摘要
HBV病毒感染人类肝脏后随着疾病的进展会逐渐造成肝脏损伤并最终导致肝硬化、肝癌而人们对于这个疾病进程中的确切的免疫学机制却并不清楚。γδT细胞是一小群天然免疫细胞,在肿瘤和病毒感染中发挥一定保护和调节性作用,但是在HBV感染疾病中的作用并不清楚。在本项研究中我们探讨了在HBV感染的不同疾病状态下γδT细胞其及亚群的表型及功能的变化。在慢性乙肝疾病患者中我们通过64例免疫活化期患者(IA)、22例免疫耐受期患者(IT)以及30例健康对照(HC)分析了γδT细胞的影响。同健康对照和免疫耐受组患者相比,外周血和肝脏的Vδ2γδ T细胞频率在免疫活化期患者中显著降低,且在免疫活化期患者中降低的V82T细胞在外周血和肝脏分别同丙氨酸氨基转移酶和肝脏炎症程度显著负相关。免疫活化期患者中,呈现活化的TEM状态的Vδ2γδ T细胞增殖能力和趋化能力均受损伤,但是分泌IFN-y的能力并未变化。最为重要的是,Vδ2γδ T细胞可以在体外通过细胞接触或是IFN-γ依赖的方式显著降低Th17的产生以及Th17相关细胞因子(IL-17, IL-22)的产生。同时,在HBV急性感染中,我们首先按HBV感染发展不同进程的患者描述了外周γδT细胞频率的变化：29名急性乙肝患者、29名慢性乙肝患者、15名慢加急性肝衰竭患者、15名肝硬化患者和25名健康对照。同健康对照相比在炎症程度较为明显的急性乙肝患者、慢性乙肝患者和慢加急性肝衰竭患者而非肝硬化患者的外周γδT细胞频率显著降低,且AHB患者外周γδT细胞频率的降低同血浆丙氨酸氨基转移酶的水平显著负相关且这些活化的TEM状态的外周γδT细胞分泌颗粒酶A的能力显著降低。在随访过程中,同急性期相比患者在恢复期病毒被清除,炎症程度降低,γδT细胞的频率上升,活化程度降低,且表面NKR抑制性受体表达降低,同时我们在ConA诱导的小鼠急性肝损伤模型中证明了CD4+T细胞有可能是造成肝损伤的原因。总之,本项研究拓展了γδT细胞在HBV感染的认识,为临床HBV患者的治疗提供新的方法。
Hepatitis B virus infection might causes progressive liver damage and eventually leads to liver cirrhosis and hepatocellular carcinoma. However, the precise immunological mechanisms involving in this process are obscure. γδ T cells comprise a subset of innate immunal T cells and play protective or regulatory role against cancer and viral infections; however, their precise role in patients with hepatitis B infection diseases remains unclear. In this study we discussed phenotypic and functional changes of γδ T cells (as well as the subsets of γδ T cells) in different stages of HBV infection. In chronic hepatitis B patients we analyze the impact of γδ T cells in64immune-activated (IA) patients,22immune-tolerant (IT) carriers and30healthy controls (HCs). The frequencies of peripheral and hepatic Vδ2γδ T cells decreased with disease progression from IT to IA. In IA patients, the decreases in peripheral and intrahepatic frequencies of Vδ2γδ T cells reversely correlated with ALT levels and histological activity index. These activated terminally differentiated meomory phenotypic Vδ2γδ T cells exhibited impaired abilities in proliferation and chemotaxis, while maintained a relative intact LFN-γ production. Importantly, Vδ2γδ T cells, in vitro, significantly suppressed the production of IL-17-producing CD4+T (Th17) cells associated cytokines in both cell contact-dependent and IFN-y-dependent mechanisms. Meanwhile, in acute hepatitis B (AHB) infection, we first characterized the peripheral frequency changes of γδ T cells in different stages of HBV infectious progression:29AHB patients,29CHB patients,15acute-on-chronic liver failure (ACLF) patients and15liver cirrhosis (LC) patients as well as25HC. The frequencies of peripheral γδ T cells significantly decreased in AHB、CHB and ACLF patients (these stage of patients showed significantly inflammatory environment) but not in LC patients compared with HC groups. In AHB patients, the decreased of peripheral γδ T cells reversely correlated with serum ALT levels and these activated terminally differentiated meomory phenotypic y8T cells exhibited impaired abilities in granzyme A secretion. In longitude study, patients in convalescent phase showed clearance of HBV, reduced inflammatory stage, increased frequency of γδ T cells, decreased activated phenotype and decreased expression of inhibitory NK receptor on y8T cells compared with in acute phase. In ConA induced acute liver damage animal model, we found that CD4+T cells might be one of the reasons for liver damage. Above all, this study extend the knowledge of γδ T cells in HBV infection and may provide a novel therapeutic approach for HBV infection patients.
