丙型肝炎病毒慢性感染临床免疫学研究
|
摘要
慢性丙型肝炎是严重危害人类健康的疾病之一。免疫应答在丙型肝炎的发病机制中起重要作用。辅助性T淋巴细胞Thl/2细胞失平衡在丙型肝炎发病中有重要作用。我们检测了64份慢性HCV感染者血清Thl/2相关细胞因子及其动态变化。结果肝炎和肝硬化组患者IL-2,IFN-Y无明显差别;肝硬化组患者IL-4,IL-10表达增强;TNF-α表达减弱。对6名患者动态血清检测发现IL-4,IL-10有逐渐增高趋势,IL-2,TNF-α,IFN-γ表达有下降趋势;急性发作时,IL-2,TNF-α,IFN-y增高;IL-4,IL-10维持在一定水平;1名患者接受peg-IFN-α2a治疗后,血清IL-2,TNF-α,IFN-γ增高,IL-4,IL-10下降。提示慢性HCV感染者外周血Th1/Th2细胞失平衡,以Th2细胞因子为主,干扰素治疗有利于恢复Th1/Th2失衡。通过调节Th相关细胞因子纠正Th1/Th2失平衡可能成为慢性HCV感染新的治疗思路。为了解慢性HCV感染者肝脏内免疫状态,对30例慢性HCV感染者的肝穿标本进行了研究,用原位杂交法检测HCV RNA表达,发现HCV RNA阳性表达在肝组织内呈散在分布,周围可伴随单个核细胞浸润。HCV RNA复制活跃可加重肝脏损伤。用免疫组化方法检测肝脏中IFN-γ、TNF-α、IL-10的表达。观察到IFN-γ、TNF-α、IL-10在肝内主要表达于淋巴细胞和窦内皮细胞等,另外炎症、坏死、脂肪变性周围的部分肝细胞也可见IFN-γ、TNF-α、IL-10表达。慢性HCV感染者肝组织中的IFN-γ、TNF-α、IL-10较正常肝组织增强。随炎症程度的增加IL-10、TNF-α表达逐渐增强,IFN-γ表达无明显增加。TNF-α与IL-10表达有较高相关性,TNF-α和IL-10与IFN-γ表达有相关性,但相关系数较低。TNF-α、IL-10与HCVRNA表达相关性较高,IFN-γ与HCVRNA相关性稍低。提示慢性HCV感染者肝内促炎因子TNF-ct和抗炎因子IL-10表达均增强,可能是HCV感染慢性化的原因之一。用免疫组化法检测了慢性HCV感染者肝脏内CD4+、CD8+、Foxp3+T细胞的分布特点,观察到CD4+、CD8+、Foxp3+T淋巴细胞主要分布于汇管区和部分胆管增生区,肝小叶内也可见散在分布。CD4+、CD8+、Foxp3+T阳性细胞分布部位与HCVRNA阳性部位较为一致。CD8+T淋巴细胞在肝小叶内炎性坏死灶及窦周炎部位增多明显。慢性HCV感染者肝脏Foxp3+表达增强,随炎症程度增加,Foxp3+表达逐渐增强,由于Foxp3+特异性地表达于Treg,推测Treg细胞可能在HCV感染慢性化中发挥重要作用。慢性HCV感染者患者肝内存在抑制HCV特异性CTL功能的机制:如调节性T淋巴细胞、IL-10等,可能是HCV慢性感染持续存在的重要原因之一。随着慢性HCV免疫学研究的进一步深入,将为临床治疗和预防HCV感染提供新的思路和方法。
Hepatitis C is an important infectious disease of human beings and immune response may play an important role in HCV infection.Th0 lymphocytes resemble functionally both Th1 and Th2 lymphocytes.Th1 lymphocytes produce cytokines such as IL-2,IFN-γ,TNF-α,which possess a potent antiviral activity.The Th2-type pattern of cytokine secretion(IL-4,IL-5,IL-6,IL-10 and IL-13)is able to activate mainly B cells and inhibit Th1 type immune responses.We detected Th1/Th2-type pattern cytokines in patients with chronic HCV.We found that IL-2,IFN-γserum levels are similar in hepatitis and cirrhosis group,IL-4,10 serum levels in cirrhosis group are hinger than hepatitis goup,but TNF-αserum level is lower.We also observed the dynamic cytokines secretion changes of six patients with chronic HCV and founded that along with the development of hepatitis,IL-4,IL-10 serum levels increases gradually, IL-2,IFN-γ,TNF-αdecreased gradually but increased in acute episode of chronic HCV infection.In an patient who received peg-IFN-α2a therapy, IL-2,IFN-γ, TNF-αincreased and IL-4,10 decreased.It is supposed that Th1/Th2 imbalance in periphery blood,espeically increased Th2-type pattern cytokines secretion may play an importment role in chronic HCV infection.Cytokines theraphy to rectificate the Th1/Th2 imbalance may be an new strategy of hepatitis C treatment.We also used in situ hybridization method to detect the expression of HCVRNA in liver biopsies of 30 patients with chronic HCV.We founded that HCVRNA positive signals are single or in some hepatic cells,dispersaled in lobuli hepatis.Little positive cells are in or near the necrosis,infiltrated by lymph cells or