Immune-mediated liver injury

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 [1Lai C.L. Ratziu V. Yuen M.F. Poynard T. Viral hepatitis B.Lancet. 2003; 362: 2089-2094Abstract Full Text Full Text PDF PubMed Scopus (724) Google Scholar, 2Poynard T. Yuen M.F. Ratziu V. Lai C.L. Viral hepatitis C.Lancet. 2003; 362: 2095-2100Abstract Full Text Full Text PDF PubMed Scopus (751) Google Scholar], toxic insult [3Robin M.A. Le Roy M. Descatoire V. Pessayre D. Plasma membrane cytochromes P450 as neoantigens and autoimmune targets in drug-induced hepatitis.J Hepatol. 1997; 26: 23-30Abstract Full Text PDF PubMed Google Scholar, 4Robin M.A. Maratrat M. Le Roy M. Le Breton F.P. Bonierbale E. Dansette P. et al.J Clin Invest. 1996; 98: 1471-1480Crossref PubMed Scopus (72) Google Scholar] or autoimmunity [5Manns M.P. Strassburg C.P. Autoimmune hepatitis: clinical challenges.Gastroenterology. 2001; 120: 1502-1517Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 6Kita H. Imawari M. Gershwin M.E. Cellular immune response in primary biliary cirrhosis.Hepatol Res. 2004; 28: 12-17Crossref PubMed Scopus (32) Google Scholar]. 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 immune-mediated 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? Which mechanisms may protect from immune-mediated liver injury? Which processes determine acuteness or chronicity of hepatitis? 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 [1Lai C.L. Ratziu V. Yuen M.F. Poynard T. Viral hepatitis B.Lancet. 2003; 362: 2089-2094Abstract Full Text Full Text PDF PubMed Scopus (724) Google Scholar, 2Poynard T. Yuen M.F. Ratziu V. Lai C.L. Viral hepatitis C.Lancet. 2003; 362: 2095-2100Abstract Full Text Full Text PDF PubMed Scopus (751) Google Scholar, 7Bertoletti A. Ferrari C. Kinetics of the immune response during HBV and HCV infection.Hepatology. 2003; 38: 4-13Crossref PubMed Scopus (237) Google Scholar, 8Bertoletti A. Naoumov N.V. Translation of immunological knowledge into better treatments of chronic hepatitis B.J Hepatol. 2003; 39: 115-124Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar]. Inhibition of hepatitis virus replication is not necessarily related to liver damage [[9]Bertoletti A. Maini M.K. Protection or damage: a dual role for the virus-specific cytotoxic T lymphocyte response in hepatitis B and C infection?.Curr Opinion Immunol. 2000; 12: 403-408Crossref PubMed Scopus (97) Google Scholar] and hepatitis virus can be efficiently cleared by anti-viral cytokines [[10]Guidotti L.G. Chisari F.V. Noncytolytic control of viral infections by the innate and adaptive immune response.Annu Rev Immunol. 2001; 19: 65-91Crossref PubMed Scopus (871) Google Scholar]. However, there seem to be fail-safe mechanisms of viral clearance, which rely on the destruction of infected hepatocytes and even of non-infected by-standers. 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]Abougergi M.S. Gidner S.J. Spady D.K. Miller B.C. Thiele D.L. Fas and TNFR1, but not cytolytic granule-dependent mechanisms, mediate clearance of murine liver adenoviral infection.Hepatology. 2004; 41: 97-105Crossref Scopus (23) Google Scholar]. However, non-virus-specific T cells may also be recruited to the liver, which aggravate liver damage without contributing to virus control [9Bertoletti A. Maini M.K. Protection or damage: a dual role for the virus-specific cytotoxic T lymphocyte response in hepatitis B and C infection?.Curr Opinion Immunol. 2000; 12: 403-408Crossref PubMed Scopus (97) Google Scholar, 12Bowen D.G. Warren A. Davis T. Hoffmann M.W. McCaughan G.W. De St Groth B.F. et al.Cytokine-dependent bystander hepatitis due to intrahepatic murine CD8 T-cell activation by bone marrow-derived cells.Gastroenterology. 