IL-12和IL-4水平对观察和预测拉米夫定治疗乙肝病毒感染中发生YMDD变异的意义
俞富军,陈永平,温州医学院附属第一医院感染内科 浙江省温州市 325000
何生松,张淑玲,李淑利,华中科技大学同济医学院附属协和医院感染内科 湖北省武汉市 430030
通讯作者:俞富军,浙江省温州市府学巷5号,温州医学院附属第一医院感染内科. tjyufujun@hotmail.com
收稿日期:2005-03-09 接受日期:2005-03-22
摘要目的:探讨在拉米夫定治疗乙型肝炎病毒感染中发生YMDD变异与治疗期间血清IL-12和IL-4水平变化的关系.
, 百拇医药
方法:慢性乙型病毒性肝炎患者给予口服拉米夫定治疗1a时发生YMDD变异和未发生YMDD变异各选择40例，测定拉米夫定治疗后3、6、12mo血清IL-12、IL-4水平、乙肝两对半、肝功能和HBVDNA.
结果:在无YMDD变异组患者中，血清IL-12和IL-4水平在治疗后各个时间点较治疗前均有统计学差异(IL-12治疗后3，6，12mo vs治疗前，t =2.691，2.351，2.158，P =0.02，0.03，0.04;IL-4治疗后3，6，12mo vs治疗前，t =2.653，2.107，2.234，P = 0.02，0.04，0.03)，表现为IL-12水平升高，IL-4水平降低;在YMDD变异组患者中，血清IL-12和IL-4水平仅治疗后3mo和治疗前相比有统计学差异(t= 2.104，2.142，P =0.04，0.04)，表现为IL-12水平升高，IL-4水平降低.YMDD变异组治疗后3 mo和无变异组治疗后同一时间相比，其变化幅度小，且有统计学差异(IL-12:t= 2.029，P= 0.04; IL-4:t = 2.028，P= 0.04).
, 百拇医药
结论:发生YMDD变异与治疗期间血清IL-12和IL-4水平变化有关，治疗期间其水平变化小而短暂者有更大的机会发生YMDD变异，动态检测血清IL-12和IL-4水平可以作为拉米夫定治疗乙型肝炎病毒发生YMDD变异的预测指标之一.
俞富军,何生松, 张淑玲,李淑利,陈永平.IL-12和IL-4水平对观察和预测拉米夫定治疗乙肝病毒感染中发生YMDD变异的意义.世界华人消化杂志 2005;13(12):1460-1462
Khokhar N, Gill ML, Alam AY. Treatment of chronichepatitis B with lamivudine.
J Coll Physicians Surg Pak 2005;15:78-80
, 百拇医药
2 Natsuizaka M, Hige S, Ono Y, Ogawa K, Nakanishi M, Chuma M, YoshidaS, Asaka M. Long-term follow-up
of chronic hepatitis B after theemergence of mutations in the hepatitis B virus polymerase region.
J Viral Hepat 2005;12:154-159
3 Huang ZM, Huang QW, Qin YQ, He YZ, Qin HJ, Zhou YN, Xu X, Huang MJ.YMDD mutations in patients with chronic
hepatitis B untreated with antiviralmedicines. World J Gastroenterol 2005;11:867-870
, http://www.100md.com
4 Bai YJ, Zhao JR, Lv GT, Zhang WH, Wang Y, Yan XJ. Rapid and highthroughput detection of HBV YMDD mutants with
fluorescence polarization. WorldJ Gastroenterol 2003;9:2344-2347
5 Yao GB, Cui ZY, Wang BE, Yao JL, Zeng MD. A 3-year clinical trialof lamivudine in treatment of patients with chronic
hepatitis B. HepatobiliaryPancreat Dis Int 2004;3:188-193
, 百拇医药 6 Tsubota A, Arase Y, Suzuki F, Kobayashi M, Matsuda M, Sato J,Suzuki Y, Akuta N, Sezaki H, Hosaka T,Someya T, Kobayashi M, Saitoh S,Ikeda K, Kumada H. Severe acute exacerbation of liver disease may reduceor
delay emergence of YMDD motifmutants in long-term lamivudine therapy for hepatitis B e antigen-positivechronic
hepatitis B. J Med Virol 2004;73:7-12
7 Suzuki F, Tsubota A, Arase Y, Suzuki Y, Akuta N, Hosaka T, SomeyaT, Kobayashi M, Saitoh S, Ikeda K, Kobayashi M,Matsuda M, Satoh J, Takagi K, KumadaH. Efficacy of lamivudine therapy and factors associated with emergenceof
, http://www.100md.com
resistance in chronic hepatitis Bvirus infection in Japan. Intervirology 2003;46:182-189
