龙胆泻肝配方颗粒抗生殖器疱疹病毒及对树突状细胞功能影响的体外实验研究
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摘要
目的：探讨中药龙胆泻肝配方颗粒对生殖器疱疹病毒增殖的抑制作用；通过研究龙胆泻肝配方颗粒对生殖器疱疹患者外周血树突状细胞表面成熟标志CD83、CD86表达的影响及对树突状细胞分泌白细胞介素-12水平的影响,探讨龙胆泻肝配方颗粒免疫作用机制的靶点。
方法：1)采用细胞培养技术对龙胆泻肝配方颗粒水溶物体外抗HSV-2的药效实验进行研究。在增殖抑制法、感染阻断法及直接杀灭法3种作用方式下,不同浓度的药物对生殖器疱疹病毒增殖的影响。2)通过体外细胞培养的方法用龙胆泻肝配方颗粒水溶物对生殖器疱疹患者的树突状细胞进行作用,然后检测患者及健康者外周血DC的表面标志CD83、CD86的表达水平。3)用ELISA法检测正常人的对照组和生殖器疱疹患者组DC的培养上清液中的IL-12含量。
结果：1)药物的细胞毒性测定：正常细胞对照的CPE均小于25％,龙胆泻肝配方颗粒及阿昔洛韦(ACV)对Vero细胞的最大无毒浓度(TC0)分别为0.16、0. lmg/ml.按Reed-Muench法算出龙胆泻肝配方颗粒、ACV对Vero细胞的TC50分别为5.631、0.457mg／ml。2)病毒感染性测定：将病毒原液行连续10倍递次稀释,进行病毒感染性测定,测得HSV-2 333病毒株的TCID50=10-4／0.1ml。3)药物对HSV-2所致CPE的抑制实验结果：三种不同药物加入方式下,实验所设病毒对照组均可见典型CPE,正常细胞对照组均无明显病变。4)MTT法药物抗HSV-2的药效：用MTT法测定正常细胞对照组及病毒对照组平均A490值分别为0.294±0.053、0.032±0.0065。方式Ⅰ加药,几乎各浓度中药实验组和西药对照组的平均A490值与病毒对照组比较,均有统计学差异P(<0.05或P<0.01)；方式Ⅱ加药,部分浓度中药实验组的平均A490值与病毒对照组比较,有统计学差异(P<0.05)；方式Ⅲ加药,几乎各浓度中药实验组的平均A490值与病毒对照组比较,均有统计学差异(P<0.05或P<0.01)；方式Ⅱ和Ⅲ加药,西药对照组的A490平均值与病毒对照组比较,均无统计学差异(P>0.05)。5)以药物浓度为横坐标(μg／ml)、病毒抑制率(IR％)为纵坐标绘出不同药物加入方式下的剂量效应关系图。方式IACV对HSV-2的抑制作用随浓度升高而增强,存在明显的量效关系；而龙胆泻肝颗粒量效应关系不甚明显。中药浓度达到40μg／ml时,其对HSV-2的抑制作用随浓度升高反而降低。方式Ⅱ中药浓度超过20μg／ml,其对HSV-2的抑制作用随浓度升高而增强.方式Ⅲ中药浓度达到80μg／ml时也出现IR随浓度升高而降低。6)正常人的空白对照组DC表面标志CD83、CD86的表达较低；而正常人中药对照组的DC的表面标志CD83、CD86的表达明显上调,与空白对照组比较有显著性差异(P<0.05)；生殖器疱疹患者对照组的DC的表面标志CD83、CD86的表达明显增高,与正常人空白对照组比较有显著差异(P<0.01)。生殖器疱疹患者中药作用组加入中药后的DC表面标志CD83、CD86与患者对照组比较表达下调,有显著性差异(P<0.01)7)正常人的空白对照组IL-12的含量为84.57ng／ml,生殖器疱疹患者对照组的含量与正常人的空白对照组比较明显升高,有显著性差异(P<0.01)；而在正常人的中药对照组的培养上清的IL-12的含量与正常人的空白对照组比较有所降低,但差异无统计学意义(P>0.05)。在生殖器疱疹患者中药组的培养上清的IL-12的含量与患者对照组比较明显下调,有显著性差异(P<0.01)。
