- Email: [email protected]
790 HIGH FREQUENCY OF CD4 CXCR5+ TFH CELLS IN PATIENTS WITH IMMUNE-ACTIVE CHRONIC HEPATITIS B AND CHRONIC HEPATITIS C
POSTERS after beads administration. These cells also increased after in vivo administration of FITC-E. coli. In vivo administration of FITC-E. coli demonstrated that among CD11b− Kupffer cells, the proportion of CD68+ CD32− cells increased, suggesting that CD32+ Kupffer cells acquire CD68 but instead loose CD32 after activation and engulfment of E. coli. In vitro coculture of Kupffer cells with pHrodo-conjugated E. coli, which detected the decreased pH in phagolysosomes after E. coli phagocytosis by fluorescence emission, revealed that CD68+ and/or CD32+ (but not CD11b+ ) Kupffer cells efficiently phagocytose and kill E. coli. Conclusions: Murine Kupffer cells are thus comprehensively subdivided into CD11b+ , CD68+ and CD32+ subsets. CD32+ Kupffer cells may be precursors of CD68+ Kupffer cells upon activation. 788 A LONGITUDINAL ANALYSIS OF INNATE AND ADAPTIVE IMMUNE PROFILE DURING TREATMENT WITH NUCLEOS(T)IDE ANALOGS FOR CHRONIC HEPATITIS B L. Wang, P. Zhao, J. Tai, J. Feng, J. Niu, Y. Jiang. First Hospital, Jilin University, Changchun, China E-mail: [email protected] Background: Chronicity of hepatitis B virus (HBV) infection is characterized by a weak immune response to the virus. Entecavir (ETV), adefovir dipivoxil (ADV) and Telbivudine (LDT) are highly effective in the suppression of HBV replication. however, host immune responsible for sustained virological respones in HBVinfected patients treated with nucleos(t)ide analogs are not understood. This study aims to evaluate the immune response and antiviral effect after nucleos(t)ide analogs or thymosin-alpha 1 (TA1) treatment. Methods: Serial analysis of intracellular or serum cytokines including IL-2, IFN-g, TNF-a, IL-4 and regulatory T cells (Tregs), CD4 and CD8 were measured using flow cytometry before and at 12, 24, 36 and 48 weeks after treatment. CD3-CD56+ NK cells, CD3+CD56+ NKT cells, CD4+CD25+FoxP3+ Treg cells) were also analysed. Extracellular cytokine production was tested by Cytotoxic Bead Array (CBA). Samples were also tested for HBV DNA, HBsAg, HBeAg, ALT and AST. Results: The cytokine productions were significantly increased from 24 to 48 weeks after nucleos(t)ide analogs treatments, higher levels of Th1 cytokines, IL-2, IFN-g and TNF-a were observed with ETV (n = 29) compared to ADV (n = 28), LDT (n = 41) or TA1(n = 19). By contrast, the levels of Tregs in all groups were markedly decreased after 24 weeks. This altered cytokine profile and cellular component is accompanied by a decreased HBV DNA and HBsAg levels in nucleos(t)ide analogs treatment group. The results showed significantly reduced numbers of CD3-CD56+ NK cells with CHB patients, while the proportion of CD3+CD4+ T cells, Treg cells and the ratio of CD4/CD8 were significantly higher than that of healthy controls. Conclusions: The enhanced immune response related to ADV, LDT and ETV treatment suggests that the anti-viral effect of the drugs may not only be attributed to its direct effect on virus suppression but also to its immune regulation capability. While the underlying mechanism remains to be understood, reduced virus load and Tregs may favor the restoration of anti-virus immunity in CHB. The mean reduction of serum HBsAg had a significant correlation with the corresponding logarithmic HBVDNA both in HBeAg positive and negative groups.