8 Wolters LM, Niesters HG, Hansen BE, van der Ende ME, Kroon FP,Richter C, Brinkman K, Meenhorst PL, de Man RA.
Development of hepatitis B virusresistance for lamivudine in chronic hepatitis B patients co-infected withthe human
immunodeficiency virus in a Dutchcohort. J Clin Virol 2002;24:173-181
, http://www.100md.com
9 Lok AS, Lai CL, Leung N, Yao GB, Cui ZY, Schiff ER, Dienstag JL,Heathcote EJ, Little NR, Griffiths DA, Gardner SD,Castiglia M. Long-term safety oflamivudine treatment in patients with chronic hepatitis B. Gastroenterology
2003;125:1714-1722
10 Smeltz RB, Chen J, Shevach EM. Transforming growth factor-beta1enhances the interferon-gamma-dependent,interleukin-12-independentpathway of T helper 1 cell differentiation. Immunology 2005;114:484-492
, 百拇医药
11 Rodriguez-Galan MC, Bream JH, Farr A, Young HA. Synergistic effectof IL-2, IL-12, and IL-18 on thymocyte apoptosis
and Th1/Th2 cytokineexpression. J Immunol 2005;174:2796-2804
12 Sehra S, Patel D, Kusam S, Wang ZY, Chang CH, Dent AL. A role forcaspases in controlling IL-4 expression in T cells.
J Immunol 2005;174:3440-3446
13 Liu Z, Liu Q, Hamed H, Anthony RM, Foster A, Finkelman FD, Urban JFJr, Gause WC. IL-2 and autocrine IL-4 drive the
, 百拇医药
in vivo development ofantigen-specific Th2 T cells elicited by nematode parasites. J Immunol 2005;174:2242-2249
14 Boni C, Penna A, Ogg GS, Bertoletti A, Pilli M, Cavallo C, CavalliA, Urbani S, Boehme R, Panebianco R,Fiaccadori F, Ferrari C.Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness inchronic hepatitis
B: new perspectives for immunetherapy. Hepatology 2001;33:963-971
15 俞富军, 何生松, 张淑玲,李淑利, 陈永平. 拉米夫定对慢性乙肝患者TNF-a影响的初步探讨.
胃肠病学和肝病学杂志 2005;14:90-91
编辑 张海宁, 百拇医药( 俞富军, 何生松, 张淑玲, 李淑利, 陈永平)
何生松,张淑玲,李淑利,华中科技大学同济医学院附属协和医院感染内科 湖北省武汉市 430030
通讯作者:俞富军,浙江省温州市府学巷5号,温州医学院附属第一医院感染内科. tjyufujun@hotmail.com
收稿日期:2005-03-09 接受日期:2005-03-22
摘要目的:探讨在拉米夫定治疗乙型肝炎病毒感染中发生YMDD变异与治疗期间血清IL-12和IL-4水平变化的关系.
, 百拇医药
方法:慢性乙型病毒性肝炎患者给予口服拉米夫定治疗1a时发生YMDD变异和未发生YMDD变异各选择40例，测定拉米夫定治疗后3、6、12mo血清IL-12、IL-4水平、乙肝两对半、肝功能和HBVDNA.
结果:在无YMDD变异组患者中，血清IL-12和IL-4水平在治疗后各个时间点较治疗前均有统计学差异(IL-12治疗后3，6，12mo vs治疗前，t =2.691，2.351，2.158，P =0.02，0.03，0.04;IL-4治疗后3，6，12mo vs治疗前，t =2.653，2.107，2.234，P = 0.02，0.04，0.03)，表现为IL-12水平升高，IL-4水平降低;在YMDD变异组患者中，血清IL-12和IL-4水平仅治疗后3mo和治疗前相比有统计学差异(t= 2.104，2.142，P =0.04，0.04)，表现为IL-12水平升高，IL-4水平降低.YMDD变异组治疗后3 mo和无变异组治疗后同一时间相比，其变化幅度小，且有统计学差异(IL-12:t= 2.029，P= 0.04; IL-4:t = 2.028，P= 0.04).
, 百拇医药
结论:发生YMDD变异与治疗期间血清IL-12和IL-4水平变化有关，治疗期间其水平变化小而短暂者有更大的机会发生YMDD变异，动态检测血清IL-12和IL-4水平可以作为拉米夫定治疗乙型肝炎病毒发生YMDD变异的预测指标之一.
俞富军,何生松, 张淑玲,李淑利,陈永平.IL-12和IL-4水平对观察和预测拉米夫定治疗乙肝病毒感染中发生YMDD变异的意义.世界华人消化杂志 2005;13(12):1460-1462
Khokhar N, Gill ML, Alam AY. Treatment of chronichepatitis B with lamivudine.