mononuclear cells.Increased expression of HCVRNA always raisd the hepatic damage. Regulatory T cells are able to suppress HCV-specific T lymphocyte proliferation and cytokine secretion during chronic HCV infection. We wished to address to what extent regulatory T cells exist in the livers of HCV+ individuals, and what the role of such cells might be in disease progression. We analysed the frequency and distribution of FOXP3+ cells, along with CD4+, CD8+ cells, IL-10,TNF-α,IFN-γ,in liver biopsies of 30 patients with chronic HCV and correlated these data with histological parameters. We found that CD4+, CD8+,FOXP3+,IL-10, TNF-α,IFN-γexpressed mainly in portal tract,folliculus lymphaticus and CD8+ expressed predominantly near necrosis area.When liver damage increased, expression of CD8+, FOXP3+,IL-10,TNF-αincreased,but CD4+,IFN-γdid not increased obversiously. Because FOXP3+ expresses specificially in Treg,it is supposed that the ratio of CD4+/CD8+ degradation revealed dysfunction of CD8+T lymphocyte and Treg may play a critical role in intrahepatic immune regulation of chronic HCV infection. Advanced understanding of immune pathogenesis of chronic HCV infection may provide new strategy and treatment to therapy or prevent HCV infection.
Hepatitis C is an important infectious disease of human beings and immune response may play an important role in HCV infection.Th0 lymphocytes resemble functionally both Th1 and Th2 lymphocytes.Th1 lymphocytes produce cytokines such as IL-2,IFN-γ,TNF-α,which possess a potent antiviral activity.The Th2-type pattern of cytokine secretion(IL-4,IL-5,IL-6,IL-10 and IL-13)is able to activate mainly B cells and inhibit Th1 type immune responses.We detected Th1/Th2-type pattern cytokines in patients with chronic HCV.We found that IL-2,IFN-γserum levels are similar in hepatitis and cirrhosis group,IL-4,10 serum levels in cirrhosis group are hinger than hepatitis goup,but TNF-αserum level is lower.We also observed the dynamic cytokines secretion changes of six patients with chronic HCV and founded that along with the development of hepatitis,IL-4,IL-10 serum levels increases gradually, IL-2,IFN-γ,TNF-αdecreased gradually but increased in acute episode of chronic HCV infection.In an patient who received peg-IFN-α2a therapy, IL-2,IFN-γ, TNF-αincreased and IL-4,10 decreased.It is supposed that Th1/Th2 imbalance in periphery blood,espeically increased Th2-type pattern cytokines secretion may play an importment role in chronic HCV infection.Cytokines theraphy to rectificate the Th1/Th2 imbalance may be an new strategy of hepatitis C treatment.We also used in situ hybridization method to detect the expression of HCVRNA in liver biopsies of 30 patients with chronic HCV.We founded that HCVRNA positive signals are single or in some hepatic cells,dispersaled in lobuli hepatis.Little positive cells are in or near the necrosis,infiltrated by lymph cells or mononuclear cells.Increased