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Immune-mediated liver injury
Journal of Hepatology 42 (2005) 920–923 www.elsevier.com/locate/jhep
Special article
Immune-mediated liver injury Johannes Herkel1,2, Marcus Schuchmann1, Gisa Tiegs3, Ansgar W. Lohse2,* 1 I. Department of Medicine, Johannes Gutenberg-University Mainz, Germany Department of Internal Medicine I, University Medical Centre Hamburg-Eppendorf, Martinistraß;e 52, 20246 Hamburg, Germany 3 Institute for Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander-University Erlangen-Nu¨rnberg, Erlangen, Germany 2
Liver diseases are a major cause of morbidity and mortality worldwide. The major clinical problem is the frequent development of liver cirrhosis or liver cancer related to chronic hepatitis. A broad variety of conditions may cause chronic hepatitis, including hepatitis virus infection [1,2], toxic insult [3,4] or autoimmunity [5,6]. Hepatitis, acute or chronic, is associated with liver injury, which is largely mediated by immune effector mechanisms. In acute hepatitis, immune-mediated liver injury is usually compensated by adequate repair, and liver function is maintained. In chronic hepatitis, in contrast, continuous liver injury seems to promote aberrant repair and the development of fibrosis/cirrhosis and liver cancer. Irrespective of the cause, liver injury seems to be facilitated by similar immune effector mechanisms common to the various liver diseases. Indeed, common immune effector mechanisms may explain the high prevalence of cirrhosis and cancer common to most forms of liver injury. Improved understanding of immune-mediated liver injury may help to develop therapeutic approaches to this widespread clinical problem; so far, there is no cure for cirrhosis or liver cancer, except liver transplantation, and therapeutic options for many patients with chronic hepatitis are unsatisfactory. To approach the mechanisms of immunemediated liver injury, an EASL workshop, entitled ‘Immune-mediated liver injury: from basic science to future therapies’, was held October 9–11, 2004 in Freiburg, Germany, bringing together scientists and clinicians who study the various facets of immune-mediated liver diseases. This review is based on the presentations of the workshop and summarises some of the currently emerging answers to the old questions: Which immune effector mechanisms cause liver injury? * Corresponding author. Tel.: 49 40 42803-3910; fax: 49 40 483065. E-mail address: [email protected] (A.W. Lohse).
Which mechanisms may protect from immune-mediated liver injury? Which processes determine acuteness or chronicity of hepatitis?
1. Mechanisms of immune-mediated liver injury It is now established that liver injury in viral hepatitis is not mediated by hepatitis virus itself, but by the immune response to the virus [1,2,7,8]. Inhibition of hepatitis virus replication is not necessarily related to liver damage [9] and hepatitis virus can be efficiently cleared by anti-viral cytokines [10]. However, there seem to be fail-safe mechanisms of viral clearance, which rely on the destruction of infected hepatocytes and even of non-infected bystanders. The most prominent mechanism of liver injury in viral hepatitis seems to be CD8 T cell-mediated killing, which is facilitated mainly by Fas, TNFR1 and DR5, rather than by cytolytic granules [11]. However, non-virus-specific T cells may also be recruited to the liver, which aggravate liver damage without contributing to virus control [9,12]. Moreover, polymorphonuclear [13] and mononuclear cells [14], as well as platelets (Guidotti LG, unpublished) may accumulate at the necroinflammatory foci in the liver and further aggravate liver injury. Thus, therapeutic strategies may aim at reducing exaggerated liver injury, however, it remains to be seen whether this is compatible with cytokinemediated non-cytopathic viral clearance. Like viral hepatitis, drug-induced liver injury seems to be largely immune-mediated [3,4,15]. It appears that the drug is enzymatically transformed to reactive metabolites, which bind to self-constituents, most frequently the metabolising enzyme, thus forming neoantigens. Neoantigens may then induce an immune response, which causes liver injury. However, the liver-damaging immune effector mechanisms
0168-8278/$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2005.02.009
J. Herkel et al. / Journal of Hepatology 42 (2005) 920–923
in toxic hepatitis are less well characterised than those in viral hepatitis. In lack of suitable animal models for druginduced hepatitis, the model of Con A-induced hepatitis has been widely used to study immune effector mechanisms of immune-mediated liver-injury [16,17]. Concanavalin A is a bean lectin, which, when injected intravenously to mice, induces activation of T cells in the liver, Valpha14 NKT cells being most important [18]. Together with Kupffer cells, NKT cells secrete large amounts of various hepatotoxic cytokines, most notably TNF-alpha and IFN-gamma [17,19]. Other factors like leptin may aggravate liver injury by promoting hepatotoxic cytokine secretion [20]. The mechanisms of autoimmune liver injury are less well understood, because only a few of the relevant target antigens are known. In autoimmune hepatitis, only one disease-specific autoantigen, the SLA/LP molecule [21], is known so far, which is relevant only in about 20% of the patients. The other known autoantigens in autoimmune hepatitis are recognised also in other hepatic diseases, as well as non-hepatic autoimmune diseases. However, as we learned from viral hepatitis, non-specific T cells can greatly enhance liver injury. In primary sclerosing cholangitis (PSC), no specific target antigen is known; however, there seems to be a close pathogenetic association to colitis. Indeed, liver injury in PSC seems to be mediated by guthoming lymphocytes, which are recruited to the liver by aberrantly expressed chemokines [22]. In primary biliary cirrhosis, several autoantigens are known, most notably the pyruvate dehydrogenase complex (PDC). Autoimmunity to PDC may be induced by various mechanisms; recently, the formation of neoantigenic PDC by covalent modification has been shown to cause PDC autoimmunity [23], reminiscent of the mechanisms in toxic hepatitis. It is thus possible that not only toxic hepatitis, but also autoimmune liver disease may be induced by the metabolic activity of the liver. Other triggers of autoimmune liver injury and hepatitis may be infection (von Herrath MG, unpublished), or an inflammatory context, like the presence of IL-12 or DNA vaccination with vectors containing immune-stimulatory DNA sequence motifs [24–26].
2. Cytoprotective mechanisms Several mechanisms have been described that seem to protect from immune-mediated liver injury. IL-6 signalling to hepatocytes protects from liver-injury [27]; this protection seems to be mediated by IL-6-dependent expression of the acute phase reactant serum amyloid A and the chemokine KC (Trautwein C, unpublished). Adiponectin is cytoprotective for hepatocytes, since it seems to decrease the sensitivity to hepatotoxic cytokines [28]. Heme oxygenase-1 (HO-1), which has been described as hepatoprotective [29], seems to mediate protection through its reaction products biliverdin and carbon monoxide [30]. HO-1 itself, among other gene products, is induced by
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hypoxia-inducible factor-1 (HIF-1), which accumulates after injury-associated hypoxia [31]. Tissue hypoxia is also associated with accumulation of extracellular adenosine, which is sensed by adenosine A2A receptors; signalling through A2A adenosine receptors blocks immune effector mechanisms, like hepatotoxic cytokines [31]. Thus, adenosine receptor antagonists can modify immunemediated liver damage. Cytokine signalling, at least TNFalpha signalling, may also be attenuated by induction of silencer of cytokine signalling-1 (SOCS-1) [32]. Whether these mechanisms really can be safely and effectively activated in patients, remains to be seen. Since T cells seem to kill hepatocytes mainly through induction of programmed cell death [11], anti-apoptotic strategies may be another therapeutic option. Immune regulatory mechanisms may dampen inflammation and cytokine release, thereby protecting from liver injury; since these mechanisms are also alleged promoters of chronicity, they will be discussed below.
3. Acute vs. chronic hepatitis Compared to other virus infections, hepatitis virus infection seems to be associated with a delayed priming of CD8 responses [33–35], due to viral factors. In chronic virus hepatitis, CD8 immunity remains persistently impaired, whereas acute self-limited infection is characterised by a recovery of CD8 responsiveness [7,36]. Several factors may promote chronicity of hepatitis virus infection: depressed CTL cytolitic activity [35,37]; defective transdifferentiation of naive CTL into CTL effector cells due to virus-induced lack of IL-2 [38,39]; IL-10-mediated inhibition of CTL effector function by regulatory CD8 T cells [40]. Indeed, regulatory cells [41] and regulatory cytokines, notably IL-10 [41,42] and TGF-beta [43], seem to be relevant inhibitors of hepatic inflammation and may thus promote chronic hepatitis. Since TGF-beta is also a profibrogenic factor, it seems to be of relevance in hepatic fibrosis associated with chronic hepatitis [44,45]. Several hepatic cell types can function as antigen-presenting cells; T cell stimulation by hepatic antigen presenting cells, which include hepatocytes [46], biliary epithelial cells [47], Kupffer cells [48,49], sinusoidal endothelial cells [49–51] and liver dendritic cells [52,53] often results in the induction of non-inflammatory effector T cell responses [54] that may promote chronicity of hepatitis. However, hepatic inflammation and acuteness of hepatitis apparently can be promoted by inflammatory cytokines like Interferon-gamma [55,56] or by molecular signals of infection, like CpG motif containing oligonucleotides [57]. Immune-mediated liver injury is not yet fully understood, but enormous progress has been made. We do know enough to start developing novel therapeutic approaches for the long-standing clinical problems in liver diseases, such as induction of cytoprotective proteins or activation of
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J. Herkel et al. / Journal of Hepatology 42 (2005) 920–923
adenosine A2A receptors. At least some of these approaches will be evaluated in the near future and should thus be discussed at a follow-up meeting on immune-mediated liver injury, which is scheduled for 2007.