J Coll Physicians Surg Pak 2005;15:78-80
, 百拇医药
2 Natsuizaka M, Hige S, Ono Y, Ogawa K, Nakanishi M, Chuma M, YoshidaS, Asaka M. Long-term follow-up
of chronic hepatitis B after theemergence of mutations in the hepatitis B virus polymerase region.
J Viral Hepat 2005;12:154-159
3 Huang ZM, Huang QW, Qin YQ, He YZ, Qin HJ, Zhou YN, Xu X, Huang MJ.YMDD mutations in patients with chronic
hepatitis B untreated with antiviralmedicines. World J Gastroenterol 2005;11:867-870
, http://www.100md.com
4 Bai YJ, Zhao JR, Lv GT, Zhang WH, Wang Y, Yan XJ. Rapid and highthroughput detection of HBV YMDD mutants with
fluorescence polarization. WorldJ Gastroenterol 2003;9:2344-2347
5 Yao GB, Cui ZY, Wang BE, Yao JL, Zeng MD. A 3-year clinical trialof lamivudine in treatment of patients with chronic
hepatitis B. HepatobiliaryPancreat Dis Int 2004;3:188-193
, 百拇医药 6 Tsubota A, Arase Y, Suzuki F, Kobayashi M, Matsuda M, Sato J,Suzuki Y, Akuta N, Sezaki H, Hosaka T,Someya T, Kobayashi M, Saitoh S,Ikeda K, Kumada H. Severe acute exacerbation of liver disease may reduceor
delay emergence of YMDD motifmutants in long-term lamivudine therapy for hepatitis B e antigen-positivechronic
hepatitis B. J Med Virol 2004;73:7-12
7 Suzuki F, Tsubota A, Arase Y, Suzuki Y, Akuta N, Hosaka T, SomeyaT, Kobayashi M, Saitoh S, Ikeda K, Kobayashi M,Matsuda M, Satoh J, Takagi K, KumadaH. Efficacy of lamivudine therapy and factors associated with emergenceof
, http://www.100md.com
resistance in chronic hepatitis Bvirus infection in Japan. Intervirology 2003;46:182-189
8 Wolters LM, Niesters HG, Hansen BE, van der Ende ME, Kroon FP,Richter C, Brinkman K, Meenhorst PL, de Man RA.
Development of hepatitis B virusresistance for lamivudine in chronic hepatitis B patients co-infected withthe human
immunodeficiency virus in a Dutchcohort. J Clin Virol 2002;24:173-181
, http://www.100md.com
9 Lok AS, Lai CL, Leung N, Yao GB, Cui ZY, Schiff ER, Dienstag JL,Heathcote EJ, Little NR, Griffiths DA, Gardner SD,Castiglia M. Long-term safety oflamivudine treatment in patients with chronic hepatitis B. Gastroenterology
2003;125:1714-1722
10 Smeltz RB, Chen J, Shevach EM. Transforming growth factor-beta1enhances the interferon-gamma-dependent,interleukin-12-independentpathway of T helper 1 cell differentiation. Immunology 2005;114:484-492
, 百拇医药
11 Rodriguez-Galan MC, Bream JH, Farr A, Young HA. Synergistic effectof IL-2, IL-12, and IL-18 on thymocyte apoptosis
and Th1/Th2 cytokineexpression. J Immunol 2005;174:2796-2804
12 Sehra S, Patel D, Kusam S, Wang ZY, Chang CH, Dent AL. A role forcaspases in controlling IL-4 expression in T cells.
J Immunol 2005;174:3440-3446
13 Liu Z, Liu Q, Hamed H, Anthony RM, Foster A, Finkelman FD, Urban JFJr, Gause WC. IL-2 and autocrine IL-4 drive the
, 百拇医药
in vivo development ofantigen-specific Th2 T cells elicited by nematode parasites. J Immunol 2005;174:2242-2249
14 Boni C, Penna A, Ogg GS, Bertoletti A, Pilli M, Cavallo C, CavalliA, Urbani S, Boehme R, Panebianco R,Fiaccadori F, Ferrari C.Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness inchronic hepatitis
B: new perspectives for immunetherapy. Hepatology 2001;33:963-971
15 俞富军, 何生松, 张淑玲,李淑利, 陈永平. 拉米夫定对慢性乙肝患者TNF-a影响的初步探讨.
胃肠病学和肝病学杂志 2005;14:90-91
编辑 张海宁, 百拇医药( 俞富军, 何生松, 张淑玲, 李淑利, 陈永平)
