人脐带来源间充质干细胞的免疫调节作用
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摘要
背景：间充质干细胞(Mesenchymal Stem cells, MSC)是一类具有自我更新(selfrenewal)和多向分化潜能(multi-lineage differentiation)的成体干细胞。它来源广泛,具有支持造血和多向分化功能；随着对MSC认识的不断加深,人们还发现MSC具有低免疫原性和较强的免疫调节功能。目前研究最多的主要是人骨髓来源的间充质干细胞(hBM-MSC).人脐带来源的间充质干细胞(hUC-MSC)由于其较人骨髓来源间充质干细胞更易于制备以及低风险病毒感染,并且脐带来源间充质干细胞易于体外培养及扩增等优势已经成为人骨髓来源间充质干细胞非常好的替代品。但是,人脐带来源间充质干细胞在免疫调节方面功能尚未有深入研究。
目的：研究人脐带来源间充质干细胞发挥免疫学效应的作用及发挥作用的机制。方法：人外周血单个核细胞由不同的刺激剂刺激后与人脐带来源间充质干细胞共培养,通过检测人外周血单个核细胞的增殖及IFN-γ分泌情况观察人脐带来源间充质干细胞免疫调节效应；用transwell培育板培养来研究间充质干细胞的免疫调节作用是否需要细胞直接接触；用各种抑制剂确定人脐带来源间充质干细胞发挥免疫学效应的因子机制；另外,通过流式检测人外周血单个核细胞Annexin-V的情况来观察人脐带来源间充质干细胞发挥效应的情况及相关机制。
结果：人脐带来源间充质干细胞能够有效有效抑制人外周血单个核细胞刺激后的增殖及IFN-γ的分泌；Transwell系统共培养结果显示此抑制效果不受细胞接触的影响,既是这种抑制作用主要通过因子发挥免疫效应；抑制剂试验排除了TGF-β,IDO和NO的可能,并确定了前列腺素E2(PGE2)是人脐带来源间充质干细胞发挥免疫学效应的介导因子；炎症因子IFN-γ和IL-1β能显著上调人脐带来源间充质干细胞PGE2的分泌；人脐带来源间充质干细胞能保护人外周血单个核细胞刺激后的凋亡发生,并且此保护效应也是通过分泌PGE2发挥的作用。
结论：人脐带来源间充质干细胞(hUC-MSC)同样能够发挥很好的免疫调节作用,并且第一次发现这种细胞的免疫学效应主要是通过PGE2的分泌实现,这一机制对于将来人脐带来源间充质干细胞的临床应用提供了理论基础。
背景：一种最近受人关注的因子IL-17,作为适应性免疫应答系统的标志炎症因子,最初由一群新T细胞群‘Th17’产生。在最近几年的研究中取得了许多相关成果,包括Thl7细胞趋导分化的分子机制的统一标准。这些对于弄清Th17细胞在宿主防御和自身免疫中的作用有很大帮助。最近的研究证实由IL-17产生细胞激发的炎症是许多人类自身免疫病动物自身免疫病模型的发展和致病的中心环节。并且激活的IL-23／IL-17轴对于系统性红斑狼疮(SLE)病免疫炎症非常重要。间充质干细胞是一种多能干细胞,可以向中胚层来源组织分化并且从各种组织分离得到。MSCs已经被认为在免疫细胞上拥有非常广泛的免疫调节作用,对许多效应功能有调节作用。最近报道胎儿骨髓来源MSCs能够促进正常供者来源的IL-17分泌细胞的扩增。而脐带来源MSCs对于免疫细胞这一效应尚不清楚。
目的：本文主要研究脐带来源间充质干细胞(hUC-MSCs)对于来自于正常供者或者SLE患者T淋巴细胞的免疫调节效应作用,特别是对于Th17细胞。这样可以扩展我们对于MSCs免疫调节功能的理解以及其作为细胞依赖治疗免疫紊乱疾病的临床运用潜力提供更多见解。
方法：我们将hPBMCs(来自于健康供者和SLE病人)或者CD4+T(来自于健康供者)细胞与hUC-MSCs培养,并将这个培养体系称为共培养细胞。hPBMCs细胞由丝裂原PHA刺激,而CD4+T细胞由ati-CD3/CD28 Dynabeads刺激。①我们用实时定量PCR,酶联免疫吸附法对比建康供者或者SLE患者来源hPBMCs表达IL-17分泌的水平。并检测加入另IL-6,PGE2和IL-1β中和试剂的IL-17表达改变。用酶联免疫吸附法和流式细胞仪检测CD4+T细胞在与hUC-MSCs作用后IL-17分泌表达量的改变。③IFN-γ和TGF-β的表达用酶联免疫吸附法检测,而Thl细胞和Treg细胞比例由流式细胞仪技术检测。④我们用酶联免疫吸附法比较健康供者和SLE患者IL-23的分泌水平改变。
结果：正常供者来源CD4+T细胞与脐带来源MSCs共培养比单纯培养正常供者CD4+T细胞能够产生高的IL-17分泌水平。相同的结果在正常供者PBMCs细胞中也得到证实。抑制试验证实这个效应可能部分是通过PGE2或者IL-1β介导产生的,并且IL-23不参与其中。接下来我们将hUC-MSCs与SLE患者来源PBMCs细胞共培养,体外诱导IL-17的能力,hUC-MSCs能够更促进SLE病人分泌,但是并不能影响IL-23的分泌。同时,hUC-MSCs降低了Thl细胞数量而增加Treg细胞数量。
结论：综上所述,我们的结果第一次报道了hUC-MSCs同时促进健康供者和SLE病人来源PBMCs产生IL-17。PGE2和IL-1β可能部分参与hUC-MSCs的这个促进作用。这个发现可能对于hUC-MSCs运用于SLE患者潜在致病作用提出观点。考虑到血清中IL-17含量与SLE患者疾病活性相关性,临床运用hUC-MSCs治疗SLE可能需要更多仔细的研究。
BACKGROUND:Mesenchymal stem cells(MSCs), the nonhematopoietic progenitor cells found in various adult tissues, are characterized by their ease of isolation and their rapid growth in vitro while maintaining their differentiation potential, allowing for extensive culture expansion to obtain large quantities suitable for therapeutic use. Mesenchymal stem cells isolated from human bone marrow, which are poorly immunogenic and have potent immunosuppressive activities, have emerged as a promising candidate for cellular therapeutics for the treatment of disorders caused by abnormal immune responses. Human umbilical cord derived mesenchymal stem cells (hUC-MSCs) resemble bone marrow MSCs (BM-MSCs) in many respects, but its immunosuppression are still lack in the literature.
OBJECTION:This study was designed to investigat the immunosuppressive action by MSCs derived from human umbilical cord, and in the meantime to analyze the potential mechanism(s).
METHODS:hUC-MSCs were co-cultured with MHC-mismatched allogeneic hPBMCs which in response to mitogenic or allogeneic stimulus. Both proliferation of human peripheral blood mononuclear cells (hPBMCs) and their IFN-γproduction were used to determine the immunosuppressive action of hUC-MSCs. And the transwell experiments were carried out for analyzing the contact necessary; Blocking experiments were used to identify which soluble factor(s) mediated the immunosuppressive effects; In addition, the data of Annexin-V showed the ability of hUC-MSCs on the apotosis of activated-hPBMCs.
RESULTS:In this study, both proliferation of human peripheral blood mononuclear cells (hPBMCs) and their IFN-γproduction in response to mitogenic or allogeneic stimulus were effectively inhibited by hUC-MSCs. Co-culture experiments in transwell systems indicated that the suppression was largely mediated by soluble factor(s). Blocking experiments identified prostaglandin E2 (PGE2) as the major factor, because inhibition of PGE2 synthesis almost completely mitigated the immunosuppressive effects, whereas neutralization of TGF-β, IDO and NO activities had little effects. Moreover, the inflammatory cytokines, IFN-γand IL-1βproduced by hPBMCs upon activation notably up-regulated the expression of cyclooxygenase-2 (COX-2) and the production of PGE2 by hUC-MSCs. In addition, PGE2 was also found able to protect hPBMCs from apoptosis.
CONCLUSION:In conclusion, our data have demonstrated for the first time that the PGE2 mediated mechanism by which hUC-MSCs exert their immunomodulatory effects. These mechanisms can render the theory basic to clinical usage of hUC-MSCs.
Background:The emerging role of interleukin(IL)-17 as a hallmark proinflammatory cytokine of the adaptive immune system, producted primarily by a new T helper cell subset termed'Th17', has received considerable attention. There has been much progress in the past year, leading to identification of the molecular mechanisms that drive differentiation of Th17 T cells. This has helped to clarify many aspects of their role in host defense as well as in autoimmunity. Recent studies have shown that inflammation instigated by IL-17-producing cells is central to the development and pathogenesis of several human autoimmune diseases and animal models of autoimmunity. And the activated IL-23/IL-17 axis is important for the inflammatory immunity in SLE. Mesenchymal stem cells (MSC) are multipotent stem cells that can differentiate into tissues of mesodermal origin and can be isolated from various tissues. MSC have also been noted to have profound immunomodulatory effects on immune cells, leading to the modulation of several effector functions. Recently, the expansion of IL-17 producing cells from healthy donors is reportedly promoted by mesenchymal stem cells derived from fetal bone marrow.
Objective:This article aimed to investigate the immunoregulatory effects of human umbilical cords-derived MSC on human T lymphocytes from healthy donors and Systemic Lupus Erythematosus patients, especially Th17 cells, so as to broaden our understanding of the immunomodulatory properties of MSC and provide insights as to their potential for clinical use as a cell-based therapy for immune-mediated disorders.
Methods:In the present study, We cultured hPBMCs(from healthy donor and SLE patients) and CD4+T cells with or without hUC-MSCs, and named the coculture of hPBMCs or CD+4 T cells with hUC-MSCs as coculture cells. hPBMCs were incubated with PHA, while CD4+T cells were incubated with ati-CD3/CD28 Dynabeads in the presence or absence of hUC-MSCs.①We used qRT-PCR, Elisa analyses to compare the expression levels of IL-17 secretion of hPBMCs from healthy donor or SLE patients. The change of IL-17 expression when supplemented with additional IL-6, PGE2 and IL-1βneutralizing reagent.
②The expression of IL-17 secretion from CD4+T cells was tested by Elisa and Th-17 cells was tested by cytometry analyses.③The expression of IFN-γand TGF-βwere tested by Elisa and the percentage of Thl cells and Treg cells were tested by cytometry analyses.④We used Elisa to compare the expression levels ofIL-23 secretion of hPBMCs from healthy donor or SLE patients.
Results:Significantly higher levels of IL-17 were produced when CD4+T cells from healthy donors were cocultured with hUC-MSCs than when CD4+T cells from healthy donors were cultured alone. The similar data was obtained on hPBMCs. Blocking experiments identified that this effect might be partially mediated through prostaglandin E2 (PGE2) and IL-1βwithout IL-23 involvement. We then cocultured hUC-MSCs with human PBMCs from Systemic Lupus Erythematosus patients. Ex vivo inductions of IL-17 by hUC-MSCs in stimulated lymphocytes were significantly higher in SLE patients than in controls, but this effect was not seen for IL-23. Also, hUC-MSC decrease the production of Thl cells and increase the production of Treg cells. Conclusion:Taken together, our results represent the first report of promotion of IL-17 production by hUC MSCs in both healthy donor and SLE patients. PGE2 and IL-1βmight also be partially involved in the promotive effect of hUC-MSCs. This finding may provide a new insight into the potential pathological roles of hUC-MSCs in SLE. Given that serum abundance of IL-17 has been correlated with SLE disease activity, clinical treatments using hUC-MSCs in SLE may require more careful research.