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[20] Siegmund B, Lear-Kaul KC, Faggioni R, Fantuzzi G. Leptin deficiency, not obesity, protects mice from ConA-induced hepatitis. Eur J Immunol 2002;32:552–560. [21] Wies I, Brunner S, Henninger J, Herkel J, Kanzler S, Meyer zum Buschenfelde KH, et al. Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis. Lancet 2000;355:1510–1515. [22] Eksteen B, Grant AJ, Miles A, Curbishley SM, Lalor PF, Hubscher SG, et al. Hepatic endothelial CCL25 mediates the recruitment of CCR9C gut-homing lymphocytes to the liver in primary sclerosing cholangitis. J Exp Med 2004;200:1511–1517. [23] Palmer JM, Robe AJ, Burt AD, Kirby JA, Jones DE. Covalent modification as a mechanism for the breakdown of immune tolerance to pyruvate dehydrogenase complex in the mouse. Hepatology 2004; 39:1583–1592. [24] Geissler M, Mohr L, Weth R, Kohler G, Grimm CF, Krohne TU, et al. Immunotherapy directed against alpha-fetoprotein results in autoimmune liver disease during liver regeneration in mice. Gastroenterology 2001;121:931–939. [25] Djilali-Saiah I, Lapierre P, Vittozi S, Alvarez F. DNA vaccination breaks tolerance for a neo-self antigen in liver: a transgenic murine model of autoimmune hepatitis. J Immunol 2002;169:4889–4896. [26] Lapierre P, Djilali-Saiah I, Vitozzi S, Alvarez F. A murine model of type 2 autoimmune hepatitis: Xenoimmunisation with with human antigens. Hepatology 2004;39:1066–1074. [27] Streetz KL, Wustefeld T, Klein C, Kallen KJ, Tronche F, Betz UA, et al. Lack of gp130 expression in hepatocytes promotes liver injury. Gastoenterology 2003;125:532–543. [28] Sennello JA, Fayad R, Morris AM, Eckel RH, Asilmaz E, Montez J, et al. Endocrinology 2005; in press. [29] Sass G, Soares MC, Yamashita K, Seyfried S, Zimmermann WH, Eschenhagen T, et al. Heme oxigenase-1 and its reaction product, carbon monoxide, prevent inflammation-related apoptotic liver damage in mice. Hepatology 2003;38:909–918. [30] Sass G, Seyfried S, Parreira Soares M, Yamashita K, Kaczmarek E, Neuhuber WL, et al. Cooperative effect of biliverdin and carbon monoxide on survival of mice in immune-mediated liver injury. Hepatology 2004;40:1128–1135. [31] Sitkovsky MV, Lukashev D, Apasov S, Kojima H, Koshiba M, Caldwell C, et al. Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu Rev Immunol 2004;22:657–682. [32] Sass G, Shembade ND, Tiegs G. Tumour necrosis factor alpha (TNF)TNF receptor 1-inducible cytoprotective proteins in the mouse liver: relevance of suppressors of cytokine signalling. Biochem J 2005;385: 537–544. [33] Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med 2001;194:1395–1406. [34] Shoukry NH, Grakoui A, Houghton M, Chien DY, Ghrayeb J, Reimann KA, et al. Memory CD8C T cells are required for protection from persistent hepatitis C virus infection. J Exp Med 2003;197: 1645–1655. [35] Urbani S, Boni C, Missale G, Elia G, Cavallo C, Massari M, et al. Virus-specific CD8C lymphocytes share the same effector-memory phenotype but exhibit functional differences in acute hepatitis B and C. J Virol 2002;76:12423–12434. [36] Webster GJ, Reignat S, Brown D, Ogg GS, Jones L, Seneviratne SL, et al. Longitudinal analysis of CD8C T cells specific for structural and nonstructural hepatitis B virus proteins in patients with chronic hepatitis B: implications for immunotherapy. J Virol 2004;78: 5707–5719. [37] Ferrari C, Missale G, Boni C, Urbani S. Immunopathogenesis of hepatitis B. J Hepatol 2003;39:S36–S42. [38] Francavilla V, Accapezzato D, De Salvo M, Rawson P, Cosimi O, Lipp M, et al. Subversion of effector CD8C T cell differentiation in acute hepatitis C virus infection: exploring the immunological mechanisms. Eur J Immunol 2004;34:427–437.