expression of HCVRNA always raisd the hepatic damage. Regulatory T cells are able to suppress HCV-specific T lymphocyte proliferation and cytokine secretion during chronic HCV infection. We wished to address to what extent regulatory T cells exist in the livers of HCV+ individuals, and what the role of such cells might be in disease progression. We analysed the frequency and distribution of FOXP3+ cells, along with CD4+, CD8+ cells, IL-10,TNF-α,IFN-γ,in liver biopsies of 30 patients with chronic HCV and correlated these data with histological parameters. We found that CD4+, CD8+,FOXP3+,IL-10, TNF-α,IFN-γexpressed mainly in portal tract,folliculus lymphaticus and CD8+ expressed predominantly near necrosis area.When liver damage increased, expression of CD8+, FOXP3+,IL-10,TNF-αincreased,but CD4+,IFN-γdid not increased obversiously. Because FOXP3+ expresses specificially in Treg,it is supposed that the ratio of CD4+/CD8+ degradation revealed dysfunction of CD8+T lymphocyte and Treg may play a critical role in intrahepatic immune regulation of chronic HCV infection. Advanced understanding of immune pathogenesis of chronic HCV infection may provide new strategy and treatment to therapy or prevent HCV infection.
引文
[1]Moriishi K,Matsuura Y.Pathogenesis of hepatitis C virus.Uirusu.2007 Dec;57(2):141-9.
[2]Lee CM,Hung CH,Lu SN,et al.Hepatitis C vires genotypes:clinical relevance and therapeutic implications.Chang Gung Med J.2008 Jan-Feb;31(1):16-25.
[3]成军。丙型肝炎病毒基因变异及其临床意义。中华肝脏病杂志。2006,14(1):16-18。
[4]Takaki A,Wiese M,Maertens G,et al.Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C.Nat Med.2000 May;6(5):578-82.
[5]Lechner F,Wong DK,Dunbar PR,et al.Analysis of successful immune responses in persons infected with hepatitis C virus.J Exp Med.2000 May 1;191(9):1499-512.
[6]Shoukry NH,Grakoui A,Houghton M,et al.Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection.J Exp Med.2003 Jun 16;197(12):1645-55.
[7]Mosnier JF,Pham BN,Scoazec JY,et al.Relationship between the effector T-cell response and viremia in symptomatic chronic hepatitis C.Arch Pathol Lab Med.1998 May;122(5):416-22.
[8]Sobue S,Nomura T,Ishikawa T,et al.Th1/Th2 cytokine profiles and their relationship to clinical features in patients with chronic hepatitis C virus infection.J Gastroenterol.2001 Aug;36(8):544-51.
[9]Zignego AL,Macchia D,Monti M,et al.Infection of peripheral mononuclear blood cells by hepatitis C virus.J Hepatol.1992 Jul;15(3):382-6.
[10]De Kossodo S,Houba V,Grau GE.Assaying tumor necrosis factor concentrations in human serum.A WHO International Collaborative study.J Immunol Methods. 1995 May 11;182(1):107-14.
[11] Gramenzi A, Andreone P, Loggi E, et al. Cytokine profile of peripheral blood mononuclear cells from patients with different outcomes of hepatitis C virus infection. J Viral Hepat. 2005 Sep;12(5):525-30.
[12]Fried MW,Shiffrnan ML,Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002 Sep 26;347 (13): 975-82.