目的：研究人脐带来源间充质干细胞发挥免疫学效应的作用及发挥作用的机制。方法：人外周血单个核细胞由不同的刺激剂刺激后与人脐带来源间充质干细胞共培养,通过检测人外周血单个核细胞的增殖及IFN-γ分泌情况观察人脐带来源间充质干细胞免疫调节效应；用transwell培育板培养来研究间充质干细胞的免疫调节作用是否需要细胞直接接触；用各种抑制剂确定人脐带来源间充质干细胞发挥免疫学效应的因子机制；另外,通过流式检测人外周血单个核细胞Annexin-V的情况来观察人脐带来源间充质干细胞发挥效应的情况及相关机制。
结果：人脐带来源间充质干细胞能够有效有效抑制人外周血单个核细胞刺激后的增殖及IFN-γ的分泌；Transwell系统共培养结果显示此抑制效果不受细胞接触的影响,既是这种抑制作用主要通过因子发挥免疫效应；抑制剂试验排除了TGF-β,IDO和NO的可能,并确定了前列腺素E2(PGE2)是人脐带来源间充质干细胞发挥免疫学效应的介导因子；炎症因子IFN-γ和IL-1β能显著上调人脐带来源间充质干细胞PGE2的分泌；人脐带来源间充质干细胞能保护人外周血单个核细胞刺激后的凋亡发生,并且此保护效应也是通过分泌PGE2发挥的作用。
结论：人脐带来源间充质干细胞(hUC-MSC)同样能够发挥很好的免疫调节作用,并且第一次发现这种细胞的免疫学效应主要是通过PGE2的分泌实现,这一机制对于将来人脐带来源间充质干细胞的临床应用提供了理论基础。
背景：一种最近受人关注的因子IL-17,作为适应性免疫应答系统的标志炎症因子,最初由一群新T细胞群‘Th17’产生。在最近几年的研究中取得了许多相关成果,包括Thl7细胞趋导分化的分子机制的统一标准。这些对于弄清Th17细胞在宿主防御和自身免疫中的作用有很大帮助。最近的研究证实由IL-17产生细胞激发的炎症是许多人类自身免疫病动物自身免疫病模型的发展和致病的中心环节。并且激活的IL-23／IL-17轴对于系统性红斑狼疮(SLE)病免疫炎症非常重要。间充质干细胞是一种多能干细胞,可以向中胚层来源组织分化并且从各种组织分离得到。MSCs已经被认为在免疫细胞上拥有非常广泛的免疫调节作用,对许多效应功能有调节作用。最近报道胎儿骨髓来源MSCs能够促进正常供者来源的IL-17分泌细胞的扩增。而脐带来源MSCs对于免疫细胞这一效应尚不清楚。
目的：本文主要研究脐带来源间充质干细胞(hUC-MSCs)对于来自于正常供者或者SLE患者T淋巴细胞的免疫调节效应作用,特别是对于Th17细胞。这样可以扩展我们对于MSCs免疫调节功能的理解以及其作为细胞依赖治疗免疫紊乱疾病的临床运用潜力提供更多见解。
方法：我们将hPBMCs(来自于健康供者和SLE病人)或者CD4+T(来自于健康供者)细胞与hUC-MSCs培养,并将这个培养体系称为共培养细胞。hPBMCs细胞由丝裂原PHA刺激,而CD4+T细胞由ati-CD3/CD28 Dynabeads刺激。①我们用实时定量PCR,酶联免疫吸附法对比建康供者或者SLE患者来源hPBMCs表达IL-17分泌的水平。并检测加入另IL-6,PGE2和IL-1β中和试剂的IL-17表达改变。用酶联免疫吸附法和流式细胞仪检测CD4+T细胞在与hUC-MSCs作用后IL-17分泌表达量的改变。③IFN-γ和TGF-β的表达用酶联免疫吸附法检测,而Thl细胞和Treg细胞比例由流式细胞仪技术检测。④我们用酶联免疫吸附法比较健康供者和SLE患者IL-23的分泌水平改变。
结果：正常供者来源CD4+T细胞与脐带来源MSCs共培养比单纯培养正常供者CD4+T细胞能够产生高的IL-17分泌水平。相同的结果在正常供者PBMCs细胞中也得到证实。抑制试验证实这个效应可能部分是通过PGE2或者IL-1β介导产生的,并且IL-23不参与其中。接下来我们将hUC-MSCs与SLE患者来源PBMCs细胞共培养,体外诱导IL-17的能力,hUC-MSCs能够更促进SLE病人分泌,但是并不能影响IL-23的分泌。同时,hUC-MSCs降低了Thl细胞数量而增加Treg细胞数量。
结论：综上所述,我们的结果第一次报道了hUC-MSCs同时促进健康供者和SLE病人来源PBMCs产生IL-17。PGE2和IL-1β可能部分参与hUC-MSCs的这个促进作用。这个发现可能对于hUC-MSCs运用于SLE患者潜在致病作用提出观点。考虑到血清中IL-17含量与SLE患者疾病活性相关性,临床运用hUC-MSCs治疗SLE可能需要更多仔细的研究。
BACKGROUND:Mesenchymal stem cells(MSCs), the nonhematopoietic progenitor cells found in various adult tissues, are characterized by their ease of isolation and their rapid growth in vitro while maintaining their differentiation potential, allowing for extensive culture expansion to obtain large quantities suitable for therapeutic use. Mesenchymal stem cells isolated from human bone marrow, which are poorly immunogenic and have potent immunosuppressive activities, have emerged as a promising candidate for cellular therapeutics for the treatment of disorders caused by abnormal immune responses. Human umbilical cord derived mesenchymal stem cells (hUC-MSCs) resemble bone marrow MSCs (BM-MSCs) in many respects, but its immunosuppression are still lack in the literature.
OBJECTION:This study was designed to investigat the immunosuppressive action by MSCs derived from human umbilical cord, and in the meantime to analyze the potential mechanism(s).
METHODS:hUC-MSCs were co-cultured with MHC-mismatched allogeneic hPBMCs which in response to mitogenic or allogeneic stimulus. Both proliferation of human peripheral blood mononuclear cells (hPBMCs) and their IFN-γproduction were used to determine the immunosuppressive action of hUC-MSCs. And the transwell experiments were carried out for analyzing the contact necessary; Blocking experiments were used to identify which soluble factor(s) mediated the immunosuppressive effects; In addition, the data of Annexin-V showed the ability of hUC-MSCs on the apotosis of activated-hPBMCs.
RESULTS:In this study, both proliferation of human peripheral blood mononuclear cells (hPBMCs) and their IFN-γproduction in response to mitogenic or allogeneic stimulus were effectively inhibited by hUC-MSCs. Co-culture experiments in transwell systems indicated that the suppression was largely mediated by soluble factor(s). Blocking experiments identified prostaglandin E2 (PGE2) as the major factor, because inhibition of PGE2 synthesis almost completely mitigated the immunosuppressive effects, whereas neutralization of TGF-β, IDO and NO activities had little effects. Moreover, the inflammatory cytokines, IFN-γand IL-1βproduced by hPBMCs upon activation notably up-regulated the expression of cyclooxygenase-2 (COX-2) and the production of PGE2 by hUC-MSCs. In addition, PGE2 was also found able to protect hPBMCs from apoptosis.
CONCLUSION:In conclusion, our data have demonstrated for the first time that the PGE2 mediated mechanism by which hUC-MSCs exert their immunomodulatory effects. These mechanisms can render the theory basic to clinical usage of hUC-MSCs.
Background:The emerging role of interleukin(IL)-17 as a hallmark proinflammatory cytokine of the adaptive immune system, producted primarily by a new T helper cell subset termed'Th17', has received considerable attention. There has been much progress in the past year, leading to identification of the molecular mechanisms that drive differentiation of Th17 T cells. This has helped to clarify many aspects of their role in host defense as well as in autoimmunity. Recent studies have shown that inflammation instigated by IL-17-producing cells is central to the development and pathogenesis of several human autoimmune diseases and animal models of autoimmunity. And the activated IL-23/IL-17 axis is important for the inflammatory immunity in SLE. Mesenchymal stem cells (MSC) are multipotent stem cells that can differentiate into tissues of mesodermal origin and can be isolated from various tissues. MSC have also been noted to have profound immunomodulatory effects on immune cells, leading to the modulation of several effector functions. Recently, the expansion of IL-17 producing cells from healthy donors is reportedly promoted by mesenchymal stem cells derived from fetal bone marrow.
Objective:This article aimed to investigate the immunoregulatory effects of human umbilical cords-derived MSC on human T lymphocytes from healthy donors and Systemic Lupus Erythematosus patients, especially Th17 cells, so as to broaden our understanding of the immunomodulatory properties of MSC and provide insights as to their potential for clinical use as a cell-based therapy for immune-mediated disorders.
Methods:In the present study, We cultured hPBMCs(from healthy donor and SLE patients) and CD4+T cells with or without hUC-MSCs, and named the coculture of hPBMCs or CD+4 T cells with hUC-MSCs as coculture cells. hPBMCs were incubated with PHA, while CD4+T cells were incubated with ati-CD3/CD28 Dynabeads in the presence or absence of hUC-MSCs.①We used qRT-PCR, Elisa analyses to compare the expression levels of IL-17 secretion of hPBMCs from healthy donor or SLE patients. The change of IL-17 expression when supplemented with additional IL-6, PGE2 and IL-1βneutralizing reagent.
②The expression of IL-17 secretion from CD4+T cells was tested by Elisa and Th-17 cells was tested by cytometry analyses.③The expression of IFN-γand TGF-βwere tested by Elisa and the percentage of Thl cells and Treg cells were tested by cytometry analyses.④We used Elisa to compare the expression levels ofIL-23 secretion of hPBMCs from healthy donor or SLE patients.
Results:Significantly higher levels of IL-17 were produced when CD4+T cells from healthy donors were cocultured with hUC-MSCs than when CD4+T cells from healthy donors were cultured alone. The similar data was obtained on hPBMCs. Blocking experiments identified that this effect might be partially mediated through prostaglandin E2 (PGE2) and IL-1βwithout IL-23 involvement. We then cocultured hUC-MSCs with human PBMCs from Systemic Lupus Erythematosus patients. Ex vivo inductions of IL-17 by hUC-MSCs in stimulated lymphocytes were significantly higher in SLE patients than in controls, but this effect was not seen for IL-23. Also, hUC-MSC decrease the production of Thl cells and increase the production of Treg cells. Conclusion:Taken together, our results represent the first report of promotion of IL-17 production by hUC MSCs in both healthy donor and SLE patients. PGE2 and IL-1βmight also be partially involved in the promotive effect of hUC-MSCs. This finding may provide a new insight into the potential pathological roles of hUC-MSCs in SLE. Given that serum abundance of IL-17 has been correlated with SLE disease activity, clinical treatments using hUC-MSCs in SLE may require more careful research.
引文
[1]Friedenstein AJ, Piatetzky S, II, Petrakova KV. Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol 1966:16:381-390.
[2]Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E. minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006;8:315-317.
[3]Hu Y, Liao L, Wang Q, Ma L, Ma G, Jiang X, Zhao RC. Isolation and identification of mesenchymal stem cells from human fetal pancreas. J Lab Clin Med 2003;141:342-349.
[4]Barry FP, Murphy JM. Mesenchymal stem cells:clinical applications and biological characterization. Int J Biochem Cell Biol 2004:36:568-584.
[5]in't Anker PS, Noort WA, Scherjon SA, Kleijburg-van der Keur C, Kruisselbrink AB, van Bezooijen RL, Beekhuizen W, Willemze R, Kanhai HH, Fibbe WE. Mesenchymal stem cells in human second-trimester bone marrow, liver, lung, and spleen exhibit a similar immunophenotype but a heterogeneous multilineage differentiation potential. Haematologica 2003:88:845-852.
[6]Lee OK, Kuo TK, Chen WM, Lee KD, Hsieh SL, Chen TH. Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood 2004:103:1669-1675.
[7]Lu LL, Liu YJ, Yang SG, Zhao QJ, Wang X, Gong W, Han ZB, Xu ZS, Lu YX, Liu D, Chen ZZ, Han ZC. Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. Haematologica 2006;91:1017-1026.
[8]Sarugaser R, Lickorish D, Baksh D, Hosseini MM, Davies JE. Human umbilical cord perivascular (HUCPV) cells:a source of mesenchymal progenitors. Stem cells (Dayton, Ohio) 2005:23:220-229.
[9]Wang HS, Hung SC, Peng ST, Huang CC, Wei HM, Guo YJ, Fu YS, Lai MC, Chen CC. Mesenchymal stem cells in the Wharton's jelly of the human umbilical cord. Stem Cells 2004:22:1330-1337.
[10]Karahuseyinoglu S, Cinar 0, Kilic E, Kara F, Akay GG, Demiralp DO, Tukun A, Uckan D, Can A. Biology of stem cells in human umbilical cord stroma:in situ and in vitro surveys. Stem Cells 2007;25:319-331.
[11]Can A, Karahuseyinoglu S. Concise review:human umbilical cord stroma with regard to the source of fetus-derived stem cells. Stem Cells 2007:25:2886-2895.
[12]Lund RD, Wang S, Lu B, Girman S, Holmes T, Sauve Y, Messina DJ, Harris IR, Kihm AJ, Harmon AM, Chin FY, Gosiewska A, Mistry SK. Cells isolated from umbilical cord tissue rescue photoreceptors and visual functions in a rodent model of retinal disease. Stem Cells 2007;25:602-611.
[13]Weiss ML, Medicetty S, Bledsoe AR, Rachakatla RS, Choi M, Merchav S, Luo Y, Rao MS, Velagaleti G, Troyer D. Human umbilical cord matrix stem cells:preliminary characterization and effect of transplantation in a rodent model of Parkinson's disease. Stem Cells 2006;24:781-792.
[14]Liao W, Xie J, Zhong J, Liu Y, Du L, Zhou B, Xu J, Liu P, Yang S, Wang J, Han Z, Han ZC. Therapeutic effect of human umbilical cord multipotent mesenchymal stromal cells in a rat model of stroke. Transplantation 2009;87:350-359.
[15]Tsai PC, Fu TW, Chen YM, Ko TL, Chen TH, Shih YH, Hung SC, Fu YS. The therapeutic potential of human umbilical mesenchymal stem cells from Wharton's jelly in the treatment of rat liver fibrosis. Liver Transpl 2009:15:484-495.