结论：1)浓度低于0.16mg／ml的龙胆泻肝配方颗粒对Vero细胞无毒,对Vero细胞非常安全。2)龙胆泻肝配方颗粒和阿昔洛韦均能不同程度地抑制Vero细胞内HSV-2的增殖,龙胆泻肝配方颗粒对HSV-2有直接杀灭作用,且对HSV-2的感染有一定的预防作用,而ACV无直接杀灭及预防作用。龙胆泻肝配方颗粒体外从多个作用环节较强地抑制HSV-2。3)ACV对HSV-2增殖抑制有明显的剂量一效应关系；龙胆泻肝配方颗粒对HSV-2感染阻断作用存在量效关系；但其对HSV-2增殖抑制及直接杀灭作无明显的剂量一效应关系。4)中药龙胆泻肝配方颗粒作用于正常人外周血树突状细胞后,细胞递呈抗原的能力明显增强,中药作用于生殖器疱疹患者的外周血树突状细胞后,细胞递呈抗原的能力受到一定的抑制,说明龙胆泻肝配方颗粒对外周血树突状细胞的抗原递呈功能起到一定调节作用。5)中药作用于外周血树突状细胞后,无论正常人还是患者,其树突状细胞的细胞因子IL-12的产生均强烈受抑制,且远远低于正常人水平,说明龙胆泻肝配方颗粒主要以细胞因子IL-12的产生为作用点来抑制Th1型的淋巴细胞的分化,以治疗生殖器疱疹患者。
Objective To probe the inhibitory effect of Longdanxiegan Chinese traditional medicine Granule on replication of herpes simplex virus (HSV-2) in Vero cells in vitro. To explore the immunological function of Longdanxiegan Granule,through studying the Dendritic cells extracted from the patients'blood by cell culture method in vitro.
Methods 1) methods as following:Method I, inhibiting virus multiplication-Confluent cell monolayers in 96-well plates were infected with HSV-2 333in medium. After adsorption at 37℃for 1.5 h, residual inoculum was replaced with 0.2ml of medium containing test drug.MethodⅡ, interdicting cells infection-Cell cultures were treated with the drugmedium for 24h,washed thrice with PBS,100 TCID50 of virus were addedto give 0.1ml per well and subsequently reincubated in drug-free medium.Method III, directly killing virus-Virus were incubated in drug medium for 24h at 37℃was added to give 0.2 ml per well.2) DC in peripheral blood in patient and healthy people were cultured for five days with medium which had GM-CSF and IL-4.Flow cytometry was used to analyze surface marker of CD83 and CD86 of DC.3) the content of IL-12 in cell culture supernatant was detected by ELISA.