[13]Karnam US,Reddy KR.Pegylated interferons. Clin Liver Dis. 2003 Feb; 7(1): 139-48.
[14]Cacciarelli TV,Martinez OM,Gish RG, et al. Immunoregulatory cytokines in chronic hepatitis C virus infection: pre- and posttreatment with interferon alfa. Hepatology. 1996 Jul;24(1):6-9.
[15] Seddiki N, Kelleher AD. Regulatory T cells in HIV infection: who's suppressing what? Curr HIV/AIDS Rep. 2008 Feb;5(1):20-6.
[16] Kim JM, Rudensky A. The role of the transcription factor Foxp3 in the development of regulatory T cells. Immunol Rev. 2006 Aug;212:86-98.
[17]Thimme R,Bukh J,Spangenberg HC, et al. Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15661-8. Epub 2002 Nov 19.
[18]Thimme R,Oldach D,Chang KM, et al. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med. 2001 Nov 19; 194(10): 1395-406.
[19] Cecere A, Marotta F, Vangieri B, et al. Progressive liver injury in chronic hepatitis C infection is related to altered cellular immune response and to different citokine profile. Panminerva Med. 2004 Sep;46(3):171-87.
[20]Gajewski TF,Fitch FW. Anti-proliferative effect of IFN-gamma in immune regulation. I. IFN-gamma inhibits the proliferation of Th2 but not Th1 murine helper T lymphocyte clones. J Immunol. 1988 Jun 15;140(12):4245-52.
[21] Tsai SL,Liaw YF,Chen MH, et al. Detection of type 2-like T-helper cells in hepatic C virus infection:implications for hepatitis C virus chronicity. Hepatology, 1997;25:449-58.
[22]Modlin RL,Nutman TB.Type 2 cytokines and negative immune regulation in human infections. Curr Opin Immunol. 1993 Aug;5(4):511-7.
[23]Kantzanou M,Lucas M,Barnes E,et al Viral escape and T cell exhaustion in hepatitis C virus infection analysed using Class I peptide tetramers.Immunol Lett. 2003 Jan 22;85(2):165-71.
[24]Mihm S,Schweyer S,Ramadori GExpression of the chemokine IP-10 correlates with the accumulation of hepatic IFN-gamma and IL-18 mRNA in chronic hepatitis C but not in hepatitis B. J Med Virol. 2003 Aug;70(4):562-70.
[25]Yoshioka M, Ito T, Miyazaki S, Nakajima Y.The release of tumor necrosis factor-alpha, interleukin-l, interleukin-6 and prostaglandin E2 in bovine Kupffer cells stimulated with bacterial lipopolysaccharide. Vet Immunol Immunopathol. 1998 Dec 11;66(3-4):301-7.
[26]Lee CH, Choi YH, Yang SH,et al. Hepatitis C virus core protein inhibits interleukin 12 and nitric oxide production from activated macrophages. Virology. 2001 Jan 5;279(1):271-9.
[27]Dolganiuc A, Chang S, Kodys K,et al. Hepatitis C virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-alpha and plasmacytoid dendritic cell loss in chronic HCV infection. J Immunol. 2006 Nov 15;177(10):6758-68.
[28]Cook DN,Prosser DM,Forster R, et al. CCR6 mediates dendritic cell localization, lymphocyte homeostasis, and immune responses in mucosal tissue. Immunity. 2000 May;12(5):495-503.
[29]Katayama K, Kasahara A, Sasaki Y,et al.Immunological response to interferon-gamma priming prior to interferon-alpha treatment in refractory chronic hepatitis C in relation to viral clearance.J Viral Hepat.2001 May;8(3):180-5.
[30]Schlaak JF,Schramm C,Radecke K,et al.Sustained suppression of HCV replication and inflammatory activity after interleukin-2 therapy in patients with HIV/hepatitis C virus coinfection.J Acquir Immune Defic Syndr.2002 Feb 1;29(2):145-8.