[16]Weiss ML, Anderson C, Medicetty S, Seshareddy KB, Weiss RJ, VanderWerff I, Troyer D, McIntosh KR. Immune properties of human umbilical cord Wharton's jelly-derived cells. Stem cells (Dayton, Ohio) 2008:26:2865-2874.
[17]Cho PS, Messina DJ, Hirsh EL, Chi N, Goldman SN, Lo DP, Harris IR, Popma SH, Sachs DH, Huang CA. Immunogenicity of umbilical cord tissue derived cells. Blood 2008;111:430-438.
[18]Weiss ML, Mitchell KE, Hix JE, Medicetty S, El-Zarkouny SZ, Grieger D, Troyer DL. Transplantation of porcine umbilical cord matrix cells into the rat brain. Exp Neurol 2003;182:288-299.
[19]Medicetty S, Bledsoe AR, Fahrenholtz CB, Troyer D, Weiss ML. Transplantation of pig stem cells into rat brain:proliferation during the first 8 weeks. Exp Neurol 2004;190:32-41.
[20]Plumas J, Chaperot L, Richard MJ, Molens JP, Bensa JC, Favrot MC. Mesenchymal stem cells induce apoptosis of activated T cells. Leukemia 2005;19:1597-1604.
[21]Benvenuto F, Ferrari S, Gerdoni E, Gualandi F, Frassoni F, Pistoia V, Mancardi G, Uccelli A. Human mesenchymal stem cells promote survival of T cells in a quiescent state. Stem cells (Dayton, Ohio) 2007;25:1753-1760.
[22]Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, Dazzi F. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003:101:3722-3729.
[23]Beyth S, Borovsky Z, Mevorach D, Liebergall M, Gazit Z, Aslan H, Galun E, Rachmilewitz J. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood 2005;105:2214-2219.
[24]Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002;99:3838-3843.
[25]Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, Dilloo D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 2004;103:4619-4621.
[26]Jarvinen L, Badri L, Wettlaufer S, Ohtsuka T, Standiford TJ, Toews GB, Pinsky DJ, Peters-Golden M, Lama VN. Lung resident mesenchymal stem cells isolated from human lung allografts inhibit T cell proliferation via a soluble mediator. J Immunol 2008; 181:4389-4396.
[27]Lahiri T, Laporte JD, Moore PE, Panettieri RA, Jr., Shore SA. Interleukin-6 family cytokines:signaling and effects in human airway smooth muscle cells. American journal of physiology 2001;280:L1225-1232.
[28]Jiang XX, Zhang Y, Liu B, Zhang SX, Wu Y, Yu XD, Mao N. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 2005;105:4120-4126.
[29]English K, Barry FP, Field-Corbett CP, Mahon BP. IFN-gamma and
TNF-alpha differentially regulate immunomodulation by murine mesenchymal stem cells. Immunology letters 2007;110:91-100.
[30]Sato K, Ozaki K, Oh I, Meguro A, Hatanaka K, Nagai T, Muroi K, Ozawa K. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 2007;109:228-234.
[31]Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005;105:1815-1822.
[32]Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A, Santarlasci V, Mazzinghi B, Pizzolo G, Vinante F, Romagnani P, Maggi E, Romagnani S, Annunziato F. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 2006;24:386-398.
[33]Baksh D, Yao R, Tuan RS. Comparison of proliferative and multilineage differentiation potential of human mesenchymal stem cells derived from umbilical cord and bone marrow. Stem Cells 2007;25:1384-1392.
[34]Cattaneo E, McKay R. Proliferation and differentiation of neuronal stem cells regulated by nerve growth factor. Nature 1990; 347:762-765.
[35]Clayton A, Evans RA, Pettit E, Hallett M, Williams JD, Steadman R. Cellular activation through the ligation of intercellular adhesion molecule-1. J Cell Sci 1998;111 (Pt 4):443-453.
[36]Noaksson K, Zoric N, Zeng X, Rao MS, Hyllner J, Semb H, Kubista M, Sartipy P. Monitoring differentiation of human embryonic stem cells using real-time PCR. Stem Cells 2005;23:1460-1467.
[37]Niwa H. Molecular mechanism to maintain stem cell renewal of ES cells. Cell Struct Funct 2001;26:137-148.
[38]Jo CH, Kim OS, Park EY, Kim BJ, Lee JH, Kang SB, Han HS, Rhee SH, Yoon KS. Fetal mesenchymal stem cells derived from human umbilical cord sustain primitive characteristics during extensive expansion. Cell Tissue Res 2008:334:423-433.
[39]Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringden 0. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease:a phase II study. Lancet 2008:371:1579-1586.
[40]Porada CD, Zanjani ED, Almeida-Porad G. Adult mesenchymal stem cells: a pluripotent population with multiple applications. Curr Stem Cell Res Ther 2006;1:365-369.
[41]Noel D, Djouad F, Bouffi C, Mrugala D, Jorgensen C. Multipotent mesenchymal stromal cells and immune tolerance. Leuk Lymphoma 2007:48:1283-1289.
[42]Selmani Z, Naji A, Zidi I, Favier B, Gaiffe E, Obert L, Borg C, Saas P, Tiberghien P, Rouas-Freiss N, Carosella ED, Deschaseaux F. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+regulatory T cells. Stem Cells 2008:26:212-222.
[43]Uccelli A, Pistoia V, Moretta L. Mesenchymal stem cells:a new strategy for immunosuppression? Trends Immunol 2007;28:219-226.
[44]Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 2003;75:389-397.
[45]Rasmusson I, Ringden 0, Sundberg B, Le Blanc K. Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms. Exp Cell Res 2005:305:33-41.
[46]Nataraj C, Thomas DW, Tilley SL, Nguyen MT, Mannon R, Koller BH, Coffman TM. Receptors for prostaglandin E(2) that regulate cellular immune responses in the mouse. J Clin Invest 2001;108:1229-1235.
[47]Kvirkvelia N, Vojnovic I, Warner TD, Athie-Morales V, Free P, Rayment N, Chain BM, Rademacher TW, Lund T, Roitt IM, Delves PJ. Placentally derived prostaglandin E2 acts via the EP4 receptor to inhibit IL-2-dependent proliferation of CTLL-2 T cells. Clin Exp Immunol 2002:127:263-269.
[48]Ryan JM, Barry F, Murphy JM, Mahon BP. Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol 2007:149:353-363.
[49]Jana B, Koszykowska M, Andronowska A. The effect of tumor necrosis factor-alpha (TNF-alpha, interleukin (IL)-lbeta and IL-6 on prostaglandins (PG)F2alpha and E2 secretion from maternal placenta in pigs. Pol J Vet Sci 2008:11:315-322.
[50]Lazarus HM, Koc ON, Devine SM, Curtin P, Maziarz RT, Holland HK, Shpall EJ, McCarthy P, Atkinson K, Cooper BW, Gerson SL, Laughlin MJ, Loberiza FR, Jr., Moseley AB, Bacigalupo A. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biol Blood Marrow Transplant 2005;11:389-398.
[51]Polchert D, Sobinsky J, Douglas G, Kidd M, Moadsiri A, Reina E, Genrich K, Mehrotra S, Setty S, Smith B, Bartholomew A. IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. European journal of immunology 2008;38:1745-1755.
[52]Porter BO, Malek TR. Prostaglandin E2 inhibits T cell activation-induced apoptosis and Fas-mediated cellular cytotoxicity by blockade of Fas-ligand induction. European journal of immunology 1999:29:2360-2365.
[1]Zvaifler NJ, Marinova-Mutafchieva L, Adams G, Edwards CJ, Moss J, Burger JA, Maini RN. Mesenchymal precursor cells in the blood of normal individuals. Arthritis Res 2000:2:477-488.
[2]Rogers I, Casper RF. Umbilical cord blood stem cells. Best Pract Res Clin Obstet Gynaecol 2004;18:893-908.
[3]Noth U, Osyczka AM, Tuli R, Hickok NJ, Danielson KG, Tuan RS. Multilineage mesenchymal differentiation potential of human trabecular bone-derived cells. J Orthop Res 2002;20:1060-1069.
[4]Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143-147.
[5]De Bari C, Dell'Accio F, Luyten FP. Human periosteum-derived cells maintain phenotypic stability and chondrogenic potential throughout expansion regardless of donor age. Arthritis Rheum 2001;44:85-95.
[6]Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, Deans RJ, Krause DS, Keating A. Clarification of the nomenclature for MSC:The International Society for Cellular Therapy position statement. Cytotherapy 2005;7:393-395.
[7]Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E. minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006:8:315-317.
[8]Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood 2007:110:3499-3506.
[9]Keating A. Mesenchymal stromal cells. Current opinion in hematology 2006:13:419-425.
[10]Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden 0. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 2003;57:11-20.
[11]Chen K, Wang D, Du WT, Han ZB, Ren H, Chi Y, Yang SG, Zhu D, Bayard F, Han ZC. Human umbilical cord mesenchymal stem cells hUC-MSCs exert immunosuppressive activities through a PGE(2)-dependent mechanism. Clin Immunol.
[12]Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, Dazzi F. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003:101:3722-3729.
[13]Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002;99:3838-3843.
[14]Rasmusson I, Ringden 0, Sundberg B, Le Blanc K. Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms. Exp Cell Res 2005:305:33-41.
[15]Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005:105:1815-1822.
[16]Rouvier E, Luciani MF, Mattei MG, Denizot F, Golstein P. 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.
[17]Yao Z, Painter SL, Fanslow WC, Ulrich D, Macduff BM, Spriggs MK, Armitage RJ. Human IL-17:a novel cytokine derived from T cells. J Immunol 1995:155:5483-5486.
[18]Yao Z, Timour M, Painter S, Fanslow W, Spriggs M. Complete nucleotide sequence of the mouse CTLA8 gene. Gene 1996:168:223-225.
[19]Fossiez F, Djossou 0, Chomarat P, Flores-Romo L, Ait-Yahia S, Maat C, Pin JJ, Garrone P, Garcia E, Saeland S, Blanchard D, Gaillard C, Das Mahapatra B, Rouvier E, Golstein P, Banchereau J, Lebecque S. T cell interleukin-17 induces stromal cells to produce pro inflammatory and hematopoietic cytokines. The Journal of experimental medicine 1996:183:2593-2603.
[20]Romani L. Cell mediated immunity to fungi:a reassessment. Med Mycol 2008:1-15.
[21]Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med 2007:13:139-145.
[22]Bronte V. Th17 and cancer:friends or foes? Blood 2008:112:214.
[23]Langowski JL, Kastelein RA, Oft M. Swords into plowshares:IL-23 repurposes tumor immune surveillance. Trends Immunol 2007;28:207-212.
[24]Iwakura Y, Nakae S, Saijo S, Ishigame H. The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol Rev 2008;226:57-79.
[25]Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M, Kuchroo VK, Hafler DA. IL-21 and TGF-beta are required for differentiation of human T(H)17 cells/Nature 2008;454:350-352.
[26]Napolitani G, Acosta-Rodriguez EV, Lanzavecchia A, Sallusto F. Prostaglandin E2 enhances Th17 responses via modulation of IL-17 and IFN-gamma production by memory CD4+T cells. Eur J Immunol 2009:39:1301-1312.
[27]Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupe P, Barillot E, Soumelis V. A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol 2008;9:650-657.
[28]Wong CK, Ho CY, Li EK, Lam CW. Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus. Lupus 2000;9:589-593.
[29]Wong CK, Lit LC, Tam LS, Li EK, Wong PT, Lam CW. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clinical immunology (Orlando, Fla 2008;127:385-393.
[30]Guo Z, Zheng C, Chen Z, Gu D, Du W, Ge J, Han Z, Yang R. Fetal BM-derived mesenchymal stem cells promote the expansion of human Th17 cells, but inhibit the production of Thl cells. Eur J Immunol 2009; 39:2840-2849.
[31]Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25:1271-1277.
[32]Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 1992;35:630-640.
[33]Chizzolini C, Chicheportiche R, Alvarez M, de Rham C, Roux-Lombard P, Ferrari-Lacraz S, Dayer JM. Prostaglandin E2 (PGE2) synergistically with interleukin-23 (IL-23) favors human Thl7 expansion. Blood 2008.
[34]Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, Dilloo D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 2004;103:4619-4621.
[35]Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 2005:105:2821-2827.
[36]Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A, Santarlasci V, Mazzinghi B, Pizzolo G, Vinante F, Romagnani P, Maggi E, Romagnani S, Annunziato F. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 2006:24:386-398.
[37]Dong C. TH17 cells in development:an updated view of their molecular identity and genetic programming. Nat Rev Immunol 2008:8:337-348.
[38]McGeachy MJ, Cua DJ. Th17 cell differentiation:the long and winding road. Immunity 2008:28:445-453.
[39]Zhou L, Ivanov, Ⅱ, Spolski R, min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 2007:8:967-974.
[40]Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006:24:179-189.
[41]McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 2007:8:1390-1397.
[42]Matusevicius D, Kivisakk P, He B, Kostulas N, Ozenci V, Fredrikson S, Link H. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler 1999:5:101-104.
[43]Linden A, Hoshino H, Laan M. Airway neutrophils and interleukin-17. Eur Respir J 2000;15:973-977.