Result 1) The results shew that the TCo and the TC50 for Longdanxiegan were 0.16 and 5.631 mg/ml, respectively. Corresponding values for ACV were 0.1 and 0.457 mg/ml, respectively.2) The Infected capability of diluted stocks of HSV-2333 strains was measured by CPE method. The results shew that the TCID50 of HSV-2 for Vero cell was 10-4/0.1ml.3) By different drug addition methods, the typical cytopathic effects in Vero cells were observed in all parallel virus controlled groups, while normal Vero cellsgroups were almost negative. By drug addition I method, the CPEs were restrained at different degrees in Longdanxiegan and ACV groups; the CPEs were only inhibited at different degrees in Longdanxiegan group under drug addition method II and 111, while the cytopathic effects were clearly visible in ACV group.4) Measured by MTT colorimetry, the mean value of A490 for the parallel virus controlled groups and normal Vero cells groups were 0.294±0.053、0.032±0.0065, respectively. By drug addition I method, compared with the values of A490 of virus controlled groups,the values of A490 of Longdanxiegan and ACV in all concentrations were almost statistically significant (P<0.05 or P<0.01).By drug addition II method, The part values of Longdanxiegan group were statistically differences compared with that of virus controlled group (P<0.05). By the last drug addition method, only the values of Longdanxiegan group was statistically significant compared with that of the virus controlled group (p<0.01).The values of acyclovir group were not statistically differences (P>0.05) under drug addition method II andⅢ. 5) The charts of dose-effect by different drug addition methods were drawn, serving drug concentrations and IR% as abscissa and y-axis respectively. Under drug addition method I, the inhibitory effects of ACV for HSV-2 became stronger with the increase of concentration, showing clear dose-effect connection. At beginning, the inhibitory effects of Longdanxiegan became stronger with the increase of concentration. After exceeding 40pg/ml, it's inhibitory effects declined with the increase of concentration. By drug addition II method, the inhibitory rates of Longdanxiegan for HSV-2 became stronger with the increase of concentration exceeding 20μg/ml. By the last drug addition method, the IR% of Longdanxiegan became weaker with the increase of concentration exceeding 80μg/ml too.6) The expression of CD83 and CD86 on DCs were higher in patients than that in healthy controls(P<0.05). After adding drug, the expression of these molecules were regulated, there were no significant differences between patients and controls(P>0.05).7) The production of IL-12 was increased obviously in control group of patient (p<0.05). After adding drug, the production of IL-12 was decreased evidently(p<0.01).