引文
1. Hilleman MR. Overview of the pathogenesis, prophylaxis and therapeusis of viral hepatitis B, with focus on reduction to practical applications [J]. Vaccine 2001,19(15-16):1837-48.
2. Ganem D, Prince AM. Hepatitis B virus infection--natural history and clinical consequences [J]. N Engl J Med 2004,350(11):1118-29.
3. Pan CQ, Zhang JX. Natural History and Clinical Consequences of Hepatitis B Virus Infection [J]. Int J Med Sci 2005,2(1):36-40.
4. Hoofnagle JH, Doo E, Liang TJ, et al. Management of hepatitis B:summary of a clinical research workshop [J]. Hepatology 2007,45(4):1056-75.
5. Liaw YF. Prevention and surveillance of hepatitis B virus-related hepatocellular carcinoma [J]. Semin Liver Dis 2005,25 Suppl 1:40-7.
6. Lok AS, McMahon BJ. Chronic hepatitis B Hepatology 2007,45(2):507-39.
7.中华医学会传染病与寄生虫病学分会、肝病学分会病毒性肝炎防治方案[J].中华内科杂志2001,40,(1)：62-68.
8. Fisicaro P, Valdatta C, Boni C, et al. Early kinetics of innate and adaptive immune responses during hepatitis B virus infection [J]. Gut 2009,58(7):974-82.
9. Missale G, Pilli M, Zerbini A, et al. Lack of full CD8 functional restoration after antiviral treatment for acute and chronic hepatitis C virus infection [J]. Gut 2012,61(7):1076-84.
10. Zhao J, Li Y, Jin L, et al. Natural killer cells are characterized by the concomitantly increased interferon-gamma and cytotoxicity in acute resolved hepatitis B patients [J]. PLoS ONE 2012,7:e49135.
11. Chang CX, Tan AT, Or MY, et al. Conditional ligands for Asian HLA variants facilitate the definition of CD8(+) T-cell responses in acute and chronic viral diseases [J]. Eur J Immunol 2012,43(4):1109-20.
12. Wei L. Natural history of chronic hepatitis B virus infection:what determines prognosis after cirrhotic decompensation? [J]. J Gastroenterol Hepatol 2008,23(11):1631-2.
13. Fattovich G. Natural history and prognosis of hepatitis B [J]. Semin Liver Dis 2003,23(1):47-58.
14. McMahon BJ. The natural history of chronic hepatitis B virus infection [J]. Hepatology 2009,49(1):S45-55.
15. Hadziyannis SJ, Papatheodoridis GV. Hepatitis B e antigen-negative chronic hepatitis B: natural history and treatment [J]. Semin Liver Dis 2006,26(4 Pt 1):130-41.
16. Liang X, Bi S, Yang W, et al. Epidemiological serosurvey of hepatitis B in China-declining HBV prevalence due to hepatitis B vaccination [J]. Vaccine 2009,27(47):6550-7.
17. Liang X, Bi S, Yang W, et al. Evaluation of the impact of hepatitis B vaccination among children born during 1992-2005 in China [J]. J Infect Dis 2009,200(1):39-47.
18. Hui CK, Lau GK. Immune system and hepatitis B virus infection [J]. J Clin Virol 2005,34Suppl 1:S44-8.
19. EASL clinical practice guidelines:Management of chronic hepatitis B virus infection [J]. J Hepatol 2012,57(1):167-85.
20. Papatheodoridis GV, Manolakopoulos S, Liaw YF, et al. Follow-up and indications for liver biopsy in HBeAg-negative chronic hepatitis B virus infection with persistently normal ALT:a systematic review [J]. J Hepatol 2012,57(1):196-202.
21. Brunetto MR, Giarin M, Oliveri F, et al.'e'antigen defective hepatitis B virus and course of chronic infection [J]. J Hepatol 1991,13 Suppl 4:S82-6.
22. Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B [J]. Hepatology 2001,34(4 Pt 1):617-24.
23. Brunetto MR, Oliveri F, Coco B, et al. Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients:a long term cohort study [J]. J Hepatol 2002,36(2):263-70.
24. Raimondo G, Allain JP, Brunetto MR, et al. Statements from the Taormina expert meeting on occult hepatitis B virus infection [J]. J Hepatol 2008,49(4):652-7.
25. Szabo G, Mandrekar P and Dolganiuc A. Innate immune response and hepatic inflammation [J]. Semin Liver Dis 2007,27(4):339-50.
26. Das A, Hoare M, Davies N, et al. Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection [J]. J Exp Med 2008,205(9):2111-24.
27. Zhang Z, Zhang JY, Wang LF, et al. Immunopathogenesis and prognostic immune markers of chronic hepatitis B virus infection [J]. J Gastroenterol Hepatol 2012,27():223-30.
28. Zhang JY, Zhang Z, Lin F, et al. Interleukin-17-producing CD4(+) T cells increase with severity of liver damage in patients with chronic hepatitis B [J]. Hepatology 2010,51(1):81-91.
29. Dong Z, Zhang J, Sun R, et al. Impairment of liver regeneration correlates with activated hepatic NKT cells in HBV transgenic mice [J]. Hepatology 2007,45(6):1400-12.
30. Zhang Z, Zhang S, Zou Z, et al. Hypercytolytic activity of hepatic natural killer cells correlates with liver injury in chronic hepatitis B patients [J]. Hepatology 2011,53(1):73-85.
31. Zhao N, Hao J, Ni Y, et al. Vgamma4 gammadelta T cell-derived IL-17A negatively regulates NKT cell function in Con A-induced fulminant hepatitis [J]. J Immunol 2011,187(10):5007-14.
32. Akbar SM, Horiike N, Onji M and Hino O. Dendritic cells and chronic hepatitis virus carriers [J]. Intervirology 2001,44(4):199-208.
33. Xu D, Fu J, Jin L, et al. Circulating and liver resident CD4+CD25+regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B [J]. J Immunol 2006,177(1):739-47.
34. Kakimi K, Isogawa M, Chung J, et al. Immimogenicity and tolerogenicity of hepatitis B virus structural and nonstructural proteins:implications for immunotherapy of persistent viral infections [J]. J Virol 2002,76(17):8609-20.
35. Beetz S, Wesch D, Marischen L, et al. Innate immune functions of human gammadelta T cells [J]. Immunobiology 2008,213(3-4):173-82.
36. Wlodzimirow K, Abu-Hanna A and Chamuleau RA. Acute-on-chronic liver failure-Its definition remains unclear [J]. J Hepatol 2013, Doi:10.1016/j.jhep.2013.02.011
37.中华医学会感染病学分会肝衰竭与人工肝学组,中华医学会肝病学分会重症肝病与人工肝学组肝衰竭诊疗指南[J].中华肝脏病杂志2006,14(9)：643-646.
38. Zhang GL, Xie DY, Lin BL, et al. Imbalance of interleukin-17-producing CD4 T cells/regulatory T cells axis occurs in remission stage of patients with hepatitis B virus-related acute-on-chronic liver failure [J]. J Gastroenterol Hepatol 2013,28(3):513-21.
39. Zou Z, Xu D, Li B, et al. Compartmentalization and its implication for peripheral immunologically-competent cells to the liver in patients with HBV-related acute-on-chronic liver failure [J]. Hepatology Research 2009,39(12):l 198-207.
40. Chen T, Zhu L, Zhou Y, et al. KCTD9 contributes to liver injury through NK cell activation during hepatitis B virus-induced acute-on-chronic liver failure [J]. Clin Immunol 2013,146(3):207-16.
41. Chen M, Hu P, Peng H, et al. Enhanced peripheral gammadeltaT cells cytotoxicity potential in patients with HBV-associated acute-on-chronic liver failure might contribute to the disease progression [J]. J Clin Immunol 2012,32(4):877-85.
42. Sun HQ, Zhang JY, Zhang H, et al. Increased Th17 cells contribute to disease progression in patients with HBV-associated liver cirrhosis [J]. J Viral Hepat 2012,19(6):396-403.
43. Allison TJ, Winter CC, Fournie JJ, et al. Structure of a human gammadelta T-cell antigen receptor [J]. Nature 2001,411(6839):820-4.