2002; 123: 1252-1264Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. Moreover, polymorphonuclear [[13]Sitia G. Isogawa M. Kakimi K. Wieland S.F. Chisari F.V. Guidotti L.G. Depletion of neutrophils blocks the recuitment of antigen-nonspecific cells into the liver without affecting the antiviral activity of hepatitis B virus-specific cytotoxic T lymphocytes.Proc Natl Acad Sci USA. 2002; 99: 13717-13722Crossref PubMed Scopus (100) Google Scholar] and mononuclear cells [[14]Sitia G. Isogawa M. Iannacone M. Campbell I.L. Chisari F.V. Guidotti L.G. MMPs are required for recruitment of antigen-nonspecific mononuclear cells into the liver by CTLs.J Clin Invest. 2004; 113: 1158-1167Crossref PubMed Scopus (115) Google Scholar], 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 cytokine-mediated non-cytopathic viral clearance. Like viral hepatitis, drug-induced liver injury seems to be largely immune-mediated [3Robin M.A. Le Roy M. Descatoire V. Pessayre D. Plasma membrane cytochromes P450 as neoantigens and autoimmune targets in drug-induced hepatitis.J Hepatol. 1997; 26: 23-30Abstract Full Text PDF PubMed Google Scholar, 4Robin M.A. Maratrat M. Le Roy M. Le Breton F.P. Bonierbale E. Dansette P. et al.J Clin Invest. 1996; 98: 1471-1480Crossref PubMed Scopus (72) Google Scholar, 15Stewart S.F. Vidali M. Day C.P. Albano E. Jones D.E. Oxidative stress as a trigger for cellular immmune responses in patients with alcoholic liver disease.Hepatology. 2004; 39: 197-203Crossref PubMed Scopus (84) Google Scholar]. 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 in toxic hepatitis are less well characterised than those in viral hepatitis. In lack of suitable animal models for drug-induced hepatitis, the model of Con A-induced hepatitis has been widely used to study immune effector mechanisms of immune-mediated liver-injury [16Tiegs G. Hentschel J. Wendel A. A T cell-dependent experimental liver injury in mice inducible by Concanavalin A.J Clin Invest. 1992; 90: 196-203Crossref PubMed Scopus (991) Google Scholar, 17Schumann J. Tiegs G. Pathophysiological mechanisms of TNF during intoxication with natural or man-made toxins.Toxicology. 1999; 138: 103-126Crossref PubMed Scopus (68) Google Scholar]. 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]Kaneko Y. Harada M. Kawano T. Yamashita M. Shibata Y. Gejyo F. et al.Augmentation of Valpha14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis.J Exp Med. 2000; 191: 105-114Crossref PubMed Scopus (377) Google Scholar]. Together with Kupffer cells, NKT cells secrete large amounts of various hepatotoxic cytokines, most notably TNF-alpha and IFN-gamma [17Schumann J. Tiegs G. Pathophysiological mechanisms of TNF during intoxication with natural or man-made toxins.Toxicology. 1999; 138: 103-126Crossref PubMed Scopus (68) Google Scholar, 19Bradham C.A. Plumpe J. Manns M.P. Brenner D.A. Trautwein C. Mechanisms of hepatic toxicity. I. TNF-induced liver injury.Am J Physiol. 1998; 275: G387-G392PubMed Google Scholar]. Other factors like leptin may aggravate liver injury by promoting hepatotoxic cytokine secretion [[20]Siegmund B. Lear-Kaul K.C. Faggioni R. Fantuzzi G. Leptin deficiency, not obesity, protects mice from ConA-induced hepatitis.Eur J Immunol. 2002; 32: 552-560Crossref PubMed Scopus (80) Google Scholar]. 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]Wies I. Brunner S. Henninger J. Herkel J. Kanzler S. Meyer zum Buschenfelde K.H. et al.Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis.Lancet. 2000; 355: 1510-1515Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar], 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 gut-homing lymphocytes, which are recruited to the liver by aberrantly expressed chemokines [[22]Eksteen B. Grant A.J. Miles A. Curbishley S.M. Lalor P.F. Hubscher S.G. et al.Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis.J Exp Med. 2004; 200: 1511-1517Crossref PubMed Scopus (267) Google Scholar]. 