Conclusion 1) Under the concentration of 0.16 mg/ml, Longdanxiegan were innocuity to Vero cells, Longdanxiegan was very safe to Vero cells.2) Multiplication of HSV-2 in Vero cells were inhibited at different degrees in Longdanxiegan and ACV groups. Only Longdanxiegan shew the activity of directly killing virus and guarding against Vero cells'infection by HSV-2 at different degree. Longdanxiegan had an activity for stronginhibition of HSV-2 at several effect points in vitro.3) The inhibitoryeffects of ACV for multiplication of HSV-2 shew clear dose-effect connection.The effects of Longdanxiegan for guarding against Vero cells'infection became stronger with the increase of concentration,but Longdanxiegan didn't show clear dose-effect connection in restraining multiplication of HSV-2 and directly killing virus.4) The compound traditional Chinese medicine has the function of immunoregulation on DC, it can make DC of healthy people have potent antigen presenting capabilities, which also can inhibit antigen presenting capabilities of DC in patient.5) The production of IL-12 was inhibited in patient and healthy subjects by compound traditional Chinese medicine,so the immune response of Thl is inhibited by compound traditional Chinese medicine,it could make the disease psoriasis vulgaris more better.
方法：1)采用细胞培养技术对龙胆泻肝配方颗粒水溶物体外抗HSV-2的药效实验进行研究。在增殖抑制法、感染阻断法及直接杀灭法3种作用方式下,不同浓度的药物对生殖器疱疹病毒增殖的影响。2)通过体外细胞培养的方法用龙胆泻肝配方颗粒水溶物对生殖器疱疹患者的树突状细胞进行作用,然后检测患者及健康者外周血DC的表面标志CD83、CD86的表达水平。3)用ELISA法检测正常人的对照组和生殖器疱疹患者组DC的培养上清液中的IL-12含量。
结果：1)药物的细胞毒性测定：正常细胞对照的CPE均小于25％,龙胆泻肝配方颗粒及阿昔洛韦(ACV)对Vero细胞的最大无毒浓度(TC0)分别为0.16、0. lmg/ml.按Reed-Muench法算出龙胆泻肝配方颗粒、ACV对Vero细胞的TC50分别为5.631、0.457mg／ml。2)病毒感染性测定：将病毒原液行连续10倍递次稀释,进行病毒感染性测定,测得HSV-2 333病毒株的TCID50=10-4／0.1ml。3)药物对HSV-2所致CPE的抑制实验结果：三种不同药物加入方式下,实验所设病毒对照组均可见典型CPE,正常细胞对照组均无明显病变。4)MTT法药物抗HSV-2的药效：用MTT法测定正常细胞对照组及病毒对照组平均A490值分别为0.294±0.053、0.032±0.0065。方式Ⅰ加药,几乎各浓度中药实验组和西药对照组的平均A490值与病毒对照组比较,均有统计学差异P(<0.05或P<0.01)；方式Ⅱ加药,部分浓度中药实验组的平均A490值与病毒对照组比较,有统计学差异(P<0.05)；方式Ⅲ加药,几乎各浓度中药实验组的平均A490值与病毒对照组比较,均有统计学差异(P<0.05或P<0.01)；方式Ⅱ和Ⅲ加药,西药对照组的A490平均值与病毒对照组比较,均无统计学差异(P>0.05)。5)以药物浓度为横坐标(μg／ml)、病毒抑制率(IR％)为纵坐标绘出不同药物加入方式下的剂量效应关系图。方式IACV对HSV-2的抑制作用随浓度升高而增强,存在明显的量效关系；而龙胆泻肝颗粒量效应关系不甚明显。中药浓度达到40μg／ml时,其对HSV-2的抑制作用随浓度升高反而降低。方式Ⅱ中药浓度超过20μg／ml,其对HSV-2的抑制作用随浓度升高而增强.方式Ⅲ中药浓度达到80μg／ml时也出现IR随浓度升高而降低。6)正常人的空白对照组DC表面标志CD83、CD86的表达较低；而正常人中药对照组的DC的表面标志CD83、CD86的表达明显上调,与空白对照组比较有显著性差异(P<0.05)；生殖器疱疹患者对照组的DC的表面标志CD83、CD86的表达明显增高,与正常人空白对照组比较有显著差异(P<0.01)。生殖器疱疹患者中药作用组加入中药后的DC表面标志CD83、CD86与患者对照组比较表达下调,有显著性差异(P<0.01)7)正常人的空白对照组IL-12的含量为84.57ng／ml,生殖器疱疹患者对照组的含量与正常人的空白对照组比较明显升高,有显著性差异(P<0.01)；而在正常人的中药对照组的培养上清的IL-12的含量与正常人的空白对照组比较有所降低,但差异无统计学意义(P>0.05)。在生殖器疱疹患者中药组的培养上清的IL-12的含量与患者对照组比较明显下调,有显著性差异(P<0.01)。
结论：1)浓度低于0.16mg／ml的龙胆泻肝配方颗粒对Vero细胞无毒,对Vero细胞非常安全。2)龙胆泻肝配方颗粒和阿昔洛韦均能不同程度地抑制Vero细胞内HSV-2的增殖,龙胆泻肝配方颗粒对HSV-2有直接杀灭作用,且对HSV-2的感染有一定的预防作用,而ACV无直接杀灭及预防作用。龙胆泻肝配方颗粒体外从多个作用环节较强地抑制HSV-2。3)ACV对HSV-2增殖抑制有明显的剂量一效应关系；龙胆泻肝配方颗粒对HSV-2感染阻断作用存在量效关系；但其对HSV-2增殖抑制及直接杀灭作无明显的剂量一效应关系。4)中药龙胆泻肝配方颗粒作用于正常人外周血树突状细胞后,细胞递呈抗原的能力明显增强,中药作用于生殖器疱疹患者的外周血树突状细胞后,细胞递呈抗原的能力受到一定的抑制,说明龙胆泻肝配方颗粒对外周血树突状细胞的抗原递呈功能起到一定调节作用。5)中药作用于外周血树突状细胞后,无论正常人还是患者,其树突状细胞的细胞因子IL-12的产生均强烈受抑制,且远远低于正常人水平,说明龙胆泻肝配方颗粒主要以细胞因子IL-12的产生为作用点来抑制Th1型的淋巴细胞的分化,以治疗生殖器疱疹患者。
Objective To probe the inhibitory effect of Longdanxiegan Chinese traditional medicine Granule on replication of herpes simplex virus (HSV-2) in Vero cells in vitro. To explore the immunological function of Longdanxiegan Granule,through studying the Dendritic cells extracted from the patients'blood by cell culture method in vitro.