[44]Garrett-Sinha LA, John S, Gaffen SL. IL-17 and the Th17 lineage in systemic lupus erythematosus. Current opinion in rheumatology 2008:20:519-525.
[45]Hsu HC, Yang P, Wang J, Wu Q, Myers R, Chen J, Yi J, Guentert T, Tousson A, Stanus AL, Le TV, Lorenz RG, Xu H, Kolls JK, Carter RH, Chaplin DD, Williams RW, Mountz JD. Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol 2008:9:166-175.
[46]Weiss ML, Anderson C, Medicetty S, Seshareddy KB, Weiss RJ, VanderWerff I, Troyer D, McIntosh KR. Immune properties of human umbilical cord Wharton's jelly-derived cells. Stem Cells 2008:26:2865-2874.
[47]Kurasawa K, Hirose K, Sano.H, Endo H, Shinkai H, Nawata Y, Takabayashi K, Iwamoto I. Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum 2000:43:2455-2463.
[48]Huang X, Hua J, Shen N, Chen S. Dysregulated expression of interleukin-23 and interleukin-12 subunits in systemic lupus erythematosus patients. Mod Rheumatol 2007:17:220-223.
[49]Laan M, Lotvall J, Chung KF, Linden A. IL-17-induced cytokine release in human bronchial epithelial cells in vitro:role of mitogen-activated protein (MAP) kinases. Br J Pharmacol 2001:133:200-206.
[50]Schwandner R, Yamaguchi K, Cao Z. Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. The Journal of experimental medicine 2000:191:1233-1240.
[51]Hwang SY, Kim JY, Kim KW, Park MK, Moon Y, Kim WU, Kim HY. IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-kappaB-and PI3-kinase/Akt-dependent pathways. Arthritis research & therapy 2004;6:R120-128.
[52]Shen F, Hu Z, Goswami J, Gaffen SL. Identification of common transcriptional regulatory elements in interleukin-17 target genes. J Biol Chem 2006:281:24138-24148.
[53]Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 2008;9:641-649.
[1]Thomas ED, Blum'e KG. Historical markers in the development of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 1999;5:341-346.
[2]Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyuk AF, Keiliss-Borok IV. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation 1974;17:331-340.
[3]Caplan AI. Mesenchymal stem cells. J Orthop Res 1991;9:641-650.
[4]Alhadlaq A, Mao JJ. Mesenchymal stem cells:isolation and therapeutics. Stem Cells Dev 2004;13:436-448.
[5]Le Blanc K,Pittenger M. Mesenchymal stem cells:progress toward promise.Cytotherapy 2005;7:36-45.
[6]Beyer Nardi N, da Silva Meirelles L. Mesenchymal stem cells:isolation, in vitro expansion and characterization. Handb Exp Pharmacol 2006:249-282.
[7]Conget PA, minguell JJ. Phenotypical and functional properties of human bone marrow mesenchymal progenitor cells. Journal of cellular physiology 1999;181:67-73.
[8]Klyushnenkova E, Mosca JD, Zernetkina V, Majumdar MK, Beggs KJ, Simonetti DW, Deans RJ, McIntosh KR. T cell responses to allogeneic human mesenchymal stem cells:immunogenicity, tolerance, and suppression. J Biomed Sci 2005;12:47-57.
[9]Kim DH, Yoo KH, Choi KS, Choi J, Choi SY, Yang SE, Yang YS, Im HJ, Kim KH, Jung HL, Sung KW, Koo HH. Gene expression profile of cytokine and growth factor during differentiation of bone marrow-derived mesenchymal stem cell. Cytokine 2005;31:119-126.
[10]Haynesworth SE, Baber MA, Caplan AI. Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro:effects of dexamethasone and IL-1 alpha. Journal of cellular physiology 1996:166:585-592.
[11]Ries C, Egea V, Karow M, Kolb H, Jochum M, Neth P. MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells:differential regulation by inflammatory cytokines. Blood 2007:109:4055-4063.
[12]Honczarenko M, Le Y, Swierkowski M, Ghiran I, Glodek AM, Silberstein LE. Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors. Stem cells (Dayton, Ohio) 2006:24:1030-1041.
[13]Von Luttichau I, Notohamiprodjo M, Wechselberger A, Peters C, Henger A, Seliger C, Djafarzadeh R, Huss R, Nelson PJ. Human adult CD34-progenitor cells functionally express the chemokine receptors CCR1, CCR4, CCR7, CXCR5, and CCR10 but not CXCR4. Stem Cells Dev 2005:14:329-336.
[14]Lama VN, Smith L, Badri L, Flint A, Andrei AC, Murray S, Wang Z, Liao H, Toews GB, Krebsbach PH, Peters-Golden M,'Pinsky DJ, Martinez FJ, Thannickal VJ. Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts. J Clin Invest 2007:117:989-996.
[15]Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: mesenchymal stem cells:their phenotype, differentiation capacity, immunological features, and potential for homing. Stem cells (Dayton, Ohio) 2007:25:2739-2749.
[16]Abdi R, Fiorina P, Adra CN, Atkinson M, Sayegh MH. Immunomodulation by mesenchymal stem cells:a potential therapeutic strategy for type 1 diabetes. Diabetes 2008:57:1759-1767.
[17]Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, Ringden 0. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004:363:1439-1441.
[18]Le Blanc K. Immunomodulatory effects of fetal and adult mesenchymal stem cells. Cytotherapy 2003:5:485-489.
[19]Lu L, Shen RN, Broxmeyer HE. Stem cells from bone marrow, umbilical cord blood and peripheral blood for clinical application:current status and future application. Crit Rev Oncol Hematol 1996:22:61-78.
[20]Shlomchik WD. Graft-versus-host disease. Nature reviews 2007:7:340-352.
[21]Shlomchik WD, Lee SJ, Couriel D, Pavletic SZ. Transplantation's greatest challenges:advances in chronic graft-versus-host disease. Biol Blood Marrow Transplant 2007;13:2-10.
[22]Jacobsohn DA. Novel therapeutics for the treatment of graft-versus-host disease. Expert Opin Investig Drugs 2002:11:1271-1280.
[23]Jacobsohn DA, Vogelsang GB. Novel pharmacotherapeutic approaches to prevention and treatment of GVHD. Drugs 2002;62:879-889.
[24]Tamada K, Shimozaki K, Chapoval AI, Zhu G, Sica G, Flies D, Boone T, Hsu H, Fu YX, Nagata S, Ni J, Chen L. Modulation of T-cell-mediated immunity in tumor and graft-versus-host disease models through the LIGHT co-stimulatory pathway. Nature medicine 2000;6:283-289.
[25]Xu K, Li C, Pan X, Du B. Study of relieving graft-versus-host disease by blocking CD137-CD137 ligand costimulatory pathway in vitro. Int J Hematol 2007:86:84-90.
[26]Xu L, Duan L, Cao K, Yuan G, Peng Y, Huang X, Xiang P, Li S. Predominant immature CD8alpha+dendritic cells prevent graft-vs.-host disease but do not increase the risk of leukemia recurrence. Eur J Haematol 2007;78:235-245.
[27]Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 2003:75:389-397.
[28]Nauta AJ, Westerhuis G, Kruisselbrink AB, Lurvink EG, Willemze R, Fibbe WE. Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting. Blood 2006:108:2114-2120.
[29]Pevsner-Fischer M, Morad V, Cohen-Sfady M, Rousso-Noori L, Zanin-Zhorov A, Cohen S, Cohen IR, Zipori D. Toll-like receptors and their ligands control mesenchymal stem cell functions.. Blood 2007:109:1422-1432.
[30]Liotta F, Angeli R, Cosmi L, Fili L, Manuelli C, Frosali F, Mazzinghi B, Maggi L, Pasini A, Lisi V, Santarlasci V, Consoloni L, Angelotti ML, Romagnani P, Parronchi P, Krampera M, Maggi E, Romagnani S, Annunziato F. Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling. Stem cells (Dayton, Ohio) 2008:26:279-289.
[31]Tomchuck SL, Zwezdaryk KJ, Coffelt SB, Waterman RS, Danka ES,
Scandurro AB. Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses. Stem cells (Dayton, Ohio) 2008:26:99-107.
[32]Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, Zhao RC, Shi Y. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell stem cell 2008:2:141-150.
[33]Sato K, Ozaki K, Oh I, Meguro A, Hatanaka K, Nagai T, Muroi K, Ozawa K. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 2007:109:228-234.
[34]Trinchieri G. Biology of natural killer cells. Adv Immunol 1989:47:187-376.
[35]Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, mingari MC, Moretta L. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production:role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 2008:111:1327-1333.
[36]Haynesworth SE, Goshima J, Goldberg VM, Caplan AI. Characterization of cells with osteogenic potential from human marrow. Bone 1992:13:81-88.
[37]Le Blanc K, Ringden 0. Mesenchymal stem cells:properties and role in clinical bone marrow transplantation. Curr Opin Immunol 2006:18:586-591.
[38]Devine SM. Mesenchymal stem cells:will they have a role in the clinic? J Cell Biochem Suppl 2002:38:73-79.
[39]Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs 2001:169:12-20.
[40]Herrera MB, Bussolati B, Bruno S, Fonsato V, Romanazzi GM, Camussi G. Mesenchymal stem cells contribute to the renal repair of acute tubular epithelial injury. Int J Mol Med 2004:14:1035-1041.
[41]Shih HN, Shih LY, Sung TH, Chang YC. Restoration of bone defect and enhancement of bone ingrowth using partially demineralized bone matrix and marrow stromal cells. J Orthop Res 2005:23:1293-1299.
[42]Wu M, Yang L, Liu S, Li H, Hui N, Wang F, Liu H. Differentiation potential of human embryonic mesenchymal stem cells for skin-related tissue. Br J Dermatol 2006:155:282-291.
[43]Yoshikawa T, Mitsuno H, Nonaka I, Sen Y, Kawanishi K, Inada Y, Takakura Y, Okuchi K, Nonomura A. Wound therapy by marrow mesenchymal cell transplantation. Plast Reconstr Surg 2008:121:860-877.
[44]Vojtassak J, Danisovic L, Kubes M, Bakos D, Jarabek L, Ulicna M, Blasko M. Autologous biograft and mesenchymal stem cells in treatment of the diabetic foot. Neuro Endocrinol Lett 2006;27 Suppl 2:134-137.
[45]Keilhoff G, Goihl A, Stang F, Wolf G, Fansa H. Peripheral nerve tissue engineering:autologous Schwann cells vs. transdifferentiated mesenchymal stem cells. Tissue Eng 2006:12:1451-1465.
[46]Li Y, Chen J, Wang L, Zhang L, Lu M, Chopp M. Intracerebral transplantation of bone marrow stromal cells in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Neurosci Lett 2001:316:67-70.
[47]Moviglia GA, Fernandez Vina R, Brizuela JA, Saslavsky J, Vrsalovic F, Varela G, Bastos F, Farina P, Etchegaray G, Barbieri M, Martinez G, Picasso F, Schmidt Y, Brizuela P, Gaeta CA, Costanzo H, Moviglia Brandolino MT, Merino S, Pes ME, Veloso MJ, Rugilo C, Tamer I, Shuster GS. Combined protocol of cell therapy for chronic spinal cord injury. Report on the electrical and functional recovery of two patients. Cytotherapy 2006; 8:202-209.
[48]Koc ON, Day J, Nieder M, Gerson SL, Lazarus HM, Krivit W. Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH). Bone Marrow Transplant 2002:30:215-222.
[49]Sonoyama W, Liu Y, Fang D, Yamaza T, Seo BM, Zhang C, Liu H, Gronthos S, Wang CY, Wang S, Shi S. Mesenchymal stem cell-mediated functional tooth regeneration in swine. PLoS ONE 2006;1:e79.
[50]Poh KK, Sperry E, Young RG, Freyman T, Barringhaus KG, Thompson CA. Repeated direct endomyocardial transplantation of allogeneic mesenchymal stem cells:safety of a high dose, "off-the-shelf", cellular cardiomyoplasty strategy. Int J Cardiol 2007;117:360-364.
[51]Grinnemo KH, Mansson A, Dellgren G, Klingberg D, Wardell E, Drvota V, Tammik C, Holgersson J, Ringden 0, Sylven C, Le Blanc K. Xenoreactivity and engraftment of human mesenchymal stem cells transplanted into infarcted rat myocardium. J Thorac Cardiovasc Surg 2004:127:1293-1300.
[52]Noiseux N, Gnecchi M, Lopez-Ilasaca M, Zhang L, Solomon SD, Deb A, Dzau VJ, Pratt RE. Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol Ther 2006:14:840-850.
[53]Zhang S, Ge J, Sun A, Xu D, Qian J, Lin J, Zhao Y, Hu H, Li Y, Wang K, Zou Y. Comparison of various kinds of bone marrow stem cells for the repair of infarcted myocardium:single clonally purified non-hematopoietic mesenchymal stem cells serve as a superior source. J Cell Biochem 2006:99:1132-1147.