44. Boismenu R, Havran WL. Gammadelta T cells in host defense and epithelial cell biology [J]. Clin Immunol Immunopathol 1998,86(2):121-33.
45. Li H, Lebedeva MI, Llera AS, et al. Structure of the Vdelta domain of a human gammadelta T-cell antigen receptor [J]. Nature 1998,391(6666):502-6.
46. Brenner MB, McLean J, Dialynas DP, et al. Identification of a putative second T-cell receptor [J]. Nature 1986,322(6075):145-9.
47. Schlissel MS, Durum SD and Muegge K. The interleukin 7 receptor is required for T cell receptor gamma locus accessibility to the-V(D)J recombinase [J]. J Exp Med 2000,191(6):1045-50.
48. Caccamo N, Meraviglia S, Ferlazzo V, et al. Differential requirements for antigen or homeostatic cytokines for proliferation and differentiation of human Vgamma9Vdelta2 naive, memory and effector T cell subsets [J]. Eur J Immunol 2005,35(6):1764-72.
49. Thedrez A, Harly C, Morice A, et al. IL-21-mediated potentiation of antitumor cytolytic and proinflammatory responses of human Vgamma9Vdelta2 T cells for adoptive immunotherapy [J]. J Immunol 2009,182(6):3423-31.
50. Holtmeier W, Geisel W, Bernert K, et al. Prenatal development of the porcine TCR delta repertoire:dominant expression of an invariant T cell receptor Vdelta3-Jdelta3 chain [J]. Eur J Immunol 2004,34(7):1941-9.
51. Hayday AC. [gamma][delta] cells:a right time and a right place for a conserved third way of protection [J]. Annu Rev Immunol 2000,18(1):975-1026.
52. Correia DV, Lopes A and Silva-Santos B. Tumor cell recognition by gammadelta T lymphocytes:T-cell receptor vs. NK-cell receptors. [J]. Oncoimmunology 2013,2:e22892
53. Kabelitz D, Wesch D and He W. Perspectives of gammadelta T cells in tumor immunology [J]. Cancer Res 2007,67(1):5-8.
54. Kabelitz D, He W. The multifunctionality of human Vgamma9Vdelta2 gammadelta T cells: clonal plasticity or distinct subsets? [J]. Scand J Immunol 2012,76(3):213-22.
55. Michael Girardi. Immunosurveillance and Immunoregulation by y8 T Cells [J]. Journal of Investigative Dermatology 2006,126(9):25-31
56. He W, Hao J, Dong S, et al. Naturally activated Vgamma4 gammadelta T cells play a protective role in tumor immunity through expression of eomesodermin [J]. J Immunol 2010,185(1):126-33.
57. Ferrarini M, Heltai S, Pupa SM, Mernard S and Zocchi R. Killing of laminin receptor-positive human lung cancers by tumor infiltrating lymphocytes bearing gammadelta(+) t-cell receptors [J]. J Natl Cancer Inst 1996,88(7):436-41.
58. Maeurer MJ, Martin D, Walter W, et al. Human intestinal Vdelta1+1 lymphocytes recognize tumor cells of epithelial origin [J]. J Exp Med 1996,183(4):1681-96.
59. Donia M, Ellebaek E, Andersen MH, et al. Analysis of Vdeltal T cells in clinical grade melanoma-infiltrating lymphocytes [J]. Oncoimmunology 2012,1(8):1297-1304.
60. Corvaisier M, Moreau-Aubry A, Diez E, et al. V gamma 9V delta 2 T cell response to colon carcinoma cells [J]. J Immunol 2005,175(8):5481-8.
61. Kobayashi H, Tanaka Y, Nakazawa H, et al. A new indicator of favorable prognosis in locally advanced renal cell carcinomas:gamma delta T-cells in peripheral blood [J]. Anticancer Res 2011,31(3):1027-31.
62. Kabelitz D, Wesch D, Pitters E, et al. Characterization of tumor reactivity of human V gamma 9V delta 2 gamma delta T cells in vitro and in SCID mice in vivo [J]. J Immunol 2004,173(11):6767-76.
63. Wilhelm M, Kunzmann V, Eckstein S, et al. Gammadelta T cells for immune therapy of patients with lymphoid malignancies [J]. Blood 2003,102(1):200-6.
64. Gober HJ, Kistowska M, Angman L, et al. Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells [J]. J Exp Med 2003,197(2):163-8.