789 SERUM IL-33 LEVELS ARE ASSOCIATED WITH LIVER DAMAGE IN PATIENTS WITH CHRONIC HEPATITIS B AND C L. Wang, P. Zhao, J. Wang, J. Feng, J. Niu, Y. Jiang. First Hospital, Jilin University, Changchun, China E-mail: [email protected] Background: Interleukin-33 (IL-33) is a novel multifunctional IL-1 family cytokine. IL-33 has been shown to drive the production of pro-inflammatory cytokines, Th2-associated cytokines, and chemokines in mast cells and NK cells. This study examined the changes of levels of peripheral IL-33 and Th1, Th2 cytokines could be associated with active immunity in patients with chronic hepatitis B and C. Methods: The levels of peripheral IL-33 and sST2 in 116 hepatitis C patients, 24 spontaneously resolved HCV patients, 33 Aimmuneactive (IA) CHB patients, and 20 healthy controls (HC) were detected by ELISA, and the concentrations of serum IL-2, IFN-g, TNF-a, IL-4, IL-6, IL-10 were detected by CBA, hepatitis C virus (HCV) loads, hepatitis B virus (HBV) loads, alanine aminotranferease (ALT), aspartate aminotransferase (AST), HBsAg, HBsAb, HBeAg and HBeAb in those patients were measured. The potential association of the cytokines with clinical measures was analyzed. Results: We found that the levels of serum IL-33 in CHC patients were significantly higher than that of SR-HCV and HC, but decreased after treatment with interferon for 12 weeks. More importantly, IL-33 were correlated with the concentrations of ALT and AST in CHC patients. The levels of sST2, as a decoy receptor of IL-33, were elevated in CHC and SR-CHC patients than HC, and no correlation was found between sST2 with IL-33. The concentrations of serum IFN-g and IL-6 in CHC patients were significantly lower than that of SR-HCV. It was found that the levels of serum IL-33 of CHB were significantly higher than that of HC, but decreased after treatment with adefovir dipivoxil for 12 weeks. The levels of serum sST2, as a decoy receptor of IL-33, were significantly higher in CHB patients than that in HC, and there was no correlation between the levels of serum sST2 and IL-33. Conclusions: These data indicate that IL-33 may participate in the HBV/HCV related immune responses and IL-33 may have important roles as markers of both infammation and hepatic injury in the course of hepatitis B and C. 790 HIGH FREQUENCY OF CD4+ CXCR5+ TFH CELLS IN PATIENTS WITH IMMUNE-ACTIVE CHRONIC HEPATITIS B AND CHRONIC HEPATITIS C X. Sun, P. Zhao, J. Tai, J. Feng, J. Wang, J. Niu, Y. Jiang. First Hospital, Jilin University, Changchun, China E-mail: [email protected] Background: T follicular helper (TFH) cells are a special subpopulation of T helper cells and can regulate humoral immune responses. This study examined whether the frequency of peripheral CD4+ CXCR5+ TFH cells could be associated with HBV and HCV. Methods: The percentage of peripheral blood TFH cells in 23 immune-active (IA), 13 immune-tolerant (IT) CHB patients, 39 HCV, 12 spontaneously resolved HCV (SR-HCV) patients, and 12 healthy controls (HC) were characterized by flow cytometry analysis. Their serum HCV RNA, HBV, ALT and AST concentrations were measured. The potential association of the percentage of peripheral TFH cells with clinical measures was analyzed. In addition, the TFH cells in HBV-transgenic mice was examined. Results: We found that the frequency of TFH in IA patients, SRHCV and HCV patients were significantly higher than that of IT patients and HC. Furthermore, the percentages of ICOS+ , PD-1+ , and ICOS+ PD-1+ in CD4+ CXCR5+ TFH cells in CHB patients were significantly higher than that of HC. In addition, treatment with
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POSTERS adefovir dipivoxil for 12 weeks reduced the frequency of PD-1+ TFH cells and the concentrations of serum HBeAg and HBeAg, but increased the concentrations of serum HBeAb, HBeAb, IL-2 and IFN-g in IA patients. Interestingly, a statistically significant negative correlation was found between the proportion of TFH cells and HCV RNA, but not with serum ALT and AST. Moreover, the frequency of splenic and liver TFH cells in HBV-transgenic mice was significantly higher than that of wild-type controls. Conclusions: These data indicate that TFH cells may participate in the HBV and HCV-related immune responses and that high frequency of TFH cells may be a biomarker for the evaluation of active immune stage of CHB patients. The humoral immune response stimulation by TFH could also take place in HCV, which is conducive to the treatment and prognosis of the disease. 791 RIBAVIRIN EXERTS DIFFERENTIAL EFFECTS ON FUNCTIONS OF CD4+ TH1, TH2, AND REGULATORY T CELL CLONES IN HEPATITIS C B. Langhans, I. Braunschweiger, S. Arndt, T. Sauerbruch, U. Spengler. Department of Internal Medicine I, University of Bonn, Bonn, Germany E-mail: [email protected] Background: Ribavirin improves outcomes of therapy in chronic hepatitis C but its mode of action has still remained unclear. Since ribavirin has been proposed to modulate the host’s T cell responses, we studied its direct effects on CD4+ T cell clones with diverse functional polarization which had been generated from patients with chronic hepatitis C. Methods: We analysed in vitro proliferation ([3 H] thymidine uptake) and cytokine responses (IL-10, IFN-gamma) at varying concentrations of ribavirin (0–10 mg/ml) in 8, 9 and 7 CD4+ TH1, TH2 and regulatory T cell (Treg) clones, respectively. In coculture experiments, we further determined effects of ribarivin on inhibition of TH1 and TH2 clones by Treg