Methods 1) methods as following:Method I, inhibiting virus multiplication-Confluent cell monolayers in 96-well plates were infected with HSV-2 333in medium. After adsorption at 37℃for 1.5 h, residual inoculum was replaced with 0.2ml of medium containing test drug.MethodⅡ, interdicting cells infection-Cell cultures were treated with the drugmedium for 24h,washed thrice with PBS,100 TCID50 of virus were addedto give 0.1ml per well and subsequently reincubated in drug-free medium.Method III, directly killing virus-Virus were incubated in drug medium for 24h at 37℃was added to give 0.2 ml per well.2) DC in peripheral blood in patient and healthy people were cultured for five days with medium which had GM-CSF and IL-4.Flow cytometry was used to analyze surface marker of CD83 and CD86 of DC.3) the content of IL-12 in cell culture supernatant was detected by ELISA.
Result 1) The results shew that the TCo and the TC50 for Longdanxiegan were 0.16 and 5.631 mg/ml, respectively. Corresponding values for ACV were 0.1 and 0.457 mg/ml, respectively.2) The Infected capability of diluted stocks of HSV-2333 strains was measured by CPE method. The results shew that the TCID50 of HSV-2 for Vero cell was 10-4/0.1ml.3) By different drug addition methods, the typical cytopathic effects in Vero cells were observed in all parallel virus controlled groups, while normal Vero cellsgroups were almost negative. By drug addition I method, the CPEs were restrained at different degrees in Longdanxiegan and ACV groups; the CPEs were only inhibited at different degrees in Longdanxiegan group under drug addition method II and 111, while the cytopathic effects were clearly visible in ACV group.4) Measured by MTT colorimetry, the mean value of A490 for the parallel virus controlled groups and normal Vero cells groups were 0.294±0.053、0.032±0.0065, respectively. By drug addition I method, compared with the values of A490 of virus controlled groups,the values of A490 of Longdanxiegan and ACV in all concentrations were almost statistically significant (P<0.05 or P<0.01).By drug addition II method, The part values of Longdanxiegan group were statistically differences compared with that of virus controlled group (P<0.05). By the last drug addition method, only the values of Longdanxiegan group was statistically significant compared with that of the virus controlled group (p<0.01).The values of acyclovir group were not statistically differences (P>0.05) under drug addition method II andⅢ. 5) The charts of dose-effect by different drug addition methods were drawn, serving drug concentrations and IR% as abscissa and y-axis respectively. Under drug addition method I, the inhibitory effects of ACV for HSV-2 became stronger with the increase of concentration, showing clear dose-effect connection. At beginning, the inhibitory effects of Longdanxiegan became stronger with the increase of concentration. After exceeding 40pg/ml, it's inhibitory effects declined with the increase of concentration. By drug addition II method, the inhibitory rates of Longdanxiegan for HSV-2 became stronger with the increase of concentration exceeding 20μg/ml. By the last drug addition method, the IR% of Longdanxiegan became weaker with the increase of concentration exceeding 80μg/ml too.6) The expression of CD83 and CD86 on DCs were higher in patients than that in healthy controls(P<0.05). After adding drug, the expression of these molecules were regulated, there were no significant differences between patients and controls(P>0.05).7) The production of IL-12 was increased obviously in control group of patient (p<0.05). After adding drug, the production of IL-12 was decreased evidently(p<0.01).