65. Kobayashi H, Tanaka Y, Yagi J, et al. Safety profile and anti-tumor effects of adoptive immunotherapy using gamma-delta T cells against advanced renal cell carcinoma:a pilot study [J]. Cancer Immunol Immunother 2007,56(4):469-76.
66. Bouet-Toussaint F, Cabillic F, Toutirais O, et al. Vgamma9Vdelta2 T cell-mediated recognition of human solid tumors. Potential for immunotherapy of hepatocellular and colorectal carcinomas [J]. Cancer Immunol Immunother 2008,57(4):531-9.
67. Li J, Herold MJ, Kimmel B, et al. Reduced expression of the mevalonate pathway enzyme farnesyl pyrophosphate synthase unveils recognition of tumor cells by Vgamma9Vdelta2 T cells [J]. J Immunol 2009,1820:8118-24.
68. Benzaid I, Monkkonen H, Stresing V, et al. High phosphoantigen levels in bisphosphonate-treated human breast tumors promote Vgamma9Vdelta2 T-cell chemotaxis and cytotoxicity in vivo [J]. Cancer Res 2011,71(6):4562-72.
69. Hao J, Dong S, Xia S, et al. Regulatory role of Vgammal gammadelta T cells in tumor immunity through IL-4 production [J]. J Immunol 2011,187(10):4979-86.
70. Peng G, Wang HY, Peng W, et al. Tumor-infiltrating gammadelta T cells suppress T and dendritic cell function via mechanisms controlled by a unique toll-like receptor signaling pathway [J]. Immunity 2007,27(2):334-48.
71. Traxlmayr MW, Wesch D, Dohnal AM, et al. Immune suppression by gammadelta T-cells as a potential regulatory mechanism after cancer vaccination with IL-12 secreting dendritic cells [J]. J Immunother 2010,33(1):40-52.
72. Bonneville M, Scotet E. Human Vgamma9Vdelta2 T cells:promising new leads for immunotherapy of infections and tumors [J]. Curr Opin Immunol 2006,18(5):539-46.
73. Himoudi N, Morgenstern DA, Yan M, et al. Human gammadelta T lymphocytes are licensed for professional antigen presentation by interaction with opsonized target cells [J]. J Immunol 2012,188(4):1708-16.
74. Brandes M, Willimann K and Moser B. Professional antigen-presentation function by human gammadelta T Cells [J]. Science 2005,309(5732):264-8.
75. Wang L, Kamath A, Das H, et al. Antibacterial effect of human V gamma 2V delta 2 T cells in vivo [J]. J Clin Invest 2001,108(9):1349-57.
76. Poccia F, Agrati C, Martini F, et al. Antiviral reactivities of gammadelta T cells [J]. Microbes Infect 2005,7(3):518-28.
77. Oyoshi MK, Nagata H, Kimura N, et al. Preferential expansion of Vgamma9-JgammaP/ Vdelta2-Jdelta3 gammadelta-T cells in nasal T-cell lymphoma and chronic active Epstein-Barr virus infection [J]. Am J Pathol 2003,162(5):1629-38.
78. Pitard V, Roumanes D, Lafarge X, et al. Long-term expansion of effector/memory Vdelta2-gammadelta T cells is a specific blood signature of CMV infection [J]. Blood 2008,112(4):1317-24.
79. Vermijlen D, Brouwer M, Dormer C, et al. Human cytomegalovirus elicits fetal gammadelta T cell responses in utero [J]. J Exp Med 2010,207(4):807-21.
80. Aoyagi M, Shimojo N, Sekine K, et al. Respiratory syncytial virus infection suppresses IFN-gamma production of gammadelta T cells [J]. Clin Exp Immunol 2003,131 (2):312-7.
81. Li H, Peng H, Ma P, et al. Association between Vgamma2Vdelta2 T cells and disease progression after infection with closely related strains of HIV in China [J]. Clin Infect Dis 2008,46(9):1466-72.
82. Sindhu ST, Ahmad R, Morisset R, et al. Peripheral blood cytotoxic gammadelta T lymphocytes from patients with human immunodeficiency virus type 1 infection and AIDS lyse uninfected CD4+T cells, and their cytocidal potential correlates with viral load [J]. J Virol 2003,77(3):1848-55.
