Interleukin-12 induction of Th1 cytokines is important for viral clearance in chronic hepatitis B. (original) (raw)
- Journal List
- J Clin Invest
- v.99(12); 1997 Jun 15
- PMC508155
J Clin Invest. 1997 Jun 15; 99(12): 3025–3033.
Institute of Liver Studies, King's College School of Medicine & Dentistry, London SE5 9PJ, UK.
Abstract
Interleukin-12, a cytokine with an important role against intracellular pathogens, promotes Th1 cell development, cellmediated cytotoxicity, and interferon-gamma production. We investigated the immunoregulatory role of IL-12 in 72 chronic hepatitis B virus (HBV) carriers, 33 of whom were monitored longitudinally during interferon-alpha treatment. Serum levels of IL-12 heterodimer, IL-12 p40 subunit, IL-4, and Th1 cytokines were determined by specific ELISAs, and hepatitis B core antigen-specific T cell response by a proliferation assay. Chronic HBV carriers had higher serum levels of IL-12 and IL-12 p40 in comparison with controls (P < 0.01), suggesting that IL-12 production is not impaired. The longitudinal analysis revealed a further substantial increase (> 2.5x baseline level) of bioactive IL-12 and Th1 cytokines in patients who cleared HBV and seroconverted to anti- hepatitis B e, unlike the 23 nonresponders with persistent HBV replication (P < 0.01). The IL-12 peak followed the peak of hepatocytolysis by 9.8+/-2.8 wk and occurred either before or simultaneously with hepatitis B e seroconversion. Hepatitis B core antigen-specific T cell proliferation closely correlated with hepatocytolysis and increased significantly in all patients (8 responders and 15 nonresponders) who developed hepatitis flare, irrespective of the virological outcome. These results provide in vivo evidence that IL-12 may have an important role for viral clearance in chronic HBV infection.
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- Chisari FV, Ferrari C. Hepatitis B virus immunopathogenesis. Annu Rev Immunol. 1995;13:29–60. [PubMed] [Google Scholar]
- Marinos G, Torre F, Chokshi S, Hussain M, Clarke BE, Rowlands DJ, Eddleston AL, Naoumov NV, Williams R. Induction of T-helper cell response to hepatitis B core antigen in chronic hepatitis B: a major factor in activation of the host immune response to the hepatitis B virus. Hepatology. 1995 Oct;22(4 Pt 1):1040–1049. [PubMed] [Google Scholar]
- Tsai SL, Chen PJ, Lai MY, Yang PM, Sung JL, Huang JH, Hwang LH, Chang TH, Chen DS. Acute exacerbations of chronic type B hepatitis are accompanied by increased T cell responses to hepatitis B core and e antigens. Implications for hepatitis B e antigen seroconversion. J Clin Invest. 1992 Jan;89(1):87–96. [PMC free article] [PubMed] [Google Scholar]
- Löhr HF, Weber W, Schlaak J, Goergen B, Meyer zum Buschenfelde KH, Gerken G. Proliferative response of CD4+ T cells and hepatitis B virus clearance in chronic hepatitis with or without hepatitis B e-minus hepatitis B virus mutants. Hepatology. 1995 Jul;22(1):61–68. [PubMed] [Google Scholar]
- Paul WE, Seder RA. Lymphocyte responses and cytokines. Cell. 1994 Jan 28;76(2):241–251. [PubMed] [Google Scholar]
- Trinchieri G. Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol. 1995;13:251–276. [PubMed] [Google Scholar]
- Maruyama T, Iino S, Koike K, Yasuda K, Milich DR. Serology of acute exacerbation in chronic hepatitis B virus infection. Gastroenterology. 1993 Oct;105(4):1141–1151. [PubMed] [Google Scholar]
- Maruyama T, McLachlan A, Iino S, Koike K, Kurokawa K, Milich DR. The serology of chronic hepatitis B infection revisited. J Clin Invest. 1993 Jun;91(6):2586–2595. [PMC free article] [PubMed] [Google Scholar]
- Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, Loudon R, Sherman F, Perussia B, Trinchieri G. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med. 1989 Sep 1;170(3):827–845. [PMC free article] [PubMed] [Google Scholar]
- Gately MK, Wolitzky AG, Quinn PM, Chizzonite R. Regulation of human cytolytic lymphocyte responses by interleukin-12. Cell Immunol. 1992 Aug;143(1):127–142. [PubMed] [Google Scholar]
- Gazzinelli RT, Wysocka M, Hayashi S, Denkers EY, Hieny S, Caspar P, Trinchieri G, Sher A. Parasite-induced IL-12 stimulates early IFN-gamma synthesis and resistance during acute infection with Toxoplasma gondii. J Immunol. 1994 Sep 15;153(6):2533–2543. [PubMed] [Google Scholar]