[54]Zhang D, Zhang F, Zhang Y, Gao X, Li C, Yang N, Cao K. Combining erythropoietin infusion with intramyocardial delivery of bone marrow cells is more effective for cardiac repair. Transpl Int 2007:20:174-183.
[55]Jo J, Nagaya N, Miyahara Y, Kataoka M, Harada-Shiba M, Kangawa K, Tabata Y. Transplantation of genetically engineered mesenchymal stem cells improves cardiac function in rats with myocardial infarction: benefit of a novel nonviral vector, cationized dextran. Tissue Eng 2007:13:313-322.
[56]Kraus KH, Kirker-Head C. Mesenchymal stem cells and bone regeneration. Vet Surg 2006:35:232-242.
[57]Kim MS, Hwang NS, Lee J, Kim TK, Leong K, Shamblott MJ, Gearhart J, Elisseeff J. Musculoskeletal differentiation of cells derived from human embryonic germ cells. Stem cells (Dayton, Ohio) 2005:23:113-123.
[58]Arinzeh TL, Peter SJ, Archambault MP, van den Bos C, Gordon S, Kraus K, Smith A, Kadiyala S. Allogeneic mesenchymal stem cells regenerate bone in a critical-sized canine segmental defect. J Bone Joint Surg Am 2003;85-A:1927-1935.
[59]Fang B, Shi M, Liao L, Yang S, Liu Y, Zhao RC. Systemic infusion of FLK1(+) mesenchymal stem cells ameliorate carbon tetrachloride-induced liver fibrosis in mice. Transplantation 2004:78:83-88.
[60]Shibata T, Naruse K, Kamiya H, Kozakae M, Kondo M, Yasuda Y, Nakamura N, Ota K, Tosaki T, Matsuki T, Nakashima E, Hamada Y, Oiso Y, Nakamura J. Transplantation of bone marrow-derived mesenchymal stem cells improves diabetic polyneuropathy in rats. Diabetes 2008:57:3099-3107.
[61]Zhang N, Li J, Luo R, Jiang J, Wang JA. Bone marrow mesenchymal stem cells induce angiogenesis and attenuate the remodeling of diabetic cardiomyopathy. Exp Clin Endocrinol Diabetes 2008:116:104-111.
[62]Lee RH, Seo MJ, Reger RL, Spees JL, Pulin AA, Olson SD, Prockop DJ. Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proceedings of the National Academy of Sciences of the United States of America 2006:103:17438-17443.
[63]Caplan AI. Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. Journal of cellular physiology 2007:213:341-347.
[64]Reiser J, Zhang XY, Hemenway CS, Mondal D, Pradhan L, La Russa VF. Potential of mesenchymal stem cells in gene therapy approaches for inherited and acquired diseases. Expert Opin Biol Ther 2005:5:1571-1584.
[65]Li A, Zhang Q, Jiang J, Yuan G, Feng Y, Hao J, Li C, Gao X, Wang G, Xie S. Co-transplantation of bone marrow stromal cells transduced with IL-7 gene enhances immune reconstitution after allogeneic bone marrow transplantation in mice. Gene Ther 2006:13:1178-1187.
[66]Yang J, Zhou W, Zheng W, Ma Y, Lin L, Tang T, Liu J, Yu J, Zhou X, Hu J. Effects of myocardial transplantation of marrow mesenchymal stem cells transfected with vascular endothelial growth factor for the improvement of heart function and angiogenesis after myocardial infarction. Cardiology 2007:107:17-29.
[67]Zachos T, Diggs A, Weisbrode S, Bartlett J, Bertone A. Mesenchymal stem cell-mediated gene delivery of bone morphogenetic protein-2 in an articular fracture model. Mol Ther 2007:15:1543-1550.
[68]Kyriakou CA, Yong KL, Benjamin R, Pizzey A, Dogan A, Singh N, Davidoff AM, Nathwani AC. Human mesenchymal stem cells (hMSCs) expressing
truncated soluble vascular endothelial growth factor receptor (tsFlk-1) following lentiviral-mediated gene transfer inhibit growth of Burkitt's lymphoma in a murine model. J Gene Med 2006;8:253-264.
[69]Ren C, Kumar S, Chanda D, Kallman L, Chen J, Mountz JD, Ponnazhagan S. Cancer gene therapy using mesenchymal stem cells expressing interferon-beta in a mouse prostate cancer lung metastasis model. Gene Ther 2008;15:1446-1453.
[1]Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med 2007:13:139-145.
[2]Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 2007:25:821-852.
[3]Ghilardi N, Ouyang W. Targeting the development and effector functions of TH17 cells. Semin Immunol 2007:19:383-393.
[4]Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003:421:744-748.
[5]Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. The Journal of experimental medicine 2005:201:233-240.
[6]Bettelli E, Kuchroo VK. IL-12-and IL-23-induced T helper cell subsets: birds of the same feather flock together. J Exp Med 2005:201:169-171.
[7]Trinchieri G, Pflanz S, Kastelein RA. The IL-12 family of heterodimeric cytokines:new players in the regulation of T cell responses. Immunity 2003:19:641-644.
[8]Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney 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.
[9]Park H, Li Z, Yang X0, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005:6:1133-1141.
[10]Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT. 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.
[11]Cua DJ, Kastelein RA. TGF-beta, a'double agent'in the immune pathology war. Nat Immunol 2006;7:557-559.
[12]Stockinger B, Veldhoen M. Differentiation and function of Thl7T cells. Curr Opin Immunol 2007;19:281-286.
[13]McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 2007; 8:1390-1397.
[14]Nurieva R, Yang X0, Martinez G, Zhang Y, Panopoulos AD, Ma L, Schluns K, Tian Q, Watowich SS, Jetten AM, Dong C. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 2007;448:480-483.
[15]Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, Oukka M, Kuchroo VK. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 2007;448:484-487.
[16]Zhou L, Ivanov, Ⅱ, Spolski R, min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 2007;8:967-974.
[17]Xu L, Kitani A, Fuss I, Strober W. Cutting edge:regulatory T cells induce CD4+CD25-Foxp3-T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta. J Immunol 2007:178:6725-6729.
[18]Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins lbeta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 2007;8:942-949.
[19]Laurence A,O' Shea JJ. T(H)-17 differentiation:of mice and men. Nat Immunol 2007;8:903-905.
[20]Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 2008;9:641-649.
[21]Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupe P, Barillot E, Soumelis V. A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol 2008;9:650-657.
[22]Shen F, Gaffen SL. Structure-function relationships in the IL-17 receptor:implications for signal transduction and therapy. Cytokine 2008;41:92-104.
[23]Akimzhanov AM, Yang XO, Dong C. Chromatin remodeling of interleukin-17 (IL-17) -IL-17F cytokine gene locus during inflammatory helper T cell differentiation. J Biol Chem 2007;282:5969-5972.
[24]Wright JF, Guo Y, Quazi A, Luxenberg DP, Bennett F, Ross JF, Qiu Y, Whitters MJ, Tomkinson KN, Dunussi-Joannopoulos K, Carreno BM, Collins M, Wolfman NM. Identification of an interleukin 17F/17A heterodimer in activated human CD4+T cells. J Biol Chem 2007:282:13447-13455.
[25]Chang SH, Dong C. A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses. Cell research 2007:17:435-440.
[26]Stumhofer JS, Laurence A, Wilson EH, Huang E, Tato CM, Johnson LM, Villarino AV, Huang Q, Yoshimura A, Sehy D, Saris CJ,O' Shea JJ, Hennighausen L, Ernst M, Hunter CA. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol 2006:7:937-945.
[27]Ruddy MJ, Wong GC, Liu XK, Yamamoto H, Kasayama S, Kirkwood KL, Gaffen SL. Functional cooperation between interleukin-17 and tumor necrosis factor-alpha is mediated by CCAAT/enhancer-binding protein family members. J Biol Chem 2004:279:2559-2567.
[28]Shen F, Ruddy MJ, Plamondon P, Gaffen SL. Cytokines link osteoblasts and inflammation:microarray analysis of interleukin-17-and TNF-alpha-induced genes in bone cells. J Leukoc Biol 2005:77:388-399.
[29]Yao Z, Timour M, Painter S, Fanslow W, Spriggs M. Complete nucleotide sequence of the mouse CTLA8 gene. Gene 1996;168:223-225.
[30]Wang D, John SA, Clements JL, Percy DH, Barton KP, Garrett-Sinha LA. Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease. Int Immunol 2005:17:1179-1191.
[31]Moisan J, Grenningloh R, Bettelli E, Oukka M, Ho IC. Ets-1 is a negative regulator of Th17 differentiation. J Exp Med 2007;204:2825-2835.
[32]Kang HK, Liu M, Datta SK. Low-dose peptide tolerance therapy of lupus generates plasmacytoid dendritic cells that cause expansion of autoantigen-specific regulatory T cells and contraction of inflammatory Th17 cells. J Immunol 2007;178:7849-7858.
[33]Chang SH, Park H, Dong C. Actl adaptor protein is an immediate and essential signaling component of interleukin-17 receptor. J Biol Chem 2006:281:35603-35607.
[34]Qian Y, Liu C, Hartupee J, Altuntas CZ, Gulen MF, Jane-Wit D, Xiao J, Lu Y, Giltiay N, Liu J, Kordula T, Zhang QW, Vallance B, Swaidani S, Aronica M, Tuohy VK, Hamilton T, Li X. The adaptor Actl is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat Immunol 2007;8:247-256.
[35]Qian Y, Qin J, Cui G, Naramura M, Snow EC, Ware CF, Fairchild RL, Omori SA, Rickert RC, Scott M, Kotzin BL, Li X. Actl, a negative regulator in CD40-and BAFF-mediated B cell survival. Immunity 2004;21:575-587.
[36]Dai J, Liu B, Cua DJ, Li Z. Essential roles of IL-12 and dendritic cells but not IL-23 and macrophages in lupus-like diseases initiated by cell surface HSP gp96. European journal of immunology 2007;37:706-715.
[37]Sullivan KE, Piliero LM, Dharia T, Goldman D, Petri MA.3' polymorphisms of ETS1 are associated with different clinical phenotypes in SLE. Hum Mutat 2000:16:49-53.
[38]Dong G, Ye R, Shi W, Liu S, Wang T, Yang X, Yang N, Yu X. IL-17 induces autoantibody overproduction and peripheral blood mononuclear cell overexpression of IL-6 in lupus nephritis patients. Chinese medical journal 2003;116:543-548.
[39]Yu JJ, Gaffen SL. Interleukin-17:a novel inflammatory cytokine that bridges innate and adaptive immunity. Front Biosci 2008;13:170-177.
[40]Kurasawa K, Hirose K, Sano H, Endo H, Shinkai H, Nawata Y, Takabayashi K, Iwamoto I. Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum 2000;43:2455-2463.
[41]Meyers JA, Mangini AJ, Nagai T, Roff CF, Sehy D, van Seventer GA, van Seventer JM. Blockade of TLR9 agonist-induced type I interferons promotes inflammatory cytokine IFN-gamma and IL-17 secretion by activated human PBMC. Cytokine 2006;35:235-246.
[42]Feldmann M, Steinman L. Design of effective immunotherapy for human autoimmunity. Nature 2005;435:612-619.
[43]Kikly K, Liu L, Na S, Sedgwick JD. The IL-23/Th(17) axis:therapeutic targets for autoimmune inflammation. Curr Opin Immunol 2006:18:670-675.
[2]Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E. minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006;8:315-317.
[3]Hu Y, Liao L, Wang Q, Ma L, Ma G, Jiang X, Zhao RC. Isolation and identification of mesenchymal stem cells from human fetal pancreas. J Lab Clin Med 2003;141:342-349.
[4]Barry FP, Murphy JM. Mesenchymal stem cells:clinical applications and biological characterization. Int J Biochem Cell Biol 2004:36:568-584.
[5]in't Anker PS, Noort WA, Scherjon SA, Kleijburg-van der Keur C, Kruisselbrink AB, van Bezooijen RL, Beekhuizen W, Willemze R, Kanhai HH, Fibbe WE. Mesenchymal stem cells in human second-trimester bone marrow, liver, lung, and spleen exhibit a similar immunophenotype but a heterogeneous multilineage differentiation potential. Haematologica 2003:88:845-852.
[6]Lee OK, Kuo TK, Chen WM, Lee KD, Hsieh SL, Chen TH. Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood 2004:103:1669-1675.
[7]Lu LL, Liu YJ, Yang SG, Zhao QJ, Wang X, Gong W, Han ZB, Xu ZS, Lu YX, Liu D, Chen ZZ, Han ZC. Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. Haematologica 2006;91:1017-1026.
[8]Sarugaser R, Lickorish D, Baksh D, Hosseini MM, Davies JE. Human umbilical cord perivascular (HUCPV) cells:a source of mesenchymal progenitors. Stem cells (Dayton, Ohio) 2005:23:220-229.
[9]Wang HS, Hung SC, Peng ST, Huang CC, Wei HM, Guo YJ, Fu YS, Lai MC, Chen CC. Mesenchymal stem cells in the Wharton's jelly of the human umbilical cord. Stem Cells 2004:22:1330-1337.