clones. All clones had been generated from peripheral blood of patients with chronic hepatitis C in the presence of HCV core protein. Results: Ribavirin had only moderate effects on proliferation and IL-10 release in TH2 clones. Conversely, ribavirin significantly enhanced proliferation (p < 0.001) and IFN-gamma secretion (p = 0.004) in the TH1 clones. In addition, it dose-dependently inhibited IL-10 release in the Treg clones. Treg clones suppressed proliferation of TH1 and TH2 clones via their IL-10 secretion. Finally, Treg-mediated suppression of TH1 and TH2 cells was reversed in the presence of ribavirin. Conclusions: Our in vitro data suggest that ribavirin affects the T cell balance by two distinct mechanisms: Ribavirin directly enhances functions of TH1 cells, and also reverses Treg-mediated inhibition of T effector cells by inhibiting IL-10 release of HCVspecificTregs. 792 HBV-HCV COINFECTION: A NOVEL MODEL SYSTEM REVEALS INSIGHTS INTO IMMUNOLOGICAL MECHANISMS OF VIRAL INTERFERENCE C. Lass1 , C. Prag ¨ 1 , D. Grimm1 , J. Gouttenoire2 , V. Lohmann3 , J. Kock ¨ 1 , M. Nassal1 , H.E. Blum1 , R. Bartenschlager3 , D. Moradpour2 , R. Thimme1 , V. Brass1 . 1 Department of Medicine II, University of Freiburg, Freiburg im Breisgau, Germany; 2 Division of Gastroenterology and Hepatology, University of Lausanne, Lausanne, Switzerland; 3 Department of Molecular Virology, University of Heidelberg, Heidelberg, Germany E-mail: [email protected] Introduction: Coinfection with HBV and HCV leads to more frequent and rapid disease progression. Furthermore, clinical observations suggest a viral interference, with reciprocal viral suppression. Previous studies using a novel model system of HBV-HCV coinfection revealed a lack of direct viral interference. S310
Therefore, the aim of this study was to further develop this system and to investigate the role of T cell-mediated immune responses in viral interference. Methods and Results: We successfully established Huh7-derived cell lines allowing the tightly regulated replication of HBV and the constitutive expression of functional HLA-A2. These cells were recognized by HBV-specific T cells. When mixed with Huh-7 cells containing an HCV replicon, HCV RNA replication was inhibited by HBV-specific T cell responses. By contrast, HCVspecific T cell responses efficiently inhibiting HCV RNA replication did not suppress HBV replication under the same co-culture conditions. Interestingly however, HCV-specific T cells inhibited HBV replication when HBV and HCV epitopes are presented by the same cell, likely by a cytotoxic effect, as indicated by increased AST levels in culture supernatants. Conclusions: Non-cytolytic and cytolytic T cell-mediated immune responses likely contribute to viral interference during HBVHCV coinfection. Our observations yield new insights into the pathogenesis of HBV-HCV coinfection and may contribute to current efforts aimed at better managing this challenging clinical condition. 793 KUPFFER CELL DERIVED INTERLEUKIN (IL)-18 INDUCES HEPATIC INFLAMMATION BY PROMOTING LYMPHOCYTE SUBSETS RECRUITMENT ON HEPATIC ENDOTHELIAL CELLS E. Liaskou1 , D.R. Withers2 , E.H. Humphreys1 , J.C. Shaw1 , L. Tuohey1 , D.H. Adams1 , Y.H. Oo1 . 1 Centre for Liver Research & NIHR BRU, 2 Immunity and Infection, University of Birmingham, Birmingham, UK E-mail: [email protected] Background/aims: IL-18, known as interferon-g inducing factor, is a potent pro-inflammatory cytokine implicated in liver allograft rejection, viral hepatitis and hepatocellular carcinoma progression, where it plays an important role in cell-mediated immune responses and inflammatory injury. In this study, we investigated the expression and cellular regulation of IL-18 secretion in the human liver and demonstrated a role in regulating T cell recruitment to the liver. Methods: IL-18 mRNA expression levels were measured in normal and diseased human livers using QRT-PCR and tissue localization assessed by immunohistochemistry and confocal microscopy. Human hepatic sinusoidal endothelial cells were treated with Il-18 in vitro and flow cytometry used to assess induction of adhesion molecules. The functional significance of these responses to IL-18 was investigated in flow based adhesion assays using IL-18 treated HSEC and CD4 and CD8 T cell subsets under physiological flow. Results: IL-18 mRNA expression was significantly higher in liver tissue form patients with ALD (19-fold), PBC (7.6 fold) and seronegative hepatitis (30.6 fold) (p < 0.05) compared with normal liver. IL-18 protein expression was restricted to hepatic sinusoids where it colocalized with CD68+ Kupffer cells, whereas CD31+ endothelial cells were IL-18− . HSEC stimulated with IL-18 lead upregulation of cell adhesion molecules ICAM-1 and VCAM-1 which translated into a 2.5 fold increase in their functional ability to recruit CD4 and CD8 T cells in flow-based adhesion assays. Total adhesion of CD4 and CD8 T cells was significantly (p < 0.05) reduced when ICAM-1, VCAM-1, and CXCR3 molecules were blocked or if G protein coupled receptors were inhibited with pertussis toxin (PTX). CD8T cell adhesion was also dependent on vascular adhesion protein-1. Conclusion: We report high IL-18 expression by kupffer cells in inflammatory liver disease. The ability of IL-18 to enhance T cell recruitment via sinusoidal endothelium suggests it acts to promote lymphocyte recruitment during the development of chronic hepatitis and is thus a novel therapeutic target in inflammatory liver disease.