83. Poccia F, Battistini L, Cipriani B, et al. Phosphoantigen-reactive Vgamma9Vdelta2 T lymphocytes suppress in vitro human immunodeficiency virus type 1 replication by cell-released antiviral factors including CC chemokines [J]. J Infect Dis 1999,180(3):858-61.
84. Biswas P, Ferrarini M, Mantelli B, et al. Double-edged effect of Vgamma9/Vdelta2 T lymphocytes on viral expression in an in vitro model of HIV-1/mycobacteria co-infection [J]. Eur J Immunol 2003,33(1):252-63.
85. Boismenu R, Feng L, Xia YY, et al. Chemokine expression by intraepithelial gamma delta T cells Implications for the recruitment of inflammatory cells to damaged epithelia [J]. J Immunol 1996,157(3):985-92.
86. Mackay CR. Chemokines:immunology's high impact factors [J]. Nat Immunol 2001,2(2):95-101.
87. Martino A, Poccia F. Gamma delta T cells and dendritic cells:close partners and biological adjuvants for new therapies [J]. Curr Mol Med 2007,7(7):658-73.
88. Conti L, Casetti R, Cardone M, et al. Reciprocal activating interaction between dendritic cells and pamidronate-stimulated gammadelta T cells:role of CD86 and inflammatory cytokines [J]. J Immunol 2005,174(1):252-60.
89. Ali Z, Yan L, Plagman N, et al. Gammadelta T cell immune manipulation during chronic phase of simian-human immunodeficiency virus infection [corrected] confers immunological benefits [J]. J Immunol 2009,183(8):5407-17.
90. Li H, Pauza CD. HIV envelope-mediated, CCR5/alpha4beta7-dependent killing of CD4-negative gammadelta T cells which are lost during progression to AIDS [J]. Blood 2011,118(22):5824-31.
91. Rossol R, Dobmeyer JM, Dobmeyer TS, et al. Increase in Vdeltal+gammadelta T cells in the peripheral blood and bone marrow as a selective feature of HIV-1 but not other virus infections [J]. Br J Haematol 1998,100(4):728-34.
92. Fenoglio D, Poggi A, Catellani S, et al. Vdeltal T lymphocytes producing IFN-gamma and IL-17 are expanded in HIV-1-infected patients and respond to Candida albicans [J]. Blood 2009,113(26):6611-8.
93. Hudspeth K, Fogli M, Correia DV, et al. Engagement of NKp30 on Vdeltal T cells induces the production of CCL3, CCL4, and CCL5 and suppresses HIV-1 replication [J]. Blood 2012,119(17):4013-6.
94. Par G, Rukavina D, Podack ER, et al. Decrease in CD3-negative-CD8dim(+) and Vdelta2/Vgamma9 TcR+peripheral blood lymphocyte counts, low perforin expression and the impairment of natural killer cell activity is associated with chronic hepatitis C virus infection [J]. J Hepatol 2002,37(4):514-2277.
95. Agrati C, Alonzi T, De Santis R, et al. Activation of Vgamma9Vdelta2 T cells by non-peptidic antigens induces the inhibition of subgenomic HCV replication [J]. Int Immunol 2006,18(1):11-8.
96. Agrati C, D'Offizi G, Narciso P, et al. Vdeltal T lymphocytes expressing a Thl phenotype are the major gammadelta T cell subset infiltrating the liver of HCV-infected persons [J]. Mol Med 2001,7(1):11-9.
97. Tseng CT, Miskovsky E, Houghton M, et al. Characterization of liver T-cell receptor gammadelta T cells obtained from individuals chronically infected with hepatitis C virus (HCV):evidence for these T cells playing a role in the liver pathology associated with HCV infections [J]. Hepatology 2001,33(5):1312-20.
98. Riedel DJ, Sajadi MM, Armstrong CL, et al. Natural viral suppressors of HIV-1 have a unique capacity to maintain gammadelta T cells [J]. AIDS 2009,23(15):1955-64.
99. Lozupone F, Pende D, Burgio VL, et al. Effect of human natural killer and gammadelta T cells on the growth of human autologous melanoma xenografts in SCID mice [J]. Cancer Res 2004,64(1):378-85.
100. Simoni D, Gebbia N, Invidiata FP, et al. Design, synthesis, and biological evaluation of novel aminobisphosphonates possessing an in vivo antitumor activity through a gammadelta-T lymphocytes-mediated activation mechanism [J]. J Med Chem 2008,51(21):6800-7.