[10]Karahuseyinoglu S, Cinar 0, Kilic E, Kara F, Akay GG, Demiralp DO, Tukun A, Uckan D, Can A. Biology of stem cells in human umbilical cord stroma:in situ and in vitro surveys. Stem Cells 2007;25:319-331.
[11]Can A, Karahuseyinoglu S. Concise review:human umbilical cord stroma with regard to the source of fetus-derived stem cells. Stem Cells 2007:25:2886-2895.
[12]Lund RD, Wang S, Lu B, Girman S, Holmes T, Sauve Y, Messina DJ, Harris IR, Kihm AJ, Harmon AM, Chin FY, Gosiewska A, Mistry SK. Cells isolated from umbilical cord tissue rescue photoreceptors and visual functions in a rodent model of retinal disease. Stem Cells 2007;25:602-611.
[13]Weiss ML, Medicetty S, Bledsoe AR, Rachakatla RS, Choi M, Merchav S, Luo Y, Rao MS, Velagaleti G, Troyer D. Human umbilical cord matrix stem cells:preliminary characterization and effect of transplantation in a rodent model of Parkinson's disease. Stem Cells 2006;24:781-792.
[14]Liao W, Xie J, Zhong J, Liu Y, Du L, Zhou B, Xu J, Liu P, Yang S, Wang J, Han Z, Han ZC. Therapeutic effect of human umbilical cord multipotent mesenchymal stromal cells in a rat model of stroke. Transplantation 2009;87:350-359.
[15]Tsai PC, Fu TW, Chen YM, Ko TL, Chen TH, Shih YH, Hung SC, Fu YS. The therapeutic potential of human umbilical mesenchymal stem cells from Wharton's jelly in the treatment of rat liver fibrosis. Liver Transpl 2009:15:484-495.
[16]Weiss ML, Anderson C, Medicetty S, Seshareddy KB, Weiss RJ, VanderWerff I, Troyer D, McIntosh KR. Immune properties of human umbilical cord Wharton's jelly-derived cells. Stem cells (Dayton, Ohio) 2008:26:2865-2874.
[17]Cho PS, Messina DJ, Hirsh EL, Chi N, Goldman SN, Lo DP, Harris IR, Popma SH, Sachs DH, Huang CA. Immunogenicity of umbilical cord tissue derived cells. Blood 2008;111:430-438.
[18]Weiss ML, Mitchell KE, Hix JE, Medicetty S, El-Zarkouny SZ, Grieger D, Troyer DL. Transplantation of porcine umbilical cord matrix cells into the rat brain. Exp Neurol 2003;182:288-299.
[19]Medicetty S, Bledsoe AR, Fahrenholtz CB, Troyer D, Weiss ML. Transplantation of pig stem cells into rat brain:proliferation during the first 8 weeks. Exp Neurol 2004;190:32-41.
[20]Plumas J, Chaperot L, Richard MJ, Molens JP, Bensa JC, Favrot MC. Mesenchymal stem cells induce apoptosis of activated T cells. Leukemia 2005;19:1597-1604.
[21]Benvenuto F, Ferrari S, Gerdoni E, Gualandi F, Frassoni F, Pistoia V, Mancardi G, Uccelli A. Human mesenchymal stem cells promote survival of T cells in a quiescent state. Stem cells (Dayton, Ohio) 2007;25:1753-1760.
[22]Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, Dazzi F. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003:101:3722-3729.
[23]Beyth S, Borovsky Z, Mevorach D, Liebergall M, Gazit Z, Aslan H, Galun E, Rachmilewitz J. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood 2005;105:2214-2219.
[24]Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002;99:3838-3843.
[25]Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, Dilloo D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 2004;103:4619-4621.
[26]Jarvinen L, Badri L, Wettlaufer S, Ohtsuka T, Standiford TJ, Toews GB, Pinsky DJ, Peters-Golden M, Lama VN. Lung resident mesenchymal stem cells isolated from human lung allografts inhibit T cell proliferation via a soluble mediator. J Immunol 2008; 181:4389-4396.
[27]Lahiri T, Laporte JD, Moore PE, Panettieri RA, Jr., Shore SA. Interleukin-6 family cytokines:signaling and effects in human airway smooth muscle cells. American journal of physiology 2001;280:L1225-1232.
[28]Jiang XX, Zhang Y, Liu B, Zhang SX, Wu Y, Yu XD, Mao N. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 2005;105:4120-4126.
[29]English K, Barry FP, Field-Corbett CP, Mahon BP. IFN-gamma and
TNF-alpha differentially regulate immunomodulation by murine mesenchymal stem cells. Immunology letters 2007;110:91-100.
[30]Sato K, Ozaki K, Oh I, Meguro A, Hatanaka K, Nagai T, Muroi K, Ozawa K. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 2007;109:228-234.
[31]Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005;105:1815-1822.
[32]Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A, Santarlasci V, Mazzinghi B, Pizzolo G, Vinante F, Romagnani P, Maggi E, Romagnani S, Annunziato F. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 2006;24:386-398.
[33]Baksh D, Yao R, Tuan RS. Comparison of proliferative and multilineage differentiation potential of human mesenchymal stem cells derived from umbilical cord and bone marrow. Stem Cells 2007;25:1384-1392.
[34]Cattaneo E, McKay R. Proliferation and differentiation of neuronal stem cells regulated by nerve growth factor. Nature 1990; 347:762-765.
[35]Clayton A, Evans RA, Pettit E, Hallett M, Williams JD, Steadman R. Cellular activation through the ligation of intercellular adhesion molecule-1. J Cell Sci 1998;111 (Pt 4):443-453.
[36]Noaksson K, Zoric N, Zeng X, Rao MS, Hyllner J, Semb H, Kubista M, Sartipy P. Monitoring differentiation of human embryonic stem cells using real-time PCR. Stem Cells 2005;23:1460-1467.
[37]Niwa H. Molecular mechanism to maintain stem cell renewal of ES cells. Cell Struct Funct 2001;26:137-148.
[38]Jo CH, Kim OS, Park EY, Kim BJ, Lee JH, Kang SB, Han HS, Rhee SH, Yoon KS. Fetal mesenchymal stem cells derived from human umbilical cord sustain primitive characteristics during extensive expansion. Cell Tissue Res 2008:334:423-433.
[39]Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringden 0. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease:a phase II study. Lancet 2008:371:1579-1586.
[40]Porada CD, Zanjani ED, Almeida-Porad G. Adult mesenchymal stem cells: a pluripotent population with multiple applications. Curr Stem Cell Res Ther 2006;1:365-369.
[41]Noel D, Djouad F, Bouffi C, Mrugala D, Jorgensen C. Multipotent mesenchymal stromal cells and immune tolerance. Leuk Lymphoma 2007:48:1283-1289.
[42]Selmani Z, Naji A, Zidi I, Favier B, Gaiffe E, Obert L, Borg C, Saas P, Tiberghien P, Rouas-Freiss N, Carosella ED, Deschaseaux F. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+regulatory T cells. Stem Cells 2008:26:212-222.
[43]Uccelli A, Pistoia V, Moretta L. Mesenchymal stem cells:a new strategy for immunosuppression? Trends Immunol 2007;28:219-226.
[44]Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 2003;75:389-397.
[45]Rasmusson I, Ringden 0, Sundberg B, Le Blanc K. Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms. Exp Cell Res 2005:305:33-41.
[46]Nataraj C, Thomas DW, Tilley SL, Nguyen MT, Mannon R, Koller BH, Coffman TM. Receptors for prostaglandin E(2) that regulate cellular immune responses in the mouse. J Clin Invest 2001;108:1229-1235.
[47]Kvirkvelia N, Vojnovic I, Warner TD, Athie-Morales V, Free P, Rayment N, Chain BM, Rademacher TW, Lund T, Roitt IM, Delves PJ. Placentally derived prostaglandin E2 acts via the EP4 receptor to inhibit IL-2-dependent proliferation of CTLL-2 T cells. Clin Exp Immunol 2002:127:263-269.
[48]Ryan JM, Barry F, Murphy JM, Mahon BP. Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol 2007:149:353-363.
[49]Jana B, Koszykowska M, Andronowska A. The effect of tumor necrosis factor-alpha (TNF-alpha, interleukin (IL)-lbeta and IL-6 on prostaglandins (PG)F2alpha and E2 secretion from maternal placenta in pigs. Pol J Vet Sci 2008:11:315-322.
[50]Lazarus HM, Koc ON, Devine SM, Curtin P, Maziarz RT, Holland HK, Shpall EJ, McCarthy P, Atkinson K, Cooper BW, Gerson SL, Laughlin MJ, Loberiza FR, Jr., Moseley AB, Bacigalupo A. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biol Blood Marrow Transplant 2005;11:389-398.
[51]Polchert D, Sobinsky J, Douglas G, Kidd M, Moadsiri A, Reina E, Genrich K, Mehrotra S, Setty S, Smith B, Bartholomew A. IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. European journal of immunology 2008;38:1745-1755.
[52]Porter BO, Malek TR. Prostaglandin E2 inhibits T cell activation-induced apoptosis and Fas-mediated cellular cytotoxicity by blockade of Fas-ligand induction. European journal of immunology 1999:29:2360-2365.
[1]Zvaifler NJ, Marinova-Mutafchieva L, Adams G, Edwards CJ, Moss J, Burger JA, Maini RN. Mesenchymal precursor cells in the blood of normal individuals. Arthritis Res 2000:2:477-488.
[2]Rogers I, Casper RF. Umbilical cord blood stem cells. Best Pract Res Clin Obstet Gynaecol 2004;18:893-908.
[3]Noth U, Osyczka AM, Tuli R, Hickok NJ, Danielson KG, Tuan RS. Multilineage mesenchymal differentiation potential of human trabecular bone-derived cells. J Orthop Res 2002;20:1060-1069.
[4]Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143-147.
[5]De Bari C, Dell'Accio F, Luyten FP. Human periosteum-derived cells maintain phenotypic stability and chondrogenic potential throughout expansion regardless of donor age. Arthritis Rheum 2001;44:85-95.
[6]Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, Deans RJ, Krause DS, Keating A. Clarification of the nomenclature for MSC:The International Society for Cellular Therapy position statement. Cytotherapy 2005;7:393-395.
[7]Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E. minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006:8:315-317.
[8]Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood 2007:110:3499-3506.
[9]Keating A. Mesenchymal stromal cells. Current opinion in hematology 2006:13:419-425.
[10]Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden 0. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 2003;57:11-20.
[11]Chen K, Wang D, Du WT, Han ZB, Ren H, Chi Y, Yang SG, Zhu D, Bayard F, Han ZC. Human umbilical cord mesenchymal stem cells hUC-MSCs exert immunosuppressive activities through a PGE(2)-dependent mechanism. Clin Immunol.
[12]Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, Dazzi F. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003:101:3722-3729.
[13]Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002;99:3838-3843.
[14]Rasmusson I, Ringden 0, Sundberg B, Le Blanc K. Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms. Exp Cell Res 2005:305:33-41.
[15]Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005:105:1815-1822.
[16]Rouvier E, Luciani MF, Mattei MG, Denizot F, Golstein P. 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.
[17]Yao Z, Painter SL, Fanslow WC, Ulrich D, Macduff BM, Spriggs MK, Armitage RJ. Human IL-17:a novel cytokine derived from T cells. J Immunol 1995:155:5483-5486.
[18]Yao Z, Timour M, Painter S, Fanslow W, Spriggs M. Complete nucleotide sequence of the mouse CTLA8 gene. Gene 1996:168:223-225.
[19]Fossiez F, Djossou 0, Chomarat P, Flores-Romo L, Ait-Yahia S, Maat C, Pin JJ, Garrone P, Garcia E, Saeland S, Blanchard D, Gaillard C, Das Mahapatra B, Rouvier E, Golstein P, Banchereau J, Lebecque S. T cell interleukin-17 induces stromal cells to produce pro inflammatory and hematopoietic cytokines. The Journal of experimental medicine 1996:183:2593-2603.
[20]Romani L. Cell mediated immunity to fungi:a reassessment. Med Mycol 2008:1-15.
[21]Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med 2007:13:139-145.
[22]Bronte V. Th17 and cancer:friends or foes? Blood 2008:112:214.
[23]Langowski JL, Kastelein RA, Oft M. Swords into plowshares:IL-23 repurposes tumor immune surveillance. Trends Immunol 2007;28:207-212.
[24]Iwakura Y, Nakae S, Saijo S, Ishigame H. The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol Rev 2008;226:57-79.
[25]Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M, Kuchroo VK, Hafler DA. IL-21 and TGF-beta are required for differentiation of human T(H)17 cells/Nature 2008;454:350-352.
[26]Napolitani G, Acosta-Rodriguez EV, Lanzavecchia A, Sallusto F. Prostaglandin E2 enhances Th17 responses via modulation of IL-17 and IFN-gamma production by memory CD4+T cells. Eur J Immunol 2009:39:1301-1312.
[27]Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupe P, Barillot E, Soumelis V. A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol 2008;9:650-657.
[28]Wong CK, Ho CY, Li EK, Lam CW. Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus. Lupus 2000;9:589-593.