[31]Barth H,Klein R,Berg PA,et al.Analysis of the effect of IL-12 therapy on immunoregulatory T-cell subsets in patients with chronic hepatitis C infection.Hepatogastroenterology.2003 Jan-Feb;50(49):201-6.
[32]Asadullah K,Sterry W,Volk HD.Interleukin-10 therapy--review of a new approach.Pharmacol Rev.2003 Jun;55(2):241-69.
[33]Louis H,Le Moine O,Goldman M,et al.Modulation of liver injury by interleukin-10.Acta Gastroenterol Belg.2003 Jan-Mar;66(1):7-14.
[34]Tsutsumi M,Urashima S,Takada A,et al.Detection of antigens related to hepatitis C virus RNA encoding the NS5 region in the livers of patients with chronic type C hepatitis.Hepatology.1994 Feb;19(2):265-72.
[35]Nouri Aria KT,Sallie R,Sangar D,et al.Detection of genomic and intermediate replicative strands of hepatitis C virus in liver tissue by in situ hybridization.J Clin Invest.1993 May;91(5):2226-34.
[36]Negro F,Pacchioni D,Shimizu Y,et al.Detection of intrahepatic replication of hepatitis C virus RNA by in situ hybridization and comparison with histopathology.Proc Natl Acad Sci U S A.1992 Mar 15;89(6):2247-51.
[37]Rico MA,Quiroga JA,Subira D,et al.Virus-specific effector CD4+ T-cell responses in hemodialysis patients with hepatitis C virus infection.J Med Virol.2004 Jan;72(1):66-74.
[38]Elpek KG,Yolcu ES,Franke DD,et al.Ex vivo expansion of CD4+CD25+FoxP3+ T regulatory cells based on synergy between IL-2 and 4-1BB signaling.J Immunol.2007 Dec 1;179(11):7295-304.
[39]Yap SH,Willems M,Van den Oord J,et al.Detection of hepatitis C virus antigen by immuno-histochemical staining:a histological marker of hepatitis C virus infection.J Hepatol.1994 Feb;20(2):275-81.
[40]Rushbrook SM,Hoare M,Alexander GJ.T-regulatory lymphocytes and chronic viral hepatitis.Expert Opin Biol Ther.2007 Nov;7(11):1689-703.
[41]Hori S,Nomura T,Sakaguchi S.Control of regulatory T cell development by the transcription factor Foxp3.Science,2003,299(5609):1057-1061.
[42]Ward SM,Fox BC,Brown PJ,Worthington J,et al.Quantification and localisation of FOXP3+ T lymphocytes and relation to hepatic inflammation during chronic HCV infection.J Hepatol.2007 Sep;47(3):316-24.Epub 2007 Apr 12.
[43]Demirkiran A,Baan CC,Kok A,et al.Intrahepatic detection of FOXP3 gene expression after liver transplantation using minimally invasive aspiration biopsy.Transplantation.2007 Mar 27;83(6):819-23.
[44]Khattri R,Kasprowicz D,Ramsdell F,et al.The amount of scurfin protein determines peripheral T cell number and responsiveness.Immunol,2001,167(11):6312-6320.
[1]Chou R,Clark EC,Helfand M.Screening for hepatitis C virus infection:a review of the evidence for the US Preventive Services Task Force[J].Ann Intern Med,2004,140(6):465-479.
[2]Bain C,Parroche P,Lavergne JP,et al.Memory T-cell-mediated immune responses specific to an alternative core protein in hepatitis C virus infecfion[J].J Virol,2004,78(19):10460-10469.
[3]Kanazawa N,Kurosaki M,Sakamoto N,et al.Regulation of hepatitis C virus replication by interferon regulatory factor 1[J].J Virol,2004,78(18):9713-9720.
[4]Jinushi M,Takehara T,Tatsumi T,et al.Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection[J].J Immunol,2004,173(10):6072-6081.
