HBeAg（+）慢性乙型肝炎患者替比夫定抗病毒治疗前后外周血iNKT细胞的变化
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摘要
目的:研究HBeAg(+)慢性乙型肝炎(CHB)患者外周血iNKT细胞数量、功能与PD-1表达情况;以及核苷(酸)类似物替比夫定抗病毒治疗对CHB患者外周血iNKT细胞数量、功能与PD-1表达的影响。
方法:选取接受替比夫定抗病毒治疗的HBeAg(+)慢性乙型肝炎患者作为研究对象,经知情同意后于抗病毒治疗前后不同时相分别抽取外周静脉血,利用CD3、TCR Vα24、TCR Vβ11、CD279(PD-1)单克隆抗体标记后经流式细胞术直接检测标本中iNKT细胞比例及其PD-1表达比例;采用PMA+Ionomycin体外活化iNKT细胞后流式细胞术检测其胞内IFN-γ及IL-4分泌情况。
结果: HBeAg(+)慢性乙型肝炎患者外周血iNKT细胞占总淋巴细胞比例为(0.15±0.08)%,与健康对照者[(0.19±0.08) %]相比无明显差异,但经体外活化后胞内IFN-γ[(23.51±7.82)% VS (41.84±12.15)%]及IL-4 [(14.07±6.1)% VS (20.86±8.21)%]分泌量降低,且iNKT细胞上PD-1的表达量显著上升[(31.21±12.59)% VS (13.64±7.41)%];替比夫定抗病毒治疗后第24周CHB患者外周血iNKT细胞的IFN-γ及IL-4分泌能力较治疗前升高,且PD-1的表达显著下降。
结论: HBeAg(+)慢性乙型肝炎患者外周血iNKT细胞处于功能低下状态,在一定程度上导致慢性HBV感染后机体不能启动有效的非特异性及特异性免疫反应,并且iNKT细胞的这种功能低下状态可能与其表面PD-1表达升高有关;替比夫定抗病毒治疗对于iNKT细胞功能的恢复及降低PD-1的表达有一定帮助,表明核苷类似物替比夫定除了具有快速地抑制HBV的复制、高的e抗原血清转换率等特点外,可能还具有一定的免疫调节作用。
Objective: To study the frequency, functions, and PD-1 expression of peripheral iNKT cells in chronic hepatitis B patients; and the effects of antiviral therapy with Telbivudine on the frequency, functions, and PD-1 expression of peripheral iNKT cells in chronic hepatitis B patients.
Methods: HBeAg(+)Chronic hepatitis B patients receiving antiviral therapy with Telbivudine were enrolled in the study. Peripheral blood samples were obtained at 0, 12, 24 weeks after informed consent from all patients. The frequencies and PD-1 expression of peripheral iNKT cells were detected by flow cytometry (FCM) after labeled with anti-CD3,TCR Vα24,TCR Vβ11 and CD279 (PD-1) monoclonal antibodies; Intracellular IFN-γand IL-4 production by iNKT cells was analyzed on flow cytometer after in vitro activation with PMA and Ionomycin.
Results: The frequencies of peripheral iNKT cells from HBeAg(+) chronic hepatitis B patients were comparable to that from healthy donors, with an impaired capability of IFN-γ(especially significant) and IL-4 secretion after in vitro activation. And it was noteworthy that the PD-1 expression on peripheral iNKT cells significantly increased. Antiviral therapy with Telbivudine, to some extent, contributed to the recovery of cytokines production and PD-1 expression of peripheral iNKT cells in the HBeAg(+)chronic hepatitis B patients.
Conclusion: Peripheral iNKT cells in HBeAg(+) chronic hepatitis B patients are in a hyporesponssive state, which to some extent result in the lack of effective innate and adaptive immune responses against HBV infection. The increased PD-1 expression may serve as a factor contributing to the impaired function of peripheral iNKT cells in HBeAg(+)chronic hepatitis B patients. Antiviral therapy with Telbivudine to some extent contributed to the recovery of functions and PD-1 expression of peripheral iNKT cells in HBeAg(+)chronic hepatitis B patients.