[29]Wong CK, Lit LC, Tam LS, Li EK, Wong PT, Lam CW. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clinical immunology (Orlando, Fla 2008;127:385-393.
[30]Guo Z, Zheng C, Chen Z, Gu D, Du W, Ge J, Han Z, Yang R. Fetal BM-derived mesenchymal stem cells promote the expansion of human Th17 cells, but inhibit the production of Thl cells. Eur J Immunol 2009; 39:2840-2849.
[31]Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25:1271-1277.
[32]Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 1992;35:630-640.
[33]Chizzolini C, Chicheportiche R, Alvarez M, de Rham C, Roux-Lombard P, Ferrari-Lacraz S, Dayer JM. Prostaglandin E2 (PGE2) synergistically with interleukin-23 (IL-23) favors human Thl7 expansion. Blood 2008.
[34]Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, Dilloo D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 2004;103:4619-4621.
[35]Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 2005:105:2821-2827.
[36]Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A, Santarlasci V, Mazzinghi B, Pizzolo G, Vinante F, Romagnani P, Maggi E, Romagnani S, Annunziato F. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 2006:24:386-398.
[37]Dong C. TH17 cells in development:an updated view of their molecular identity and genetic programming. Nat Rev Immunol 2008:8:337-348.
[38]McGeachy MJ, Cua DJ. Th17 cell differentiation:the long and winding road. Immunity 2008:28:445-453.
[39]Zhou L, Ivanov, Ⅱ, Spolski R, min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 2007:8:967-974.
[40]Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006:24:179-189.
[41]McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 2007:8:1390-1397.
[42]Matusevicius D, Kivisakk P, He B, Kostulas N, Ozenci V, Fredrikson S, Link H. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler 1999:5:101-104.
[43]Linden A, Hoshino H, Laan M. Airway neutrophils and interleukin-17. Eur Respir J 2000;15:973-977.
[44]Garrett-Sinha LA, John S, Gaffen SL. IL-17 and the Th17 lineage in systemic lupus erythematosus. Current opinion in rheumatology 2008:20:519-525.
[45]Hsu HC, Yang P, Wang J, Wu Q, Myers R, Chen J, Yi J, Guentert T, Tousson A, Stanus AL, Le TV, Lorenz RG, Xu H, Kolls JK, Carter RH, Chaplin DD, Williams RW, Mountz JD. Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol 2008:9:166-175.
[46]Weiss ML, Anderson C, Medicetty S, Seshareddy KB, Weiss RJ, VanderWerff I, Troyer D, McIntosh KR. Immune properties of human umbilical cord Wharton's jelly-derived cells. Stem Cells 2008:26:2865-2874.
[47]Kurasawa K, Hirose K, Sano.H, Endo H, Shinkai H, Nawata Y, Takabayashi K, Iwamoto I. Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum 2000:43:2455-2463.
[48]Huang X, Hua J, Shen N, Chen S. Dysregulated expression of interleukin-23 and interleukin-12 subunits in systemic lupus erythematosus patients. Mod Rheumatol 2007:17:220-223.
[49]Laan M, Lotvall J, Chung KF, Linden A. IL-17-induced cytokine release in human bronchial epithelial cells in vitro:role of mitogen-activated protein (MAP) kinases. Br J Pharmacol 2001:133:200-206.
[50]Schwandner R, Yamaguchi K, Cao Z. Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. The Journal of experimental medicine 2000:191:1233-1240.
[51]Hwang SY, Kim JY, Kim KW, Park MK, Moon Y, Kim WU, Kim HY. IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-kappaB-and PI3-kinase/Akt-dependent pathways. Arthritis research & therapy 2004;6:R120-128.
[52]Shen F, Hu Z, Goswami J, Gaffen SL. Identification of common transcriptional regulatory elements in interleukin-17 target genes. J Biol Chem 2006:281:24138-24148.
[53]Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 2008;9:641-649.
[1]Thomas ED, Blum'e KG. Historical markers in the development of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 1999;5:341-346.
[2]Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyuk AF, Keiliss-Borok IV. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation 1974;17:331-340.
[3]Caplan AI. Mesenchymal stem cells. J Orthop Res 1991;9:641-650.
[4]Alhadlaq A, Mao JJ. Mesenchymal stem cells:isolation and therapeutics. Stem Cells Dev 2004;13:436-448.
[5]Le Blanc K,Pittenger M. Mesenchymal stem cells:progress toward promise.Cytotherapy 2005;7:36-45.
[6]Beyer Nardi N, da Silva Meirelles L. Mesenchymal stem cells:isolation, in vitro expansion and characterization. Handb Exp Pharmacol 2006:249-282.
[7]Conget PA, minguell JJ. Phenotypical and functional properties of human bone marrow mesenchymal progenitor cells. Journal of cellular physiology 1999;181:67-73.
[8]Klyushnenkova E, Mosca JD, Zernetkina V, Majumdar MK, Beggs KJ, Simonetti DW, Deans RJ, McIntosh KR. T cell responses to allogeneic human mesenchymal stem cells:immunogenicity, tolerance, and suppression. J Biomed Sci 2005;12:47-57.
[9]Kim DH, Yoo KH, Choi KS, Choi J, Choi SY, Yang SE, Yang YS, Im HJ, Kim KH, Jung HL, Sung KW, Koo HH. Gene expression profile of cytokine and growth factor during differentiation of bone marrow-derived mesenchymal stem cell. Cytokine 2005;31:119-126.
[10]Haynesworth SE, Baber MA, Caplan AI. Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro:effects of dexamethasone and IL-1 alpha. Journal of cellular physiology 1996:166:585-592.
[11]Ries C, Egea V, Karow M, Kolb H, Jochum M, Neth P. MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells:differential regulation by inflammatory cytokines. Blood 2007:109:4055-4063.
[12]Honczarenko M, Le Y, Swierkowski M, Ghiran I, Glodek AM, Silberstein LE. Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors. Stem cells (Dayton, Ohio) 2006:24:1030-1041.
[13]Von Luttichau I, Notohamiprodjo M, Wechselberger A, Peters C, Henger A, Seliger C, Djafarzadeh R, Huss R, Nelson PJ. Human adult CD34-progenitor cells functionally express the chemokine receptors CCR1, CCR4, CCR7, CXCR5, and CCR10 but not CXCR4. Stem Cells Dev 2005:14:329-336.
[14]Lama VN, Smith L, Badri L, Flint A, Andrei AC, Murray S, Wang Z, Liao H, Toews GB, Krebsbach PH, Peters-Golden M,'Pinsky DJ, Martinez FJ, Thannickal VJ. Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts. J Clin Invest 2007:117:989-996.
[15]Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: mesenchymal stem cells:their phenotype, differentiation capacity, immunological features, and potential for homing. Stem cells (Dayton, Ohio) 2007:25:2739-2749.
[16]Abdi R, Fiorina P, Adra CN, Atkinson M, Sayegh MH. Immunomodulation by mesenchymal stem cells:a potential therapeutic strategy for type 1 diabetes. Diabetes 2008:57:1759-1767.
[17]Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, Ringden 0. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004:363:1439-1441.
[18]Le Blanc K. Immunomodulatory effects of fetal and adult mesenchymal stem cells. Cytotherapy 2003:5:485-489.
[19]Lu L, Shen RN, Broxmeyer HE. Stem cells from bone marrow, umbilical cord blood and peripheral blood for clinical application:current status and future application. Crit Rev Oncol Hematol 1996:22:61-78.
[20]Shlomchik WD. Graft-versus-host disease. Nature reviews 2007:7:340-352.
[21]Shlomchik WD, Lee SJ, Couriel D, Pavletic SZ. Transplantation's greatest challenges:advances in chronic graft-versus-host disease. Biol Blood Marrow Transplant 2007;13:2-10.
[22]Jacobsohn DA. Novel therapeutics for the treatment of graft-versus-host disease. Expert Opin Investig Drugs 2002:11:1271-1280.
[23]Jacobsohn DA, Vogelsang GB. Novel pharmacotherapeutic approaches to prevention and treatment of GVHD. Drugs 2002;62:879-889.
[24]Tamada K, Shimozaki K, Chapoval AI, Zhu G, Sica G, Flies D, Boone T, Hsu H, Fu YX, Nagata S, Ni J, Chen L. Modulation of T-cell-mediated immunity in tumor and graft-versus-host disease models through the LIGHT co-stimulatory pathway. Nature medicine 2000;6:283-289.
[25]Xu K, Li C, Pan X, Du B. Study of relieving graft-versus-host disease by blocking CD137-CD137 ligand costimulatory pathway in vitro. Int J Hematol 2007:86:84-90.
[26]Xu L, Duan L, Cao K, Yuan G, Peng Y, Huang X, Xiang P, Li S. Predominant immature CD8alpha+dendritic cells prevent graft-vs.-host disease but do not increase the risk of leukemia recurrence. Eur J Haematol 2007;78:235-245.
[27]Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 2003:75:389-397.
[28]Nauta AJ, Westerhuis G, Kruisselbrink AB, Lurvink EG, Willemze R, Fibbe WE. Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting. Blood 2006:108:2114-2120.
[29]Pevsner-Fischer M, Morad V, Cohen-Sfady M, Rousso-Noori L, Zanin-Zhorov A, Cohen S, Cohen IR, Zipori D. Toll-like receptors and their ligands control mesenchymal stem cell functions.. Blood 2007:109:1422-1432.
[30]Liotta F, Angeli R, Cosmi L, Fili L, Manuelli C, Frosali F, Mazzinghi B, Maggi L, Pasini A, Lisi V, Santarlasci V, Consoloni L, Angelotti ML, Romagnani P, Parronchi P, Krampera M, Maggi E, Romagnani S, Annunziato F. Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling. Stem cells (Dayton, Ohio) 2008:26:279-289.
[31]Tomchuck SL, Zwezdaryk KJ, Coffelt SB, Waterman RS, Danka ES,
Scandurro AB. Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses. Stem cells (Dayton, Ohio) 2008:26:99-107.
[32]Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, Zhao RC, Shi Y. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell stem cell 2008:2:141-150.
[33]Sato K, Ozaki K, Oh I, Meguro A, Hatanaka K, Nagai T, Muroi K, Ozawa K. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 2007:109:228-234.
[34]Trinchieri G. Biology of natural killer cells. Adv Immunol 1989:47:187-376.
[35]Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, mingari MC, Moretta L. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production:role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 2008:111:1327-1333.
[36]Haynesworth SE, Goshima J, Goldberg VM, Caplan AI. Characterization of cells with osteogenic potential from human marrow. Bone 1992:13:81-88.
[37]Le Blanc K, Ringden 0. Mesenchymal stem cells:properties and role in clinical bone marrow transplantation. Curr Opin Immunol 2006:18:586-591.
[38]Devine SM. Mesenchymal stem cells:will they have a role in the clinic? J Cell Biochem Suppl 2002:38:73-79.
[39]Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs 2001:169:12-20.
[40]Herrera MB, Bussolati B, Bruno S, Fonsato V, Romanazzi GM, Camussi G. Mesenchymal stem cells contribute to the renal repair of acute tubular epithelial injury. Int J Mol Med 2004:14:1035-1041.
[41]Shih HN, Shih LY, Sung TH, Chang YC. Restoration of bone defect and enhancement of bone ingrowth using partially demineralized bone matrix and marrow stromal cells. J Orthop Res 2005:23:1293-1299.
[42]Wu M, Yang L, Liu S, Li H, Hui N, Wang F, Liu H. Differentiation potential of human embryonic mesenchymal stem cells for skin-related tissue. Br J Dermatol 2006:155:282-291.
[43]Yoshikawa T, Mitsuno H, Nonaka I, Sen Y, Kawanishi K, Inada Y, Takakura Y, Okuchi K, Nonomura A. Wound therapy by marrow mesenchymal cell transplantation. Plast Reconstr Surg 2008:121:860-877.
[44]Vojtassak J, Danisovic L, Kubes M, Bakos D, Jarabek L, Ulicna M, Blasko M. Autologous biograft and mesenchymal stem cells in treatment of the diabetic foot. Neuro Endocrinol Lett 2006;27 Suppl 2:134-137.
[45]Keilhoff G, Goihl A, Stang F, Wolf G, Fansa H. Peripheral nerve tissue engineering:autologous Schwann cells vs. transdifferentiated mesenchymal stem cells. Tissue Eng 2006:12:1451-1465.
[46]Li Y, Chen J, Wang L, Zhang L, Lu M, Chopp M. Intracerebral transplantation of bone marrow stromal cells in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Neurosci Lett 2001:316:67-70.
[47]Moviglia GA, Fernandez Vina R, Brizuela JA, Saslavsky J, Vrsalovic F, Varela G, Bastos F, Farina P, Etchegaray G, Barbieri M, Martinez G, Picasso F, Schmidt Y, Brizuela P, Gaeta CA, Costanzo H, Moviglia Brandolino MT, Merino S, Pes ME, Veloso MJ, Rugilo C, Tamer I, Shuster GS. Combined protocol of cell therapy for chronic spinal cord injury. Report on the electrical and functional recovery of two patients. Cytotherapy 2006; 8:202-209.