[5]de Andrade DR Jr,de Andrade DR.The influence of the human genome on chronic viral hepatitis outcome[J].Rev Inst Med Trop Sao Paulo,2004,46(3):119-126.
[6]Eisen-Vandervelde AL,Waggoner SN,Yao ZQ,et aI.Hepatitis C virus core selectively suppresses interleukin-12 synthesis in human macrophages by interfering with AP-1 activation[J].J Biol Chem,2004,279(42):43479-43486.
[7]Konan KV,Giddings TH Jr,Ikeda M,et al.Nonstructural protein precursor NS4A/B from hepatitis C virus alters function and ultrastructure of host secretory apparatus[J].J Virol,2003,77(14):7843-7855.
[8]McKeating JA,Zhang LQ,Logvinoff C,et al.Diverse hepatitis C virus glycoproteins mediate viral infection in a CD81-dependent manner[J].J Virol,2004,78(16):8496-8505.
[2]Lee CM,Hung CH,Lu SN,et al.Hepatitis C vires genotypes:clinical relevance and therapeutic implications.Chang Gung Med J.2008 Jan-Feb;31(1):16-25.
[3]成军。丙型肝炎病毒基因变异及其临床意义。中华肝脏病杂志。2006,14(1):16-18。
[4]Takaki A,Wiese M,Maertens G,et al.Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C.Nat Med.2000 May;6(5):578-82.
[5]Lechner F,Wong DK,Dunbar PR,et al.Analysis of successful immune responses in persons infected with hepatitis C virus.J Exp Med.2000 May 1;191(9):1499-512.
[6]Shoukry NH,Grakoui A,Houghton M,et al.Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection.J Exp Med.2003 Jun 16;197(12):1645-55.
[7]Mosnier JF,Pham BN,Scoazec JY,et al.Relationship between the effector T-cell response and viremia in symptomatic chronic hepatitis C.Arch Pathol Lab Med.1998 May;122(5):416-22.
[8]Sobue S,Nomura T,Ishikawa T,et al.Th1/Th2 cytokine profiles and their relationship to clinical features in patients with chronic hepatitis C virus infection.J Gastroenterol.2001 Aug;36(8):544-51.
[9]Zignego AL,Macchia D,Monti M,et al.Infection of peripheral mononuclear blood cells by hepatitis C virus.J Hepatol.1992 Jul;15(3):382-6.
[10]De Kossodo S,Houba V,Grau GE.Assaying tumor necrosis factor concentrations in human serum.A WHO International Collaborative study.J Immunol Methods. 1995 May 11;182(1):107-14.
[11] Gramenzi A, Andreone P, Loggi E, et al. Cytokine profile of peripheral blood mononuclear cells from patients with different outcomes of hepatitis C virus infection. J Viral Hepat. 2005 Sep;12(5):525-30.
[12]Fried MW,Shiffrnan ML,Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002 Sep 26;347 (13): 975-82.
[13]Karnam US,Reddy KR.Pegylated interferons. Clin Liver Dis. 2003 Feb; 7(1): 139-48.
[14]Cacciarelli TV,Martinez OM,Gish RG, et al. Immunoregulatory cytokines in chronic hepatitis C virus infection: pre- and posttreatment with interferon alfa. Hepatology. 1996 Jul;24(1):6-9.
[15] Seddiki N, Kelleher AD. Regulatory T cells in HIV infection: who's suppressing what? Curr HIV/AIDS Rep. 2008 Feb;5(1):20-6.
[16] Kim JM, Rudensky A. The role of the transcription factor Foxp3 in the development of regulatory T cells. Immunol Rev. 2006 Aug;212:86-98.
[17]Thimme R,Bukh J,Spangenberg HC, et al. Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15661-8. Epub 2002 Nov 19.
[18]Thimme R,Oldach D,Chang KM, et al. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med. 2001 Nov 19; 194(10): 1395-406.