J. Herkel et al. / Journal of Hepatology 42 (2005) 920–923 [39] Accapezzato D, Francavilla V, Rawson P, Cerino A, Cividini A, Mondelli MU, et al. Subversion of effector CD8C T cell differentiation in acute hepatitis C virus infection: the role of the virus. Eur J Immunol 2004;34:438–446. [40] Accapezzato D, Francavilla V, Paroli M, Casciaro M, Chircu LV, Cividini A, et al. Hepatic expansion of a virus-specific regulatory CD8(C) T cell population in chronic hepatitis C virus infection. J Clin Invest 2004;113:963–972. [41] Dikopoulos N, Bertoletti A, Kroger A, Hauser H, Schirmbeck R, Reimann J. Type l IIFN negatively regulates CD8C T cell responses through IL1-10-producing CD4C T regulatory 1 cells. J Immunol 2005;174:99–109. [42] Louis H, Le Moine O, Peny MO, Quertinmont E, Fokan D, Goldman M, et al. Production and role of interleukin-10 in concanavalin A-induced hepatitis in mice. Hepatology 1997;25: 1382–1389. [43] Schramm C, Protschka M, Kohler HH, Podlech J, Reddehase MJ, Schirmacher P, et al. Impairment of TGF-beta signalling in T cells increases susceptibility to experimental autoimmune hepatitis in mice. Am J Physiol Gastrointest Liver Physiol 2003;284:G525–G535. [44] Bayer EM, Herr W, Kanzler S, Waldmann C, Meyer zum Buschenfelde KH, Dienes HP, et al. Transforming growth factorbeta1 in autoimmune hepatitis: correlation of liver tissue expression and serum levels with disease activity. J Hepatol 1998;28:803–811. [45] Kanzler S, Baumann M, Schirmacher P, Dries V, Bayer E, Gerken G, et al. Prediction of progressive liver fibrosis in hepatitis C infection by serum and tissue levels of transforming growth factor-beta. J Viral Hepat 2001;8:430–437. [46] Herkel J, Jagemann B, Wiegard C, Lazaro JF, Lueth S, Kanzler S, et al. MHC class II expressing hepatocytes function as antigen presenting cells and activate specific CD4 T lymphocytes. Hepatology 2003;37:1079–1085. [47] Hreha G, Jefferson DM, Yu CH, Grubman SA, Alsabeh R, Geller SA, et al. Immortalized intrahepatic mouse biliary epithelial cells: immunologic characterization and immunogenicity. Hepatology 1999;30:358–371. [48] Hayashi N, Matsui K, Tsutsui H, Osada Y, Mohamed RT, Nakano H, et al. Kupffer cells from Schistosoma mansoni-infected mice
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Special article
Immune-mediated liver injury Johannes Herkel1,2, Marcus Schuchmann1, Gisa Tiegs3, Ansgar W. Lohse2,* 1 I. Department of Medicine, Johannes Gutenberg-University Mainz, Germany Department of Internal Medicine I, University Medical Centre Hamburg-Eppendorf, Martinistraß;e 52, 20246 Hamburg, Germany 3 Institute for Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander-University Erlangen-Nu¨rnberg, Erlangen, Germany 2
Liver diseases are a major cause of morbidity and mortality worldwide. The major clinical problem is the frequent development of liver cirrhosis or liver cancer related to chronic hepatitis. A broad variety of conditions may cause chronic hepatitis, including hepatitis virus infection [1,2], toxic insult [3,4] or autoimmunity [5,6]. Hepatitis, acute or chronic, is associated with liver injury, which is largely mediated by immune effector mechanisms. In acute hepatitis, immune-mediated liver injury is usually compensated by adequate repair, and liver function is maintained. In chronic hepatitis, in contrast, continuous liver injury seems to promote aberrant repair and the development of fibrosis/cirrhosis and liver cancer. Irrespective of the cause, liver injury seems to be facilitated by similar immune effector mechanisms common to the various liver diseases. Indeed, common immune effector mechanisms may explain the high prevalence of cirrhosis and cancer common to most forms of liver injury. Improved understanding of immune-mediated liver injury may help to develop therapeutic approaches to this widespread clinical problem; so far, there is no cure for cirrhosis or liver cancer, except liver transplantation, and therapeutic options for many patients with chronic hepatitis are unsatisfactory. To approach the mechanisms of immunemediated liver injury, an EASL workshop, entitled ‘Immune-mediated liver injury: from basic science to future therapies’, was held October 9–11, 2004 in Freiburg, Germany, bringing together scientists and clinicians who study the various facets of immune-mediated liver diseases. This review is based on the presentations of the workshop and summarises some of the currently emerging answers to the old questions: Which immune effector mechanisms cause liver injury? * Corresponding author. Tel.: 49 40 42803-3910; fax: 49 40 483065. E-mail address: [email protected] (A.W. Lohse).