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]Palmer J.M. Robe A.J. Burt A.D. Kirby J.A. Jones D.E. Covalent modification as a mechanism for the breakdown of immune tolerance to pyruvate dehydrogenase complex in the mouse.Hepatology. 2004; 39: 1583-1592Crossref PubMed Scopus (24) Google Scholar], 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 [24Geissler M. Mohr L. Weth R. Kohler G. Grimm C.F. Krohne T.U. et al.Immunotherapy directed against alpha-fetoprotein results in autoimmune liver disease during liver regeneration in mice.Gastroenterology. 2001; 121: 931-939Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 25Djilali-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: 4889-4896PubMed Google Scholar, 26Lapierre P. Djilali-Saiah I. Vitozzi S. Alvarez F. A murine model of type 2 autoimmune hepatitis: Xenoimmunisation with with human antigens.Hepatology. 2004; 39: 1066-1074Crossref PubMed Scopus (141) Google Scholar]. Several mechanisms have been described that seem to protect from immune-mediated liver injury. IL-6 signalling to hepatocytes protects from liver-injury [[27]Streetz K.L. Wustefeld T. Klein C. Kallen K.J. Tronche F. Betz U.A. et al.Lack of gp130 expression in hepatocytes promotes liver injury.Gastoenterology. 2003; 125: 532-543Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar]; 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]Sennello JA, Fayad R, Morris AM, Eckel RH, Asilmaz E, Montez J, et al. Endocrinology 2005; in press.Google Scholar]. Heme oxygenase-1 (HO-1), which has been described as hepatoprotective [[29]Sass G. Soares M.C. Yamashita K. Seyfried S. Zimmermann W.H. Eschenhagen T. et al.Heme oxigenase-1 and its reaction product, carbon monoxide, prevent inflammation-related apoptotic liver damage in mice.Hepatology. 2003; 38: 909-918Crossref PubMed Scopus (160) Google Scholar], seems to mediate protection through its reaction products biliverdin and carbon monoxide [[30]Sass G. Seyfried S. Parreira Soares M. Yamashita K. Kaczmarek E. Neuhuber W.L. et al.Cooperative effect of biliverdin and carbon monoxide on survival of mice in immune-mediated liver injury.Hepatology. 2004; 40: 1128-1135Crossref PubMed Scopus (60) Google Scholar]. HO-1 itself, among other gene products, is induced by hypoxia-inducible factor-1 (HIF-1), which accumulates after injury-associated hypoxia [[31]Sitkovsky M.V. 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: 657-682Crossref PubMed Scopus (616) Google Scholar]. 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]Sitkovsky M.V. 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: 657-682Crossref PubMed Scopus (616) Google Scholar]. Thus, adenosine receptor antagonists can modify immune-mediated liver damage. Cytokine signalling, at least TNF-alpha signalling, may also be attenuated by induction of silencer of cytokine signalling-1 (SOCS-1) [[32]Sass G. Shembade N.D. 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: 537-544Crossref PubMed Scopus (30) Google Scholar]. 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]Abougergi M.S. Gidner S.J. Spady D.K. Miller B.C. Thiele D.L. Fas and TNFR1, but not cytolytic granule-dependent mechanisms, mediate clearance of murine liver adenoviral infection.Hepatology. 2004; 41: 97-105Crossref Scopus (23) Google Scholar], 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. Compared to other virus infections, hepatitis virus infection seems to be associated with a delayed priming of CD8 responses [33Thimme R. Oldach D. Chang K.M. Steiger C. Ray S.C. Chisari F.V. Determinants of viral clearance and persistence during acute hepatitis C virus infection.J Exp Med. 2001; 194: 1395-1406Crossref PubMed Scopus (1038) Google Scholar, 34Shoukry N.H. Grakoui A. Houghton M. Chien D.Y. Ghrayeb J. Reimann K.A. et al.Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection.J Exp Med. 2003; 197: 1645-1655Crossref PubMed Scopus (546) Google Scholar, 35Urbani S. Boni C. Missale G. Elia G. Cavallo C. Massari M. et al.Virus-specific CD8+ lymphocytes share the same effector-memory phenotype but exhibit functional differences in acute hepatitis B and C.J Virol. 2002; 76: 12423-12434Crossref PubMed Scopus (165) Google Scholar], 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 [7Bertoletti A. Ferrari C. Kinetics of the immune response during HBV and HCV infection.Hepatology. 2003; 38: 4-13Crossref PubMed Scopus (237) Google Scholar, 36Webster G.J. Reignat S. Brown D. Ogg G.S. Jones L. Seneviratne S.L. et al.Longitudinal analysis of CD8+ T cells specific for structural and nonstructural hepatitis B virus proteins in patients with chronic hepatitis B: implications for immunotherapy.J Virol. 2004; 78: 5707-5719Crossref PubMed Scopus (348) Google Scholar]. Several factors may promote chronicity of hepatitis virus infection: depressed CTL cytolitic activity [35Urbani S. Boni C. Missale G. Elia G. Cavallo C. Massari M. et al.Virus-specific CD8+ lymphocytes share the same effector-memory phenotype but exhibit functional differences in acute hepatitis B and C.J Virol. 2002; 76: 12423-12434Crossref PubMed Scopus (165) Google Scholar, 37Ferrari C. Missale G. Boni C. Urbani S. Immunopathogenesis of hepatitis B.J Hepatol. 2003; 39: S36-S42Abstract Full Text Full Text PDF PubMed Google Scholar]; defective transdifferentiation of naive CTL into CTL effector cells due to virus-induced lack of IL-2 [38Francavilla V. Accapezzato D. De Salvo M. Rawson P. Cosimi O. Lipp M. et al.Subversion of effector CD8+ T cell differentiation in acute hepatitis C virus infection: exploring the immunological mechanisms.Eur J Immunol. 2004; 34: 427-437Crossref PubMed Scopus (62) Google Scholar, 39Accapezzato D. Francavilla V. Rawson P. Cerino A. Cividini A. Mondelli M.U. et al.Subversion of effector CD8+ T cell differentiation in acute hepatitis C virus infection: the role of the virus.Eur J Immunol. 2004; 34: 438-446Crossref PubMed Scopus (50) Google Scholar]; IL-10-mediated inhibition of CTL effector function by regulatory CD8 T cells [[40]Accapezzato D. Francavilla V. Paroli M. Casciaro M. Chircu L.V. Cividini A. et al.Hepatic expansion of a virus-specific regulatory CD8(+) T cell population in chronic hepatitis C virus infection.J Clin Invest. 2004; 113: 963-972Crossref PubMed Scopus (276) Google Scholar]. Indeed, regulatory cells [[41]Dikopoulos N. Bertoletti A. Kroger A. Hauser H. Schirmbeck R. Reimann J. Type l IIFN negatively regulates CD8+ T cell responses through IL1-10-producing CD4+ T regulatory 1 cells.J Immunol. 2005; 174: 99-109PubMed Google Scholar] and regulatory cytokines, notably IL-10 [41Dikopoulos N. Bertoletti A. Kroger A. Hauser H. Schirmbeck R. Reimann J. Type l IIFN negatively regulates CD8+ T cell responses through IL1-10-producing CD4+ T regulatory 1 cells.J Immunol. 2005; 174: 99-109PubMed Google Scholar, 42Louis H. Le Moine O. Peny M.O. Quertinmont E. Fokan D. Goldman M. et al.Production and role of interleukin-10 in concanavalin A-induced hepatitis in mice.Hepatology. 1997; 25: 1382-1389Crossref PubMed Scopus (163) Google Scholar] and TGF-beta [[43]Schramm C. Protschka M. Kohler H.H. Podlech J. Reddehase M.J. 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-G535PubMed Google Scholar], seem to be relevant inhibitors of hepatic inflammation and may thus promote chronic hepatitis. Since TGF-beta is also a pro-fibrogenic factor, it seems to be of relevance in hepatic fibrosis associated with chronic hepatitis [44Bayer E.M. Herr W. Kanzler S. Waldmann C. Meyer zum Buschenfelde K.H. Dienes H.P. et al.Transforming growth factor-beta1 in autoimmune hepatitis: correlation of liver tissue expression and serum levels with disease activity.J Hepatol. 