Conclusion 1) Under the concentration of 0.16 mg/ml, Longdanxiegan were innocuity to Vero cells, Longdanxiegan was very safe to Vero cells.2) Multiplication of HSV-2 in Vero cells were inhibited at different degrees in Longdanxiegan and ACV groups. Only Longdanxiegan shew the activity of directly killing virus and guarding against Vero cells'infection by HSV-2 at different degree. Longdanxiegan had an activity for stronginhibition of HSV-2 at several effect points in vitro.3) The inhibitoryeffects of ACV for multiplication of HSV-2 shew clear dose-effect connection.The effects of Longdanxiegan for guarding against Vero cells'infection became stronger with the increase of concentration,but Longdanxiegan didn't show clear dose-effect connection in restraining multiplication of HSV-2 and directly killing virus.4) The compound traditional Chinese medicine has the function of immunoregulation on DC, it can make DC of healthy people have potent antigen presenting capabilities, which also can inhibit antigen presenting capabilities of DC in patient.5) The production of IL-12 was inhibited in patient and healthy subjects by compound traditional Chinese medicine,so the immune response of Thl is inhibited by compound traditional Chinese medicine,it could make the disease psoriasis vulgaris more better.
引文
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[1]Neuman J,EisHubingberAM,KochA.Herpes simplex virus type 1 tar-gets theMHC class Ⅱ processing pathway for immune evasion[J]. J Im-muno,l 2003,17(6):3075-3083.
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[4]Mikloska Z, Bosnjak L, Cunningham AL. Immature monocytederived dendritic cells are productively infected with herpes simplex virus type 1. J Virol 2001;75:5958-64.
[5]Jugovic P, Hill AM, Tomazin R, Ploegh H, Johnson DC. Inhibition of major histocompatibility complex class I antigen presentation in pig and primate cells by herpes simplex virus type 1 and 2 ICP47.J Virol 1998; 72:5076-84.
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[10]Hock BD, Kato M, McKenzie JL, Hart DN. A soluble form of CD83 is released from activated dendritic cells and B lymphocytes, and is detectable in normal human sera. Int Immunol 2001;13:959-67.
[11]Neumann J, Eis-Hubinger AM, Koch N. Herpes simplex virus typel targets the MHC class II processing pathway for immune evasion.J Immunol 2003; 171:3075-83.
[12]Smith CM, Belz GT, Wilson NS et al.Cutting edge:conventional CD8 alpha+dendritic cells are preferentially involved in CTL primingafter footpad infection with herpes simplex virus-1. J Immunol 2003; 170:4437-40.
[13]Smith CM, Wilson NS, Waithman J et al.Cognate CD4(+) T cell licensing of dendritic cells in CD8(+) T cell immunity. Nat Immunol 2004;5:1143-8.
[14]Mueller SN, Jones CM, Smith CM, Heath WR, Carbone FR. Rapid cytotoxic T lymphocyte activation occurs in the draining lymph nodes after cutaneous herpes simplex virus infection as a result of early antigen presentation and not the presence of virus. J Exp Med 2002; 195:651-6.
[15]Medici MA, Sciortino MT, Perri D et al.Protection by herpes simplex virus glycoprotein D against Fas-mediated apoptosis:role of nuclear factor kappaB. J Biol Chem 2003; 19:36059-67.
[16]Jones CA, Fernandez M, Herc K et al.Herpes simplex virus type 2 induces rapid cell death and functional impairment of murine dendritic cells in vitro. J Virol 2003;77:11139-49.
[17]Prechtel AT, Turza NM, Kobelt DJ et al.Infection of mature dendritic cells with herpes simplex virus type 1 dramatically reduces lymphoid chemokine-mediated migration. J Gen Virol 2005;86:1645-57.
[18]Friedman HM, Wang L, Pangburn MK, Lambris JD, Lubinski J.Novel mechanism of antibody-independent complement neutralizationof herpes simplex virus type 1. J Immunol 2000; 165:4528-36.
[19]Judson KA, Lubinski JM, Jiang M et al.Blocking immune evasion as a novel approach for prevention and treatment of herpes simplexvirus infection. J Virol 2003; 77:12639-45.