101. He X, Chen H, Wu D, et al. Tandem-epitope pepti.de:a novel stimulator for gammadelta T cells in tumor immunotherapy [J]. Cancer Lett 2010,288(1):86-93.
102. Liu Z, Eltoum IE, Guo B, et al. Protective immunosurveillance and therapeutic antitumor activity of gammadelta T cells demonstrated in a mouse model of prostate cancer [J]. J Immunol 2008,180(9):6044-53.
103. Kang N, Zhou J, Zhang T, et al. Adoptive immunotherapy of lung cancer with immobilized anti-TCRgammadelta antibody-expanded human gammadelta T-cells in peripheral blood [J]. Cancer Biol Ther 2009,8(16):1540-9.
104. Zhou J, Kang N, Cui L, et al. Anti-gammadelta TCR antibody-expanded gammadelta T cells: a better choice for the adoptive immunotherapy of lymphoid malignancies [J]. Cell Mol Immunol 2012,9(1):34-44.
105. Kobayashi HT, Y. Shimmura HM, N. Tanabe K. Complete remission of lung metastasis following adoptive immunotherapy using activated autologous gammadelta T-cells in a patient with renal cell carcinoma [J]. Anticancer Res.2010,30(2):575-9.
106. Bennouna JB, E. Neidhardt EMR, F. Philip IG, et al. Phase-I study of Innacell gammadelta, an autologous cell-therapy product highly enriched in gamma9delta2 T lymphocytes, in combination with IL-2, in patients with metastatic renal cell carcinoma [J]. Cancer Immunol Immunother.2008,57(11):1599-609.
107. Viey E, Fromont G, Escudier B, et al. Phosphostim-activated gamma delta T cells kill autologous metastatic renal cell carcinoma [J]. J Immunol.2005.174(3):1338-47.
108. Abe Y, Muto M, Nieda M, et al. Clinical and immunological evaluation of zoledronate-activated Vgamma9gammadelta T-cell-based immunotherapy for patients with multiple myeloma [J]. Hematol 2009,37(8):956-68.
109. Sakamoto M, Nakajima J, Murakawa T, et al. Adoptive Immunotherapy for Advanced Non-small Cell Lung Cancer Using Zoledronate-expanded gammadelta T Cells:APhase I Clinical Study [J]. J Immunother.2011,34(2):202-11.
110. Nakajima J, Murakawa T, Fukami T, et al. A phase I study of adoptive immunotherapy for recurrent non-small-cell lung cancer patients with autologous gammadelta T cells [J]. Eur J Cardiothorac Surg 2010,37(5):1191-7.
111. Noguchi AK, T. Kamigaki TF, K. Ozawa MS, et al. Zoledronate-activated Vgamma9 gammadelta T cell-based immunotherapy is feasible and restores the impairment of gammadelta T cells in patients with solid tumors [J]. Cytotherapy.2011,13(1):92-7.
112. Siegers GM, Dhamko H, Wang XH, et al. Human Vdeltal gammadelta T cells expanded from peripheral blood exhibit specific cytotoxicity against B-cell chronic lymphocytic leukemia-derived cells [J]. Cytotherapy 2011,13(6):753-64
113. Qieli F, Vermijlen D, Fulfaro F, et al. Targeting human{gammadelta} T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer [J]. Cancer Res 2007,67(15):7450-7.
114. Hao J, Wu X, Xia S, et al. Current progress in gammadelta T-cell biology [J]. Cell Mol Immunol 2010,7(6):409-13.
115. Meraviglia S, Eberl M, Vermijlen D, et al. In vivo manipulation of Vgamma9Vdelta2 T cells with zoledronate and low-dose interleukin-2 for immunotherapy of advanced breast cancer patients [J]. Clin Exp Immunol 2010,161(2):290-7.
116. D'Asaro M, La Mendola C, Di Liberto D, et al. V gamma 9V delta 2 T lymphocytes efficiently recognize and kill zoledronate-sensitized, imatinib-sensitive, and imatinib-resistant chronic myelogenous leukemia cells [J]. J Immunol 2010,184(6):3260-8.