1998; 28: 803-811Abstract Full Text PDF PubMed Scopus (76) Google Scholar, 45Kanzler 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: 430-437Crossref PubMed Scopus (120) Google Scholar]. Several hepatic cell types can function as antigen-presenting cells; T cell stimulation by hepatic antigen presenting cells, which include hepatocytes [[46]Herkel J. Jagemann B. Wiegard C. Lazaro J.F. 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: 1079-1085Crossref PubMed Scopus (122) Google Scholar], biliary epithelial cells [[47]Hreha G. Jefferson D.M. Yu C.H. Grubman S.A. Alsabeh R. Geller S.A. et al.Immortalized intrahepatic mouse biliary epithelial cells: immunologic characterization and immunogenicity.Hepatology. 1999; 30: 358-371Crossref PubMed Scopus (22) Google Scholar], Kupffer cells [48Hayashi N. Matsui K. Tsutsui H. Osada Y. Mohamed R.T. Nakano H. et al.Kupffer cells from Schistosoma mansoni-infected mice participate in the prompt type 2 differentiation of hepatic T cells in response to worm antigens.J Immunol. 1999; 163: 6702-6711PubMed Google Scholar, 49Lohse A.W. Knolle P.A. Bilo K. Uhrig A. Waldmann C. Ibe M. et al.Antigen presenting function of murine sinusoidal endothelial cells and Kupffer cells.Gastroenterology. 1996; 110: 1175-1181Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar], sinusoidal endothelial cells [49Lohse A.W. Knolle P.A. Bilo K. Uhrig A. Waldmann C. Ibe M. et al.Antigen presenting function of murine sinusoidal endothelial cells and Kupffer cells.Gastroenterology. 1996; 110: 1175-1181Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, 50Knolle P.A. Schmitt E. Jin S.C. Germann T. Duchmann R. Hegenbarth S. et al.Induction of cytokine production in naive CD4(+) T cells by antigen-presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward Th1 cells.Gastroenterology. 1999; 116: 1428-1440Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar, 51Limmer A.J. Ohl J. Kurts C. Ljunggren H.G. Reiss Y. Groettrup M. et al.Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T cell tolerance.Nat Med. 2000; 6: 1348-1354Crossref PubMed Scopus (615) Google Scholar] and liver dendritic cells [52Goddard S. Youster J. Morgan E. Adams D.H. Interleukin-10 secretion differentiates dendritic cells from human liver and skin.Am J Pathol. 2004; 164: 511-519Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 53Lian Z.X. Okada T. He X.S. Kita H. Liu Y.J. Ansari A.A. et al.Heterogeneity of dendritic cells in the mouse liver: identification adnd characterization of four distinct populations.J Immunol. 2003; 170: 2323-2330PubMed Google Scholar] often results in the induction of non-inflammatory effector T cell responses [[54]Bowen D.G. Zen M. Holz L. Davis T. McCaughan G.W. Bertolino P. The site of primmary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity.J Clin Invest. 2004; 114: 701-712Crossref PubMed Scopus (283) Google Scholar] that may promote chronicity of hepatitis. However, hepatic inflammation and acuteness of hepatitis apparently can be promoted by inflammatory cytokines like Interferon-gamma [55Toyonaga T. Hino O. Sugai S. Wakasugi S. Abe K. Shichiri M. et al.Chronic active hepatitis in transgenic mice expressing interferon-gamma in the liver.Proc Natl Acad Sci USA. 1994; 91: 614-618Crossref PubMed Scopus (200) Google Scholar, 56Gorham J.D. Lin T.J. Sung J.L. Rudner L.A. French M.A. Genetic regulation of autoimmune disease: BALB/c background TGF-beta 1-deficient mice develop necroinflammatory IFN-gamma-dependend hepatitis.J Immunol. 2001; 166: 6413-6422PubMed Google Scholar] or by molecular signals of infection, like CpG motif containing oligonucleotides [[57]Sacher T. Knolle P. Nichterlein T. Arnold B. Hammerling G.J. Limmer A. CpG-ODN-induced inflammation is sufficient to cause T-cell-mediated autoaggression against hepatocytes.Eur J Immunol. 2002; 32: 3628-3637Crossref PubMed Scopus (62) Google Scholar]. 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 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.