[20]Lubinski JM, Jiang M, Hook L et al.Herpes simplex virus type 1 evades the effects of antibody and complement in vivo. J Virol 2002;76:9232-41.
[21]Takai Y, Irie K, Shimizu K, Sakisaka T, Ikeda W. Nectins and nectin-like molecules. roles in cell adhesion, migration, and polarization.Cancer Sci 2003; 94:655-67.
[22]Salio M, Cella M, Suter M, Lanzavecchia A. Inhibition of dendritic cell maturation by herpes simplex virus. Eur J Immunol 1999; 29:3245-53.
[23]Sakisaka T, Taniguchi T, Nakanishi H et al.Requirement of interaction of nectin-lalpha/HveC with afadin for efficient cell-cellspread of herpes simplex virus type 1. J Virol 2001; 75:4734-43.
[24]Harrop JA, McDonnell PC, Brigham-Burke M et al.Herpesvirus entry mediator ligand (HVEM-L), a novel ligand for HVEM/TR2, stimulates proliferation of T cells and inhibits HT29 cell growth. J Biol Chem 1998; 273:27548-56.
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[35]Gill N, Deacon PM, Lichty B, et al. Induction of innate immunity against herpes simplex virus type 2 infection via local delivery ofToll-like receptor ligands correlate with beta interferon production. J Virol 2006;80(20):9943-9950.
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[1]Neuman J,EisHubingberAM,KochA.Herpes simplex virus type 1 tar-gets theMHC class Ⅱ processing pathway for immune evasion[J]. J Im-muno,l 2003,17(6):3075-3083.
[2]Vandenabeele S, Wu L. Dendritic cell origins:puzzles and paradoxes.Immunol Cell Biol 1999; 77:411-19.
[3]Rissoan MC, Soumelis V, Kadowaki N et al.Reciprocal control of T helper cell and dendritic cell differentiation. Science 1999; 283:1183-6.
[4]Mikloska Z, Bosnjak L, Cunningham AL. Immature monocytederived dendritic cells are productively infected with herpes simplex virus type 1. J Virol 2001;75:5958-64.
[5]Jugovic P, Hill AM, Tomazin R, Ploegh H, Johnson DC. Inhibition of major histocompatibility complex class I antigen presentation in pig and primate cells by herpes simplex virus type 1 and 2 ICP47.J Virol 1998; 72:5076-84.
[6]Pollara G, Speidel K, Samady L et al.Herpes simplex virus infection of dendritic cells:balance among activation, inhibition, and immunity.J Infect Dis 2003; 187:165-78.
[7]Kruse M, Rosorius O, Kratzer F, et al.Mature dendritic cells infected with herpes simplex virus type 1 exhibit inhibited T cell stimulatory capacity. J Virol 2000; 74:7127-36.
[8]Zinser E, Lechmann M, Golka A, Lutz MB, Steinkasserer A. Prevention and treatment-of experimental autoimmune encephalomyelitis by soluble CD83. J Exp Med 2004;200:345-51.
[9]Kurt-Jones EA, Chan M, Zhou S et al.Herpes simplex virus 1 interaction with Toll-like receptor 2 contributes to lethal encephalitis.Proc Natl Acad Sci USA 2004; 101:1315-20.
[10]Hock BD, Kato M, McKenzie JL, Hart DN. A soluble form of CD83 is released from activated dendritic cells and B lymphocytes, and is detectable in normal human sera. Int Immunol 2001;13:959-67.
[11]Neumann J, Eis-Hubinger AM, Koch N. Herpes simplex virus typel targets the MHC class II processing pathway for immune evasion.J Immunol 2003; 171:3075-83.
[12]Smith CM, Belz GT, Wilson NS et al.Cutting edge:conventional CD8 alpha+dendritic cells are preferentially involved in CTL primingafter footpad infection with herpes simplex virus-1. J Immunol 2003; 170:4437-40.
[13]Smith CM, Wilson NS, Waithman J et al.Cognate CD4(+) T cell licensing of dendritic cells in CD8(+) T cell immunity. Nat Immunol 2004;5:1143-8.
