like receptor 4 and IL-23 in IL-17 expression in response to Klebsiella pneumoniae infection.J.Immunol.2003,170:4432-4436
28、Stark MA,Huo Y,Burcin TL,et al.Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17.Immunity.2005,22:285-294
29、Kolls,J.K.and Linden,A.Interleukin-17 family members and inflammation.Immunity 2004,21:467-476
30、Aggarwal S,Ghilardi N,Xie MH,et al.Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17.J.Biol.Chem.2003,278:1910-1914
31.Bettelli,E,Y.Carrier,W.Gao,et al.Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cell.Nature.2006,441:235-8
32.Mangan,P.R.,L.E.Harrington,D.B.O' Quinn,et al.Transforming growth factor-beta induces development of th T(H)17 lineage.Nature.2006,441:231-237
33.Veldhoen,M.,R.J.Hocking,C.J.Atkins,et al.TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells Immunity.2006,24:179-89
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[28]Veckman V,Miettinen M,Pirhonen J,et al.Streptococcus pyogenes and Lactobacillus rhamnosus differentially induce maturation and production of Th1-type cytokines and chemokines in human monocyte-derived dendritic cells.J.Leukoc.Biol.2004,75:764-771
[29]Fedele G,Stefanelli P,Spensieri F,et al.Bordetella pertussis-infected human monocyte-derived dendritic cells undergo maturation and induce Th1. polarization and interleukin-23 expression.Infect.Immun.2005,73:1590-1597
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[31]Mosmann TR,Cherwinski H,Bond MW,et al.Two types of murine helper T cell clone.I.Definition according to profiles of lymphokine activities and secreted proteins.J.Immunol.1986,136:2348-2357
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[35]Kotake S,UdagawaN,Takahashi N,et al.IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis.J.Clin.Invest.1999,103:1345-1352
[36]Li J,Li D,Tan Z.The expression of interleukin-17,interferon-gamma,and macrophage inflammatory protein-3 alpha mRNA in patients with psoriasis vulgaris.J Huazhong Univ Sci Technolog Med Sci.2004,24:294-296
[37]Afkarian M,Sedy JR,Yang J,et al.T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4C T cells.Nat.Immunol.2002,3:549-557
[38]Lovett-Racke AE,Rocchini AE,Choy J,et al.Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes.Immunity.2004,21,719-731
[39]Lugo-Villarino G,Maldonado-Lopez R,Possemato R,et al.T-bet is required for optimal production of IFN-gamma and antigen-specific T cell activation by dendritic cells.Proc.Natl.Acad.Sci.U.S.A.2003,100:7749-7754
[40]Happel KI,Zheng M,Young E,et al.Cutting edge:roles of Toll-like receptor 4 and IL-23 in IL-17 expression in response to Klebsiella pneumoniae infection.J.Immunol.2003,170:4432-4436
[41]Stark MA,Huo Y,Burcin TL,et al.Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17.Immunity.2005,22:285-294
[42]Kolls,J.K.and Linden,A.Interleukin-17 family members and inflammation.Immunity 2004,21:467-476
[43]Rice L,Orlow D,Ceonzo K,Stahl GL et al.CpG oligodeoxynucleotide protection in polymicrob(?) sepsis is dependent on interleukin-17.J.Infect.Dis.2005,191:1368-1376
[44]Halloran,P.,T.Batiuk,N.Goes,et al.An overview of the cytokines in transplantation.Transplant Sci.1993,3:69.
[45]Paul,L.C.Growth factors in chronic rejection.Transplant Sci.1993,3:113.
[46]Kirkman,R.L.,L.V.Barrett,G.N.Gaulton,et al Administration ofanti-interleukin-2 monoclonal antibody prolongs cardiac allograft survival in mice.J.Exp.Med.1985,162:358.
[47]Kupiec-Weglinski,J.W.,T.Sablinski,W.W.Hancock,et al.Modulation of accelerated rejection of cardiac allografts in sensitized rats by anti-interleukin-2 receptor monoclonal antibody and cyclosporine therapy.Transplantation 1991,51:300.
[48]Imagawa,D.K.,J.M.Millis,P.Seu,et al.The role of tumor necrosis factor in allograft rejection.Ⅲ.Evidence that anti-TNF antibody therapy prolongs allograft survival in rats with acute rejection.Transplantation 1991,51:57.
[49]Landolfo,S.,F.Cofano,M.Giovarelli,et al.Inhibition of interferon-g may suppress allograft reactivity by T lymphocytes in vitro and in vivo.Science 1985,229:176.
[50]Maliszewski,C.R.,P.J.Morrissey,W.C.Fanslow,et al.Delayed allograft rejection in mice transgenic for a soluble form of the IL-4 receptor.Cell.Immunol.1992,143:434.
[51]Williamson,E.,P.Garside,J.A.Bradley,et al.Neutralizing IL-12 during induction of murine acute graft-versus-host disease polarizes the cytokine profile toward a Th2-type alloimmune response and confers long term protection from disease.J.Immunol.1997,159:1208.
[52]Pugh-Humphreys,R.G.P.,A.W.Thomson,et al.Cytokines and their receptors as potential therapeutic targets.In The Cytokine Handbook,3rd Ed.A.W.Thomson,ed.Academic Press,San Diego,1998,p.885.
[53]Yao,Z.,W.C.Fanslow,M.F.Seldin,et al.Herpesvirus saimiri encodes a new cytokine,IL-17,which binds to a novel cytokine receptor.Immunity1995,3:811.
[54]Jovanovic,D.V.,J.A.Di Battista,J.Martel-Pelletier,et al.IL-17 stimulates the production and expression of proinflammatory cytokines,IL-1b and TNF-a,by human macrophages.J.Immunol.1998,160:3513.
[55]Mary A.Antonysamy,William C.et al Evidence for a Role of IL-17 in Organ Allograft Rejection:IL-17 Promotes the Functional Differentiation of Dendritic Cell Progenitorsl The Journal of Immunology,1999,162:577-584.
[56]Che-Chuan Loong,Hsian-Guey Hsieh,Wing-Yiu Lui,et al Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection.J Pathol 2002,197:322-332.
[57]Jianping Li,Eleonora Simeoni,Sylvain Fleury,et al Gene transfer of soluble interleukin-17 receptor prolongs cardiac allograft survival in a rat model.European Journal of Cardio-thoracic Surgery 2006,29:779—783
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