方法:选取接受替比夫定抗病毒治疗的HBeAg(+)慢性乙型肝炎患者作为研究对象,经知情同意后于抗病毒治疗前后不同时相分别抽取外周静脉血,利用CD3、TCR Vα24、TCR Vβ11、CD279(PD-1)单克隆抗体标记后经流式细胞术直接检测标本中iNKT细胞比例及其PD-1表达比例;采用PMA+Ionomycin体外活化iNKT细胞后流式细胞术检测其胞内IFN-γ及IL-4分泌情况。
结果: HBeAg(+)慢性乙型肝炎患者外周血iNKT细胞占总淋巴细胞比例为(0.15±0.08)%,与健康对照者[(0.19±0.08) %]相比无明显差异,但经体外活化后胞内IFN-γ[(23.51±7.82)% VS (41.84±12.15)%]及IL-4 [(14.07±6.1)% VS (20.86±8.21)%]分泌量降低,且iNKT细胞上PD-1的表达量显著上升[(31.21±12.59)% VS (13.64±7.41)%];替比夫定抗病毒治疗后第24周CHB患者外周血iNKT细胞的IFN-γ及IL-4分泌能力较治疗前升高,且PD-1的表达显著下降。
结论: HBeAg(+)慢性乙型肝炎患者外周血iNKT细胞处于功能低下状态,在一定程度上导致慢性HBV感染后机体不能启动有效的非特异性及特异性免疫反应,并且iNKT细胞的这种功能低下状态可能与其表面PD-1表达升高有关;替比夫定抗病毒治疗对于iNKT细胞功能的恢复及降低PD-1的表达有一定帮助,表明核苷类似物替比夫定除了具有快速地抑制HBV的复制、高的e抗原血清转换率等特点外,可能还具有一定的免疫调节作用。
Objective: To study the frequency, functions, and PD-1 expression of peripheral iNKT cells in chronic hepatitis B patients; and the effects of antiviral therapy with Telbivudine on the frequency, functions, and PD-1 expression of peripheral iNKT cells in chronic hepatitis B patients.
Methods: HBeAg(+)Chronic hepatitis B patients receiving antiviral therapy with Telbivudine were enrolled in the study. Peripheral blood samples were obtained at 0, 12, 24 weeks after informed consent from all patients. The frequencies and PD-1 expression of peripheral iNKT cells were detected by flow cytometry (FCM) after labeled with anti-CD3,TCR Vα24,TCR Vβ11 and CD279 (PD-1) monoclonal antibodies; Intracellular IFN-γand IL-4 production by iNKT cells was analyzed on flow cytometer after in vitro activation with PMA and Ionomycin.
Results: The frequencies of peripheral iNKT cells from HBeAg(+) chronic hepatitis B patients were comparable to that from healthy donors, with an impaired capability of IFN-γ(especially significant) and IL-4 secretion after in vitro activation. And it was noteworthy that the PD-1 expression on peripheral iNKT cells significantly increased. Antiviral therapy with Telbivudine, to some extent, contributed to the recovery of cytokines production and PD-1 expression of peripheral iNKT cells in the HBeAg(+)chronic hepatitis B patients.
Conclusion: Peripheral iNKT cells in HBeAg(+) chronic hepatitis B patients are in a hyporesponssive state, which to some extent result in the lack of effective innate and adaptive immune responses against HBV infection. The increased PD-1 expression may serve as a factor contributing to the impaired function of peripheral iNKT cells in HBeAg(+)chronic hepatitis B patients. Antiviral therapy with Telbivudine to some extent contributed to the recovery of functions and PD-1 expression of peripheral iNKT cells in HBeAg(+)chronic hepatitis B patients.
引文
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[6] Moll M, Kuylenstierna C, Gonzalez VD, et al. Severe functional impairment and elevated PD-1 expression in CD1d-restricted NKT cells retained during chronic HIV-1 infection[J]. Eur J Immunol.2009,39(3):902-911.
[7]中华医学会传染病与寄生虫病学会肝病学分会病毒性肝炎防治方案[J].中华肝脏病杂志.2000,8(2):132-134.
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[9] Lucas M, Gadola S, Meier U, et al. Frequency and phenotype of circulating Valpha24/Vbeta11 double-positive natural killer T cells during hepatitis C virus infection[J]. J Virol.2003,77(3):2251-2257.
[10] Yonekura K, Ichida T, Sato K, et al. Liver-infiltrating CD56 positive T lymphocytes in hepatitis C virus infection[J]. Liver. 2000 ,20(5):357-365.
[11] de Lalla C, Galli G, Aldrighetti L, et al. Production of profibrotic cytokines by invariant NKT cells characterizes cirrhosis progression in chronic viral hepatitis[J].J Immunol.2004,173(2):1417-1425.
[12] Agrati C, Nisii C, Oliva A, et al. Lymphocyte distribution and intrahepatic compartmentalization during HCV infection: a main role for MHC-unrestricted T cells[J]. Arch Immunol Ther Exp (Warsz).2002,50(5):307-316.
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[14] ]Takagi D, Iwabuchi K, Iwabuchi C,et al. Immunoregulatory defects of Va24+ Vβ11+ NKT cells in development of Wegener's granulomatosis and relapsing polychondritis [J]. Clin Exp Immunol.2004,136(3):591-600.
[15] Mühlbauer M, Fleck M, Schütz C,et al. PD-L1 is induced in hepatocytes by viral infection and by interferon-alpha and -gamma and mediates T cell apoptosis[J]. J Hepatol. 2006 ,45(4):520-528.
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[17] Trautmann L, Janbazian L, Chomont N, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction[J]. Nat Med. 2006,12(10):1198-1202.