Which mechanisms may protect from immune-mediated liver injury? Which processes determine acuteness or chronicity of hepatitis?
1. Mechanisms of immune-mediated liver injury It is now established that liver injury in viral hepatitis is not mediated by hepatitis virus itself, but by the immune response to the virus [1,2,7,8]. Inhibition of hepatitis virus replication is not necessarily related to liver damage [9] and hepatitis virus can be efficiently cleared by anti-viral cytokines [10]. However, there seem to be fail-safe mechanisms of viral clearance, which rely on the destruction of infected hepatocytes and even of non-infected bystanders. The most prominent mechanism of liver injury in viral hepatitis seems to be CD8 T cell-mediated killing, which is facilitated mainly by Fas, TNFR1 and DR5, rather than by cytolytic granules [11]. However, non-virus-specific T cells may also be recruited to the liver, which aggravate liver damage without contributing to virus control [9,12]. Moreover, polymorphonuclear [13] and mononuclear cells [14], as well as platelets (Guidotti LG, unpublished) may accumulate at the necroinflammatory foci in the liver and further aggravate liver injury. Thus, therapeutic strategies may aim at reducing exaggerated liver injury, however, it remains to be seen whether this is compatible with cytokinemediated non-cytopathic viral clearance. Like viral hepatitis, drug-induced liver injury seems to be largely immune-mediated [3,4,15]. It appears that the drug is enzymatically transformed to reactive metabolites, which bind to self-constituents, most frequently the metabolising enzyme, thus forming neoantigens. Neoantigens may then induce an immune response, which causes liver injury. However, the liver-damaging immune effector mechanisms
0168-8278/$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2005.02.009
J. Herkel et al. / Journal of Hepatology 42 (2005) 920–923
in toxic hepatitis are less well characterised than those in viral hepatitis. In lack of suitable animal models for druginduced hepatitis, the model of Con A-induced hepatitis has been widely used to study immune effector mechanisms of immune-mediated liver-injury [16,17]. Concanavalin A is a bean lectin, which, when injected intravenously to mice, induces activation of T cells in the liver, Valpha14 NKT cells being most important [18]. Together with Kupffer cells, NKT cells secrete large amounts of various hepatotoxic cytokines, most notably TNF-alpha and IFN-gamma [17,19]. Other factors like leptin may aggravate liver injury by promoting hepatotoxic cytokine secretion [20]. The mechanisms of autoimmune liver injury are less well understood, because only a few of the relevant target antigens are known. In autoimmune hepatitis, only one disease-specific autoantigen, the SLA/LP molecule [21], is known so far, which is relevant only in about 20% of the patients. The other known autoantigens in autoimmune hepatitis are recognised also in other hepatic diseases, as well as non-hepatic autoimmune diseases. However, as we learned from viral hepatitis, non-specific T cells can greatly enhance liver injury. In primary sclerosing cholangitis (PSC), no specific target antigen is known; however, there seems to be a close pathogenetic association to colitis. Indeed, liver injury in PSC seems to be mediated by guthoming lymphocytes, which are recruited to the liver by aberrantly expressed chemokines [22]. In primary biliary cirrhosis, several autoantigens are known, most notably the pyruvate dehydrogenase complex (PDC). Autoimmunity to PDC may be induced by various mechanisms; recently, the formation of neoantigenic PDC by covalent modification has been shown to cause PDC autoimmunity [23], reminiscent of the mechanisms in toxic hepatitis. It is thus possible that not only toxic hepatitis, but also autoimmune liver disease may be induced by the metabolic activity of the liver. Other triggers of autoimmune liver injury and hepatitis may be infection (von Herrath MG, unpublished), or an inflammatory context, like the presence of IL-12 or DNA vaccination with vectors containing immune-stimulatory DNA sequence motifs [24–26].