[48]Koc ON, Day J, Nieder M, Gerson SL, Lazarus HM, Krivit W. Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH). Bone Marrow Transplant 2002:30:215-222.
[49]Sonoyama W, Liu Y, Fang D, Yamaza T, Seo BM, Zhang C, Liu H, Gronthos S, Wang CY, Wang S, Shi S. Mesenchymal stem cell-mediated functional tooth regeneration in swine. PLoS ONE 2006;1:e79.
[50]Poh KK, Sperry E, Young RG, Freyman T, Barringhaus KG, Thompson CA. Repeated direct endomyocardial transplantation of allogeneic mesenchymal stem cells:safety of a high dose, "off-the-shelf", cellular cardiomyoplasty strategy. Int J Cardiol 2007;117:360-364.
[51]Grinnemo KH, Mansson A, Dellgren G, Klingberg D, Wardell E, Drvota V, Tammik C, Holgersson J, Ringden 0, Sylven C, Le Blanc K. Xenoreactivity and engraftment of human mesenchymal stem cells transplanted into infarcted rat myocardium. J Thorac Cardiovasc Surg 2004:127:1293-1300.
[52]Noiseux N, Gnecchi M, Lopez-Ilasaca M, Zhang L, Solomon SD, Deb A, Dzau VJ, Pratt RE. Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol Ther 2006:14:840-850.
[53]Zhang S, Ge J, Sun A, Xu D, Qian J, Lin J, Zhao Y, Hu H, Li Y, Wang K, Zou Y. Comparison of various kinds of bone marrow stem cells for the repair of infarcted myocardium:single clonally purified non-hematopoietic mesenchymal stem cells serve as a superior source. J Cell Biochem 2006:99:1132-1147.
[54]Zhang D, Zhang F, Zhang Y, Gao X, Li C, Yang N, Cao K. Combining erythropoietin infusion with intramyocardial delivery of bone marrow cells is more effective for cardiac repair. Transpl Int 2007:20:174-183.
[55]Jo J, Nagaya N, Miyahara Y, Kataoka M, Harada-Shiba M, Kangawa K, Tabata Y. Transplantation of genetically engineered mesenchymal stem cells improves cardiac function in rats with myocardial infarction: benefit of a novel nonviral vector, cationized dextran. Tissue Eng 2007:13:313-322.
[56]Kraus KH, Kirker-Head C. Mesenchymal stem cells and bone regeneration. Vet Surg 2006:35:232-242.
[57]Kim MS, Hwang NS, Lee J, Kim TK, Leong K, Shamblott MJ, Gearhart J, Elisseeff J. Musculoskeletal differentiation of cells derived from human embryonic germ cells. Stem cells (Dayton, Ohio) 2005:23:113-123.
[58]Arinzeh TL, Peter SJ, Archambault MP, van den Bos C, Gordon S, Kraus K, Smith A, Kadiyala S. Allogeneic mesenchymal stem cells regenerate bone in a critical-sized canine segmental defect. J Bone Joint Surg Am 2003;85-A:1927-1935.
[59]Fang B, Shi M, Liao L, Yang S, Liu Y, Zhao RC. Systemic infusion of FLK1(+) mesenchymal stem cells ameliorate carbon tetrachloride-induced liver fibrosis in mice. Transplantation 2004:78:83-88.
[60]Shibata T, Naruse K, Kamiya H, Kozakae M, Kondo M, Yasuda Y, Nakamura N, Ota K, Tosaki T, Matsuki T, Nakashima E, Hamada Y, Oiso Y, Nakamura J. Transplantation of bone marrow-derived mesenchymal stem cells improves diabetic polyneuropathy in rats. Diabetes 2008:57:3099-3107.
[61]Zhang N, Li J, Luo R, Jiang J, Wang JA. Bone marrow mesenchymal stem cells induce angiogenesis and attenuate the remodeling of diabetic cardiomyopathy. Exp Clin Endocrinol Diabetes 2008:116:104-111.
[62]Lee RH, Seo MJ, Reger RL, Spees JL, Pulin AA, Olson SD, Prockop DJ. Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proceedings of the National Academy of Sciences of the United States of America 2006:103:17438-17443.
[63]Caplan AI. Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. Journal of cellular physiology 2007:213:341-347.
[64]Reiser J, Zhang XY, Hemenway CS, Mondal D, Pradhan L, La Russa VF. Potential of mesenchymal stem cells in gene therapy approaches for inherited and acquired diseases. Expert Opin Biol Ther 2005:5:1571-1584.
[65]Li A, Zhang Q, Jiang J, Yuan G, Feng Y, Hao J, Li C, Gao X, Wang G, Xie S. Co-transplantation of bone marrow stromal cells transduced with IL-7 gene enhances immune reconstitution after allogeneic bone marrow transplantation in mice. Gene Ther 2006:13:1178-1187.
[66]Yang J, Zhou W, Zheng W, Ma Y, Lin L, Tang T, Liu J, Yu J, Zhou X, Hu J. Effects of myocardial transplantation of marrow mesenchymal stem cells transfected with vascular endothelial growth factor for the improvement of heart function and angiogenesis after myocardial infarction. Cardiology 2007:107:17-29.
[67]Zachos T, Diggs A, Weisbrode S, Bartlett J, Bertone A. Mesenchymal stem cell-mediated gene delivery of bone morphogenetic protein-2 in an articular fracture model. Mol Ther 2007:15:1543-1550.
[68]Kyriakou CA, Yong KL, Benjamin R, Pizzey A, Dogan A, Singh N, Davidoff AM, Nathwani AC. Human mesenchymal stem cells (hMSCs) expressing
truncated soluble vascular endothelial growth factor receptor (tsFlk-1) following lentiviral-mediated gene transfer inhibit growth of Burkitt's lymphoma in a murine model. J Gene Med 2006;8:253-264.
[69]Ren C, Kumar S, Chanda D, Kallman L, Chen J, Mountz JD, Ponnazhagan S. Cancer gene therapy using mesenchymal stem cells expressing interferon-beta in a mouse prostate cancer lung metastasis model. Gene Ther 2008;15:1446-1453.
[1]Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med 2007:13:139-145.
[2]Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 2007:25:821-852.
[3]Ghilardi N, Ouyang W. Targeting the development and effector functions of TH17 cells. Semin Immunol 2007:19:383-393.
[4]Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003:421:744-748.
[5]Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. The Journal of experimental medicine 2005:201:233-240.
[6]Bettelli E, Kuchroo VK. IL-12-and IL-23-induced T helper cell subsets: birds of the same feather flock together. J Exp Med 2005:201:169-171.
[7]Trinchieri G, Pflanz S, Kastelein RA. The IL-12 family of heterodimeric cytokines:new players in the regulation of T cell responses. Immunity 2003:19:641-644.
[8]Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney 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.
[9]Park H, Li Z, Yang X0, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005:6:1133-1141.
[10]Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT. 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.
[11]Cua DJ, Kastelein RA. TGF-beta, a'double agent'in the immune pathology war. Nat Immunol 2006;7:557-559.
[12]Stockinger B, Veldhoen M. Differentiation and function of Thl7T cells. Curr Opin Immunol 2007;19:281-286.
[13]McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 2007; 8:1390-1397.
[14]Nurieva R, Yang X0, Martinez G, Zhang Y, Panopoulos AD, Ma L, Schluns K, Tian Q, Watowich SS, Jetten AM, Dong C. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 2007;448:480-483.
[15]Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, Oukka M, Kuchroo VK. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 2007;448:484-487.
[16]Zhou L, Ivanov, Ⅱ, Spolski R, min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 2007;8:967-974.
[17]Xu L, Kitani A, Fuss I, Strober W. Cutting edge:regulatory T cells induce CD4+CD25-Foxp3-T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta. J Immunol 2007:178:6725-6729.
[18]Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins lbeta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 2007;8:942-949.
[19]Laurence A,O' Shea JJ. T(H)-17 differentiation:of mice and men. Nat Immunol 2007;8:903-905.
[20]Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 2008;9:641-649.
[21]Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupe P, Barillot E, Soumelis V. A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol 2008;9:650-657.
[22]Shen F, Gaffen SL. Structure-function relationships in the IL-17 receptor:implications for signal transduction and therapy. Cytokine 2008;41:92-104.
[23]Akimzhanov AM, Yang XO, Dong C. Chromatin remodeling of interleukin-17 (IL-17) -IL-17F cytokine gene locus during inflammatory helper T cell differentiation. J Biol Chem 2007;282:5969-5972.
[24]Wright JF, Guo Y, Quazi A, Luxenberg DP, Bennett F, Ross JF, Qiu Y, Whitters MJ, Tomkinson KN, Dunussi-Joannopoulos K, Carreno BM, Collins M, Wolfman NM. Identification of an interleukin 17F/17A heterodimer in activated human CD4+T cells. J Biol Chem 2007:282:13447-13455.
[25]Chang SH, Dong C. A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses. Cell research 2007:17:435-440.
[26]Stumhofer JS, Laurence A, Wilson EH, Huang E, Tato CM, Johnson LM, Villarino AV, Huang Q, Yoshimura A, Sehy D, Saris CJ,O' Shea JJ, Hennighausen L, Ernst M, Hunter CA. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol 2006:7:937-945.
[27]Ruddy MJ, Wong GC, Liu XK, Yamamoto H, Kasayama S, Kirkwood KL, Gaffen SL. Functional cooperation between interleukin-17 and tumor necrosis factor-alpha is mediated by CCAAT/enhancer-binding protein family members. J Biol Chem 2004:279:2559-2567.
[28]Shen F, Ruddy MJ, Plamondon P, Gaffen SL. Cytokines link osteoblasts and inflammation:microarray analysis of interleukin-17-and TNF-alpha-induced genes in bone cells. J Leukoc Biol 2005:77:388-399.
[29]Yao Z, Timour M, Painter S, Fanslow W, Spriggs M. Complete nucleotide sequence of the mouse CTLA8 gene. Gene 1996;168:223-225.
[30]Wang D, John SA, Clements JL, Percy DH, Barton KP, Garrett-Sinha LA. Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease. Int Immunol 2005:17:1179-1191.
[31]Moisan J, Grenningloh R, Bettelli E, Oukka M, Ho IC. Ets-1 is a negative regulator of Th17 differentiation. J Exp Med 2007;204:2825-2835.
[32]Kang HK, Liu M, Datta SK. Low-dose peptide tolerance therapy of lupus generates plasmacytoid dendritic cells that cause expansion of autoantigen-specific regulatory T cells and contraction of inflammatory Th17 cells. J Immunol 2007;178:7849-7858.
[33]Chang SH, Park H, Dong C. Actl adaptor protein is an immediate and essential signaling component of interleukin-17 receptor. J Biol Chem 2006:281:35603-35607.
[34]Qian Y, Liu C, Hartupee J, Altuntas CZ, Gulen MF, Jane-Wit D, Xiao J, Lu Y, Giltiay N, Liu J, Kordula T, Zhang QW, Vallance B, Swaidani S, Aronica M, Tuohy VK, Hamilton T, Li X. The adaptor Actl is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat Immunol 2007;8:247-256.
[35]Qian Y, Qin J, Cui G, Naramura M, Snow EC, Ware CF, Fairchild RL, Omori SA, Rickert RC, Scott M, Kotzin BL, Li X. Actl, a negative regulator in CD40-and BAFF-mediated B cell survival. Immunity 2004;21:575-587.
[36]Dai J, Liu B, Cua DJ, Li Z. Essential roles of IL-12 and dendritic cells but not IL-23 and macrophages in lupus-like diseases initiated by cell surface HSP gp96. European journal of immunology 2007;37:706-715.
[37]Sullivan KE, Piliero LM, Dharia T, Goldman D, Petri MA.3' polymorphisms of ETS1 are associated with different clinical phenotypes in SLE. Hum Mutat 2000:16:49-53.
[38]Dong G, Ye R, Shi W, Liu S, Wang T, Yang X, Yang N, Yu X. IL-17 induces autoantibody overproduction and peripheral blood mononuclear cell overexpression of IL-6 in lupus nephritis patients. Chinese medical journal 2003;116:543-548.
[39]Yu JJ, Gaffen SL. Interleukin-17:a novel inflammatory cytokine that bridges innate and adaptive immunity. Front Biosci 2008;13:170-177.
[40]Kurasawa K, Hirose K, Sano H, Endo H, Shinkai H, Nawata Y, Takabayashi K, Iwamoto I. Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum 2000;43:2455-2463.
[41]Meyers JA, Mangini AJ, Nagai T, Roff CF, Sehy D, van Seventer GA, van Seventer JM. Blockade of TLR9 agonist-induced type I interferons promotes inflammatory cytokine IFN-gamma and IL-17 secretion by activated human PBMC. Cytokine 2006;35:235-246.
[42]Feldmann M, Steinman L. Design of effective immunotherapy for human autoimmunity. Nature 2005;435:612-619.
[43]Kikly K, Liu L, Na S, Sedgwick JD. The IL-23/Th(17) axis:therapeutic targets for autoimmune inflammation. Curr Opin Immunol 2006:18:670-675.