[18] Barber DL, Wherry EJ, Masopust D et al. Restoring function in exhausted CD8 T cells during chronic viral infection[J]. Nature.2006,439(7077):682-687.
[19] Harada M, Seino K, Wakao H, et al. Down-regulation of the invariant Valpha14 antigen receptor in NKT cells upon activation[J]. Int Immunol. 2004,16(2):241-247.
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[23] Wang J, Cheng L, Wondimu Z, et al. Cutting edge: CD28 engagement releases antigen-activated invariant NKT cells from the inhibitory effects of PD-1[J]. J Immunol.2009,182(11):6644-6647.
[24] Evans A, Riva A, Cooksley H, et al. Programmed death 1 expression during antiviral treatment of chronic hepatitis B: Impact of hepatitis B e-antigen seroconversion[J]. Hepatology. 2008,48(3):759-769.
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[46] Mühlbauer M, Fleck M, Schütz C, et al. PD-L1 is induced in hepatocytes by viral infection and by interferon-alpha and -gamma and mediates T cell apoptosis[J]. J Hepatol.2006,45(4):520-528.
[47] Ito T, Ueno T, Clarkson MR, et al. Analysis of the role of negative T cell costimulatory pathways in CD4 and CD8 T cell-mediated alloimmune responses in vivo[J]. J Immunol.2005,174(11):6648-6656
[48] Trautmann L, Janbazian L, Chomont N, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction[J]. Nat Med. 2006,12(10):1198-1202.
[49] Urbani S, Amadei B, Tola D, et al. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion[J]. J Virol. 2006,80(22):11398-11403.
[50] Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection[J]. Nature.2006,439(7077):682-687.
[51] Harada M, Seino K, Wakao H, et al. Down-regulation of the invariant Valpha14 antigen receptor in NKT cells upon activation[J]. Int Immunol. 2004,16(2):241-247.
[52] Parekh VV, Wilson MT, Olivares-Villagómez D, et al. Glycolipid antigen induces long-term natural killer T cell anergy in mice[J]. J Clin Invest.2005, 115(9):2572-2583.
[53] Chang WS, Kim JY, Kim YJ, et al. Cutting edge: Programmed death-1/programmed death ligand 1 interaction regulates the induction and maintenance of invariant NKT cell anergy[J]. J Immunol.2008,181(10):6707-6710.
[54] Parekh VV, Lalani S, Kim S, et al. PD-1/PD-L blockade prevents anergy inductionand enhances the anti-tumor activities of glycolipid-activated invariant NKT cells[J]. J Immunol.2009,182(5):2816-2826.
[55] Wang J, Cheng L, Wondimu Z, Swain M, Santamaria P, Yang Y. Cutting edge: CD28 engagement releases antigen-activated invariant NKT cells from the inhibitory effects of PD-1[J]. J Immunol.2009,182(11):6644-6647.
[2] Kakimi K, Guidotti LG, Koezuka Y, et al. Natural killer T cell activation inhibits hepatitis B virus replication in vivo[J]. J Exp Med. 2000,192(7):921-930.
[3] Day CL, Kaufmann DE, Kiepiela P, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression [J]. Nature. 2006, 443 (7109):350-354.
[4] Urbani S, Amadei B, Tola D,et al. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion[J]. J Virol. 2006, 80(22):11398-11403.
[5]谢谆怡,陈永文,付晓岚,赵婷婷,吴玉章.慢性乙型肝炎患者HBV特异性细胞毒性T细胞PD-1的表达研究[J].免疫学杂志.2007,23(6):602-605.
[6] Moll M, Kuylenstierna C, Gonzalez VD, et al. Severe functional impairment and elevated PD-1 expression in CD1d-restricted NKT cells retained during chronic HIV-1 infection[J]. Eur J Immunol.2009,39(3):902-911.
[7]中华医学会传染病与寄生虫病学会肝病学分会病毒性肝炎防治方案[J].中华肝脏病杂志.2000,8(2):132-134.
[8] Durante-Mangoni E, Wang R, Shaulov A, et al. Hepatic CD1d expression in hepatitis C virus infection and recognition by resident proinflammatory CD1d-reactive T cells[J]. J Immunol. 2004,173(3):2159-2166.
[9] Lucas M, Gadola S, Meier U, et al. Frequency and phenotype of circulating Valpha24/Vbeta11 double-positive natural killer T cells during hepatitis C virus infection[J]. J Virol.2003,77(3):2251-2257.
[10] Yonekura K, Ichida T, Sato K, et al. Liver-infiltrating CD56 positive T lymphocytes in hepatitis C virus infection[J]. Liver. 2000 ,20(5):357-365.
[11] de Lalla C, Galli G, Aldrighetti L, et al. Production of profibrotic cytokines by invariant NKT cells characterizes cirrhosis progression in chronic viral hepatitis[J].J Immunol.2004,173(2):1417-1425.
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