- Zhang M, Gately MK, Wang E, Gong J, Wolf SF, Lu S, Modlin RL, Barnes PF. Interleukin 12 at the site of disease in tuberculosis. J Clin Invest. 1994 Apr;93(4):1733–1739. [PMC free article] [PubMed] [Google Scholar]
- Clerici M, Lucey DR, Berzofsky JA, Pinto LA, Wynn TA, Blatt SP, Dolan MJ, Hendrix CW, Wolf SF, Shearer GM. Restoration of HIV-specific cell-mediated immune responses by interleukin-12 in vitro. Science. 1993 Dec 10;262(5140):1721–1724. [PubMed] [Google Scholar]
- Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology. 1994 Jun;19(6):1513–1520. [PubMed] [Google Scholar]
- Rossol S, Voth R, Laubenstein HP, Müller WE, Schröder HC, Meyer zum Büschenfelde KH, Hess G. Interferon production in patients infected with HIV-1. J Infect Dis. 1989 May;159(5):815–821. [PubMed] [Google Scholar]
- Chisari FV. Hepatitis B virus transgenic mice: insights into the virus and the disease. Hepatology. 1995 Oct;22(4 Pt 1):1316–1325. [PubMed] [Google Scholar]
- Gilles PN, Fey G, Chisari FV. Tumor necrosis factor alpha negatively regulates hepatitis B virus gene expression in transgenic mice. J Virol. 1992 Jun;66(6):3955–3960. [PMC free article] [PubMed] [Google Scholar]
- Guilhot S, Guidotti LG, Chisari FV. Interleukin-2 downregulates hepatitis B virus gene expression in transgenic mice by a posttranscriptional mechanism. J Virol. 1993 Dec;67(12):7444–7449. [PMC free article] [PubMed] [Google Scholar]
- Guidotti LG, Guilhot S, Chisari FV. Interleukin-2 and alpha/beta interferon down-regulate hepatitis B virus gene expression in vivo by tumor necrosis factor-dependent and -independent pathways. J Virol. 1994 Mar;68(3):1265–1270. [PMC free article] [PubMed] [Google Scholar]
- Guidotti LG, Ando K, Hobbs MV, Ishikawa T, Runkel L, Schreiber RD, Chisari FV. Cytotoxic T lymphocytes inhibit hepatitis B virus gene expression by a noncytolytic mechanism in transgenic mice. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3764–3768. [PMC free article] [PubMed] [Google Scholar]
- Guidotti LG, Ishikawa T, Hobbs MV, Matzke B, Schreiber R, Chisari FV. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity. 1996 Jan;4(1):25–36. [PubMed] [Google Scholar]
- Jilbert AR, Wu TT, England JM, Hall PM, Carp NZ, O'Connell AP, Mason WS. Rapid resolution of duck hepatitis B virus infections occurs after massive hepatocellular involvement. J Virol. 1992 Mar;66(3):1377–1388. [PMC free article] [PubMed] [Google Scholar]
- Kajino K, Jilbert AR, Saputelli J, Aldrich CE, Cullen J, Mason WS. Woodchuck hepatitis virus infections: very rapid recovery after a prolonged viremia and infection of virtually every hepatocyte. J Virol. 1994 Sep;68(9):5792–5803. [PMC free article] [PubMed] [Google Scholar]
- Jung MC, Spengler U, Schraut W, Hoffmann R, Zachoval R, Eisenburg J, Eichenlaub D, Riethmüller G, Paumgartner G, Ziegler-Heitbrock HW, et al. Hepatitis B virus antigen-specific T-cell activation in patients with acute and chronic hepatitis B. J Hepatol. 1991 Nov;13(3):310–317. [PubMed] [Google Scholar]
- Marinos G, Smith HM, Naoumov NV, Williams R. Quantitative assessment of serum IgM anti-HBc in the natural course and during interferon treatment of chronic hepatitis B virus infection. Hepatology. 1994 Feb;19(2):303–311. [PubMed] [Google Scholar]
- Maruyama T, Schödel F, Iino S, Koike K, Yasuda K, Peterson D, Milich DR. Distinguishing between acute and symptomatic chronic hepatitis B virus infection. Gastroenterology. 1994 Apr;106(4):1006–1015. [PubMed] [Google Scholar]
- Milich DR, Wolf SF, Hughes JL, Jones JE. Interleukin 12 suppresses autoantibody production by reversing helper T-cell phenotype in hepatitis B e antigen transgenic mice. Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6847–6851. [PMC free article] [PubMed] [Google Scholar]
- Wenner CA, Güler ML, Macatonia SE, O'Garra A, Murphy KM. Roles of IFN-gamma and IFN-alpha in IL-12-induced T helper cell-1 development. J Immunol. 1996 Feb 15;156(4):1442–1447. [PubMed] [Google Scholar]
- Bertagnolli MM, Lin BY, Young D, Herrmann SH. IL-12 augments antigen-dependent proliferation of activated T lymphocytes. J Immunol. 1992 Dec 15;149(12):3778–3783. [PubMed] [Google Scholar]
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