117. Poccia F, Gioia C, Martini F,-et al. Zoledronic acid and interleukin-2 treatment improves immunocompetence in HFV-infected persons by activating Vgamma9Vdelta2 T cells. [J]. AIDS 2009,23(5):555-65
118. Chen M, Zhang D, Zhen W, et al. Characteristics of circulating T cell receptor gamma-delta T cells from individuals chronically infected with hepatitis B virus (HBV):an association between V(delta)2 subtype and chronic HBV infection. [J]. J Infect Dis 2008,198(11):1643-50
119. Zhang S, Liang R, Luo W, et al. High susceptibility to liver injury in IL-27 p28 conditional knockout mice involves intrinsic interferon-gamma dysregulation of CD4(+) T cells. [J]. Hepatology 2013,57(4):1620-31
120. Yang W, Ding X, Deng J, et al. Interferon-gamma negatively regulates Th17-mediated immunopathology during mouse hepatitis virus infection [J]. J Mol Med (Berl) 2011,89(4):399-409.
121. Rutitzky LI, Smith PM and Stadecker MJ. T-bet protects against exacerbation of schistosome egg-induced immunopathology by regulating Th17-mediated inflammation [J]. Eur J Immunol 2009,39(9):2470-81.
122. Bertoletti A, Ferrari C. Innate and adaptive immune responses in chronic hepatitis B virus infections:towards restoration of immune control of viral infection [J]. Gut 2012,61(12): 754-64.
123. Dunn C, Peppa D, Khanna P, et al. Temporal analysis of early immune responses in patients with acute hepatitis B virus infection [J]. Gastroenterology 2009,137(4):1289-300.
124. Webster GJ, Reignat S, Maini MK, et al. Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms [J]. Hepatology 2000,32(5):1117-24.
125. Li J, Han Y, Jin K, et al. Dynamic changes of cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, and natural killer T (NKT) cells in patients with acute hepatitis B infection [J]. Virol J 2011,8(5):199.
126. Nakamoto N, Ebinuma H, Kanai T, et al. CCR9+macrophages are required for acute liver inflammation in mouse models of hepatitis [J]. Gastroenterology 2012,142(2):366-76.
127. Sato T, Thorlacius H, Johnston B, et al. Role for CXCR6 in recruitment of activated CD8+ lymphocytes to inflamed liver [J]. J Immunol 2005,174(1):277-83.
128. Deng G, Zhou G, Zhang R, et al. Regulatory polymorphisms in the promoter of CXCL10 gene and disease progression in male hepatitis B virus carriers [J]. Gastroenterology 2008,134(3):716-26.
129. Hassanshahi G, Arababadi MK, Khoramdelazad H, et al. Assessment of CXCL12 (SDF-1 alpha) polymorphisms and its serum level in posttransfusion occult HBV-infected patients in Southeastern. Iran [J]. Arch Med Res 2010,41(5):338-42.
130. Wang J, Wang PP, Xiang GJ, et al. Relationship between the expression of IP-10 and IP-10 mRNA in peripheral blood and HBV DNA level in patients with cirrhosis [J]. Hepatobiliary Pancreat Dis Int 2010,9(3):280-6.
131. Li B, Bassiri H, Rossman MD, et al. Involvement of the Fas/Fas ligand pathway in activation-induced cell death of mycobacteria-reactive human gamma delta T cells:a mechanism for the loss of gamma delta T cells in patients with pulmonary tuberculosis [J]. J Immunol 1998,161(3):1558-67.
132. Feng D, Kong X, Weng H, et al. Interleukin-22 promotes proliferation of liver stem/progenitor cells in mice and patients with chronic hepatitis B virus infection [J]. Gastroenterology 2012,143(1):188-198.e7.
133. Arshad MI, Rauch M, L'Helgoualc'h A, et al. NKT cells are required to induce high IL-33 expression in hepatocytes during ConA-induced acute hepatitis [J]. Eur J Immunol 2011,41(8):2341-8.
134. Ewen CL, Kane KP and Bleackley RC. A quarter century of granzymes [J]. Cell Death Differ 2012,19(1):28-35.
135. Susanto O, Trapani JA and Brasacchio D. Controversies in granzyme biology [J]. Tissue Antigens 2012,80(6):477-87.
136. Lopez JA, Brennan AJ, Whisstock JC, et al. Protecting a serial killer:pathways for perforin trafficking and self-defence ensure sequential target cell death [J]. Trends Immunol 2012,33(8):406-12.
137. Urban EM, Li H, Armstrong C, et al. Control of CD56 expression and tumor cell cytotoxicity in human Vgamma2Vdelta2 T cells [J]. BMC Immunol 2009,10(9):50.