[19] Cecere A, Marotta F, Vangieri B, et al. Progressive liver injury in chronic hepatitis C infection is related to altered cellular immune response and to different citokine profile. Panminerva Med. 2004 Sep;46(3):171-87.
[20]Gajewski TF,Fitch FW. Anti-proliferative effect of IFN-gamma in immune regulation. I. IFN-gamma inhibits the proliferation of Th2 but not Th1 murine helper T lymphocyte clones. J Immunol. 1988 Jun 15;140(12):4245-52.
[21] Tsai SL,Liaw YF,Chen MH, et al. Detection of type 2-like T-helper cells in hepatic C virus infection:implications for hepatitis C virus chronicity. Hepatology, 1997;25:449-58.
[22]Modlin RL,Nutman TB.Type 2 cytokines and negative immune regulation in human infections. Curr Opin Immunol. 1993 Aug;5(4):511-7.
[23]Kantzanou M,Lucas M,Barnes E,et al Viral escape and T cell exhaustion in hepatitis C virus infection analysed using Class I peptide tetramers.Immunol Lett. 2003 Jan 22;85(2):165-71.
[24]Mihm S,Schweyer S,Ramadori GExpression of the chemokine IP-10 correlates with the accumulation of hepatic IFN-gamma and IL-18 mRNA in chronic hepatitis C but not in hepatitis B. J Med Virol. 2003 Aug;70(4):562-70.
[25]Yoshioka M, Ito T, Miyazaki S, Nakajima Y.The release of tumor necrosis factor-alpha, interleukin-l, interleukin-6 and prostaglandin E2 in bovine Kupffer cells stimulated with bacterial lipopolysaccharide. Vet Immunol Immunopathol. 1998 Dec 11;66(3-4):301-7.
[26]Lee CH, Choi YH, Yang SH,et al. Hepatitis C virus core protein inhibits interleukin 12 and nitric oxide production from activated macrophages. Virology. 2001 Jan 5;279(1):271-9.
[27]Dolganiuc A, Chang S, Kodys K,et al. Hepatitis C virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-alpha and plasmacytoid dendritic cell loss in chronic HCV infection. J Immunol. 2006 Nov 15;177(10):6758-68.
[28]Cook DN,Prosser DM,Forster R, et al. CCR6 mediates dendritic cell localization, lymphocyte homeostasis, and immune responses in mucosal tissue. Immunity. 2000 May;12(5):495-503.
[29]Katayama K, Kasahara A, Sasaki Y,et al.Immunological response to interferon-gamma priming prior to interferon-alpha treatment in refractory chronic hepatitis C in relation to viral clearance.J Viral Hepat.2001 May;8(3):180-5.
[30]Schlaak JF,Schramm C,Radecke K,et al.Sustained suppression of HCV replication and inflammatory activity after interleukin-2 therapy in patients with HIV/hepatitis C virus coinfection.J Acquir Immune Defic Syndr.2002 Feb 1;29(2):145-8.
[31]Barth H,Klein R,Berg PA,et al.Analysis of the effect of IL-12 therapy on immunoregulatory T-cell subsets in patients with chronic hepatitis C infection.Hepatogastroenterology.2003 Jan-Feb;50(49):201-6.
[32]Asadullah K,Sterry W,Volk HD.Interleukin-10 therapy--review of a new approach.Pharmacol Rev.2003 Jun;55(2):241-69.
[33]Louis H,Le Moine O,Goldman M,et al.Modulation of liver injury by interleukin-10.Acta Gastroenterol Belg.2003 Jan-Mar;66(1):7-14.
[34]Tsutsumi M,Urashima S,Takada A,et al.Detection of antigens related to hepatitis C virus RNA encoding the NS5 region in the livers of patients with chronic type C hepatitis.Hepatology.1994 Feb;19(2):265-72.