2. Cytoprotective mechanisms Several mechanisms have been described that seem to protect from immune-mediated liver injury. IL-6 signalling to hepatocytes protects from liver-injury [27]; this protection seems to be mediated by IL-6-dependent expression of the acute phase reactant serum amyloid A and the chemokine KC (Trautwein C, unpublished). Adiponectin is cytoprotective for hepatocytes, since it seems to decrease the sensitivity to hepatotoxic cytokines [28]. Heme oxygenase-1 (HO-1), which has been described as hepatoprotective [29], seems to mediate protection through its reaction products biliverdin and carbon monoxide [30]. HO-1 itself, among other gene products, is induced by
921
hypoxia-inducible factor-1 (HIF-1), which accumulates after injury-associated hypoxia [31]. Tissue hypoxia is also associated with accumulation of extracellular adenosine, which is sensed by adenosine A2A receptors; signalling through A2A adenosine receptors blocks immune effector mechanisms, like hepatotoxic cytokines [31]. Thus, adenosine receptor antagonists can modify immunemediated liver damage. Cytokine signalling, at least TNFalpha signalling, may also be attenuated by induction of silencer of cytokine signalling-1 (SOCS-1) [32]. Whether these mechanisms really can be safely and effectively activated in patients, remains to be seen. Since T cells seem to kill hepatocytes mainly through induction of programmed cell death [11], anti-apoptotic strategies may be another therapeutic option. Immune regulatory mechanisms may dampen inflammation and cytokine release, thereby protecting from liver injury; since these mechanisms are also alleged promoters of chronicity, they will be discussed below.
3. Acute vs. chronic hepatitis Compared to other virus infections, hepatitis virus infection seems to be associated with a delayed priming of CD8 responses [33–35], due to viral factors. In chronic virus hepatitis, CD8 immunity remains persistently impaired, whereas acute self-limited infection is characterised by a recovery of CD8 responsiveness [7,36]. Several factors may promote chronicity of hepatitis virus infection: depressed CTL cytolitic activity [35,37]; defective transdifferentiation of naive CTL into CTL effector cells due to virus-induced lack of IL-2 [38,39]; IL-10-mediated inhibition of CTL effector function by regulatory CD8 T cells [40]. Indeed, regulatory cells [41] and regulatory cytokines, notably IL-10 [41,42] and TGF-beta [43], seem to be relevant inhibitors of hepatic inflammation and may thus promote chronic hepatitis. Since TGF-beta is also a profibrogenic factor, it seems to be of relevance in hepatic fibrosis associated with chronic hepatitis [44,45]. Several hepatic cell types can function as antigen-presenting cells; T cell stimulation by hepatic antigen presenting cells, which include hepatocytes [46], biliary epithelial cells [47], Kupffer cells [48,49], sinusoidal endothelial cells [49–51] and liver dendritic cells [52,53] often results in the induction of non-inflammatory effector T cell responses [54] that may promote chronicity of hepatitis. However, hepatic inflammation and acuteness of hepatitis apparently can be promoted by inflammatory cytokines like Interferon-gamma [55,56] or by molecular signals of infection, like CpG motif containing oligonucleotides [57]. Immune-mediated liver injury is not yet fully understood, but enormous progress has been made. We do know enough to start developing novel therapeutic approaches for the long-standing clinical problems in liver diseases, such as induction of cytoprotective proteins or activation of
922
J. Herkel et al. / Journal of Hepatology 42 (2005) 920–923
adenosine A2A receptors. At least some of these approaches will be evaluated in the near future and should thus be discussed at a follow-up meeting on immune-mediated liver injury, which is scheduled for 2007.
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