Journal of Hepatology 2012 vol. 56 | S225–S388
789 SERUM IL-33 LEVELS ARE ASSOCIATED WITH LIVER DAMAGE IN PATIENTS WITH CHRONIC HEPATITIS B AND C L. Wang, P. Zhao, J. Wang, J. Feng, J. Niu, Y. Jiang. First Hospital, Jilin University, Changchun, China E-mail: [email protected] Background: Interleukin-33 (IL-33) is a novel multifunctional IL-1 family cytokine. IL-33 has been shown to drive the production of pro-inflammatory cytokines, Th2-associated cytokines, and chemokines in mast cells and NK cells. This study examined the changes of levels of peripheral IL-33 and Th1, Th2 cytokines could be associated with active immunity in patients with chronic hepatitis B and C. Methods: The levels of peripheral IL-33 and sST2 in 116 hepatitis C patients, 24 spontaneously resolved HCV patients, 33 Aimmuneactive (IA) CHB patients, and 20 healthy controls (HC) were detected by ELISA, and the concentrations of serum IL-2, IFN-g, TNF-a, IL-4, IL-6, IL-10 were detected by CBA, hepatitis C virus (HCV) loads, hepatitis B virus (HBV) loads, alanine aminotranferease (ALT), aspartate aminotransferase (AST), HBsAg, HBsAb, HBeAg and HBeAb in those patients were measured. The potential association of the cytokines with clinical measures was analyzed. Results: We found that the levels of serum IL-33 in CHC patients were significantly higher than that of SR-HCV and HC, but decreased after treatment with interferon for 12 weeks. More importantly, IL-33 were correlated with the concentrations of ALT and AST in CHC patients. The levels of sST2, as a decoy receptor of IL-33, were elevated in CHC and SR-CHC patients than HC, and no correlation was found between sST2 with IL-33. The concentrations of serum IFN-g and IL-6 in CHC patients were significantly lower than that of SR-HCV. It was found that the levels of serum IL-33 of CHB were significantly higher than that of HC, but decreased after treatment with adefovir dipivoxil for 12 weeks. The levels of serum sST2, as a decoy receptor of IL-33, were significantly higher in CHB patients than that in HC, and there was no correlation between the levels of serum sST2 and IL-33. Conclusions: These data indicate that IL-33 may participate in the HBV/HCV related immune responses and IL-33 may have important roles as markers of both infammation and hepatic injury in the course of hepatitis B and C. 790 HIGH FREQUENCY OF CD4+ CXCR5+ TFH CELLS IN PATIENTS WITH IMMUNE-ACTIVE CHRONIC HEPATITIS B AND CHRONIC HEPATITIS C X. Sun, P. Zhao, J. Tai, J. Feng, J. Wang, J. Niu, Y. Jiang. First Hospital, Jilin University, Changchun, China E-mail: [email protected] Background: T follicular helper (TFH) cells are a special subpopulation of T helper cells and can regulate humoral immune responses. This study examined whether the frequency of peripheral CD4+ CXCR5+ TFH cells could be associated with HBV and HCV. Methods: The percentage of peripheral blood TFH cells in 23 immune-active (IA), 13 immune-tolerant (IT) CHB patients, 39 HCV, 12 spontaneously resolved HCV (SR-HCV) patients, and 12 healthy controls (HC) were characterized by flow cytometry analysis. Their serum HCV RNA, HBV, ALT and AST concentrations were measured. The potential association of the percentage of peripheral TFH cells with clinical measures was analyzed. In addition, the TFH cells in HBV-transgenic mice was examined. Results: We found that the frequency of TFH in IA patients, SRHCV and HCV patients were significantly higher than that of IT patients and HC. Furthermore, the percentages of ICOS+ , PD-1+ , and ICOS+ PD-1+ in CD4+ CXCR5+ TFH cells in CHB patients were significantly higher than that of HC. In addition, treatment with
Journal of Hepatology 2012 vol. 56 | S225–S388
S309