[35]Nouri Aria KT,Sallie R,Sangar D,et al.Detection of genomic and intermediate replicative strands of hepatitis C virus in liver tissue by in situ hybridization.J Clin Invest.1993 May;91(5):2226-34.
[36]Negro F,Pacchioni D,Shimizu Y,et al.Detection of intrahepatic replication of hepatitis C virus RNA by in situ hybridization and comparison with histopathology.Proc Natl Acad Sci U S A.1992 Mar 15;89(6):2247-51.
[37]Rico MA,Quiroga JA,Subira D,et al.Virus-specific effector CD4+ T-cell responses in hemodialysis patients with hepatitis C virus infection.J Med Virol.2004 Jan;72(1):66-74.
[38]Elpek KG,Yolcu ES,Franke DD,et al.Ex vivo expansion of CD4+CD25+FoxP3+ T regulatory cells based on synergy between IL-2 and 4-1BB signaling.J Immunol.2007 Dec 1;179(11):7295-304.
[39]Yap SH,Willems M,Van den Oord J,et al.Detection of hepatitis C virus antigen by immuno-histochemical staining:a histological marker of hepatitis C virus infection.J Hepatol.1994 Feb;20(2):275-81.
[40]Rushbrook SM,Hoare M,Alexander GJ.T-regulatory lymphocytes and chronic viral hepatitis.Expert Opin Biol Ther.2007 Nov;7(11):1689-703.
[41]Hori S,Nomura T,Sakaguchi S.Control of regulatory T cell development by the transcription factor Foxp3.Science,2003,299(5609):1057-1061.
[42]Ward SM,Fox BC,Brown PJ,Worthington J,et al.Quantification and localisation of FOXP3+ T lymphocytes and relation to hepatic inflammation during chronic HCV infection.J Hepatol.2007 Sep;47(3):316-24.Epub 2007 Apr 12.
[43]Demirkiran A,Baan CC,Kok A,et al.Intrahepatic detection of FOXP3 gene expression after liver transplantation using minimally invasive aspiration biopsy.Transplantation.2007 Mar 27;83(6):819-23.
[44]Khattri R,Kasprowicz D,Ramsdell F,et al.The amount of scurfin protein determines peripheral T cell number and responsiveness.Immunol,2001,167(11):6312-6320.
[1]Chou R,Clark EC,Helfand M.Screening for hepatitis C virus infection:a review of the evidence for the US Preventive Services Task Force[J].Ann Intern Med,2004,140(6):465-479.
[2]Bain C,Parroche P,Lavergne JP,et al.Memory T-cell-mediated immune responses specific to an alternative core protein in hepatitis C virus infecfion[J].J Virol,2004,78(19):10460-10469.
[3]Kanazawa N,Kurosaki M,Sakamoto N,et al.Regulation of hepatitis C virus replication by interferon regulatory factor 1[J].J Virol,2004,78(18):9713-9720.
[4]Jinushi M,Takehara T,Tatsumi T,et al.Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection[J].J Immunol,2004,173(10):6072-6081.
[5]de Andrade DR Jr,de Andrade DR.The influence of the human genome on chronic viral hepatitis outcome[J].Rev Inst Med Trop Sao Paulo,2004,46(3):119-126.
[6]Eisen-Vandervelde AL,Waggoner SN,Yao ZQ,et aI.Hepatitis C virus core selectively suppresses interleukin-12 synthesis in human macrophages by interfering with AP-1 activation[J].J Biol Chem,2004,279(42):43479-43486.
[7]Konan KV,Giddings TH Jr,Ikeda M,et al.Nonstructural protein precursor NS4A/B from hepatitis C virus alters function and ultrastructure of host secretory apparatus[J].J Virol,2003,77(14):7843-7855.
[8]McKeating JA,Zhang LQ,Logvinoff C,et al.Diverse hepatitis C virus glycoproteins mediate viral infection in a CD81-dependent manner[J].J Virol,2004,78(16):8496-8505.