[14]Mueller SN, Jones CM, Smith CM, Heath WR, Carbone FR. Rapid cytotoxic T lymphocyte activation occurs in the draining lymph nodes after cutaneous herpes simplex virus infection as a result of early antigen presentation and not the presence of virus. J Exp Med 2002; 195:651-6.
[15]Medici MA, Sciortino MT, Perri D et al.Protection by herpes simplex virus glycoprotein D against Fas-mediated apoptosis:role of nuclear factor kappaB. J Biol Chem 2003; 19:36059-67.
[16]Jones CA, Fernandez M, Herc K et al.Herpes simplex virus type 2 induces rapid cell death and functional impairment of murine dendritic cells in vitro. J Virol 2003;77:11139-49.
[17]Prechtel AT, Turza NM, Kobelt DJ et al.Infection of mature dendritic cells with herpes simplex virus type 1 dramatically reduces lymphoid chemokine-mediated migration. J Gen Virol 2005;86:1645-57.
[18]Friedman HM, Wang L, Pangburn MK, Lambris JD, Lubinski J.Novel mechanism of antibody-independent complement neutralizationof herpes simplex virus type 1. J Immunol 2000; 165:4528-36.
[19]Judson KA, Lubinski JM, Jiang M et al.Blocking immune evasion as a novel approach for prevention and treatment of herpes simplexvirus infection. J Virol 2003; 77:12639-45.
[20]Lubinski JM, Jiang M, Hook L et al.Herpes simplex virus type 1 evades the effects of antibody and complement in vivo. J Virol 2002;76:9232-41.
[21]Takai Y, Irie K, Shimizu K, Sakisaka T, Ikeda W. Nectins and nectin-like molecules. roles in cell adhesion, migration, and polarization.Cancer Sci 2003; 94:655-67.
[22]Salio M, Cella M, Suter M, Lanzavecchia A. Inhibition of dendritic cell maturation by herpes simplex virus. Eur J Immunol 1999; 29:3245-53.
[23]Sakisaka T, Taniguchi T, Nakanishi H et al.Requirement of interaction of nectin-lalpha/HveC with afadin for efficient cell-cellspread of herpes simplex virus type 1. J Virol 2001; 75:4734-43.
[24]Harrop JA, McDonnell PC, Brigham-Burke M et al.Herpesvirus entry mediator ligand (HVEM-L), a novel ligand for HVEM/TR2, stimulates proliferation of T cells and inhibits HT29 cell growth. J Biol Chem 1998; 273:27548-56.
[25]Medzhitov R, Janeway CA Jr. Decoding the patterns of self and nonself by the innate immune system. Science 2002; 296:298-300.
[26]Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004; 4:499-511.
[27]Lund JM, Alexopoulou L, Sato A et al.Recognition of singlestranded RNA viruses by Toll-like receptor 7. Proc Natl Acad Sci USA 2004; 101:5598-603.
[28]Schlender J, Hornung V, Finke S et al.Inhibition of Toll-like receptor 7-and 9-mediated alpha/beta interferon production in human plasmacytoid dendritic cells by respiratory syncytial virus and measles virus. J Virol 2005; 79:5507-15.
[29]Dai J, Megjugorac NJ, Amrute SB, Fitzgerald-Bocarsly P. Regulation of IFN regulatory factor-7 and IFN-alpha production byenveloped virus and lipopolysaccharide in human plasmacytoid dendritic cells. J Immunol 2004; 173:1535-48.
[30]Hochrein H, Schlatter B, O'Keeffe M et al.Herpes simplex virus type-1 induces IFN-alpha production via Toll-like receptor 9-dependent and-independent pathways. Proc Natl Acad Sci USA 2004; 101:11416-21.
[31]Allan RS, Smith CM, Belz GT et al. Epidermal viral immunity induced by CD8alpha+ dendritic cells but not by Langerhans cells.Science 2003; 301:1925-8.
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