POSTERS adefovir dipivoxil for 12 weeks reduced the frequency of PD-1+ TFH cells and the concentrations of serum HBeAg and HBeAg, but increased the concentrations of serum HBeAb, HBeAb, IL-2 and IFN-g in IA patients. Interestingly, a statistically significant negative correlation was found between the proportion of TFH cells and HCV RNA, but not with serum ALT and AST. Moreover, the frequency of splenic and liver TFH cells in HBV-transgenic mice was significantly higher than that of wild-type controls. Conclusions: These data indicate that TFH cells may participate in the HBV and HCV-related immune responses and that high frequency of TFH cells may be a biomarker for the evaluation of active immune stage of CHB patients. The humoral immune response stimulation by TFH could also take place in HCV, which is conducive to the treatment and prognosis of the disease. 791 RIBAVIRIN EXERTS DIFFERENTIAL EFFECTS ON FUNCTIONS OF CD4+ TH1, TH2, AND REGULATORY T CELL CLONES IN HEPATITIS C B. Langhans, I. Braunschweiger, S. Arndt, T. Sauerbruch, U. Spengler. Department of Internal Medicine I, University of Bonn, Bonn, Germany E-mail: [email protected] Background: Ribavirin improves outcomes of therapy in chronic hepatitis C but its mode of action has still remained unclear. Since ribavirin has been proposed to modulate the host’s T cell responses, we studied its direct effects on CD4+ T cell clones with diverse functional polarization which had been generated from patients with chronic hepatitis C. Methods: We analysed in vitro proliferation ([3 H] thymidine uptake) and cytokine responses (IL-10, IFN-gamma) at varying concentrations of ribavirin (0–10 mg/ml) in 8, 9 and 7 CD4+ TH1, TH2 and regulatory T cell (Treg) clones, respectively. In coculture experiments, we further determined effects of ribarivin on inhibition of TH1 and TH2 clones by Treg clones. All clones had been generated from peripheral blood of patients with chronic hepatitis C in the presence of HCV core protein. Results: Ribavirin had only moderate effects on proliferation and IL-10 release in TH2 clones. Conversely, ribavirin significantly enhanced proliferation (p < 0.001) and IFN-gamma secretion (p = 0.004) in the TH1 clones. In addition, it dose-dependently inhibited IL-10 release in the Treg clones. Treg clones suppressed proliferation of TH1 and TH2 clones via their IL-10 secretion. Finally, Treg-mediated suppression of TH1 and TH2 cells was reversed in the presence of ribavirin. Conclusions: Our in vitro data suggest that ribavirin affects the T cell balance by two distinct mechanisms: Ribavirin directly enhances functions of TH1 cells, and also reverses Treg-mediated inhibition of T effector cells by inhibiting IL-10 release of HCVspecificTregs. 792 HBV-HCV COINFECTION: A NOVEL MODEL SYSTEM REVEALS INSIGHTS INTO IMMUNOLOGICAL MECHANISMS OF VIRAL INTERFERENCE C. Lass1 , C. Prag ¨ 1 , D. Grimm1 , J. Gouttenoire2 , V. Lohmann3 , J. Kock ¨ 1 , M. Nassal1 , H.E. Blum1 , R. Bartenschlager3 , D. Moradpour2 , R. Thimme1 , V. Brass1 . 1 Department of Medicine II, University of Freiburg, Freiburg im Breisgau, Germany; 2 Division of Gastroenterology and Hepatology, University of Lausanne, Lausanne, Switzerland; 3 Department of Molecular Virology, University of Heidelberg, Heidelberg, Germany E-mail: [email protected] Introduction: Coinfection with HBV and HCV leads to more frequent and rapid disease progression. Furthermore, clinical observations suggest a viral interference, with reciprocal viral suppression. Previous studies using a novel model system of HBV-HCV coinfection revealed a lack of direct viral interference. S310
Therefore, the aim of this study was to further develop this system and to investigate the role of T cell-mediated immune responses in viral interference. Methods and Results: We successfully established Huh7-derived cell lines allowing the tightly regulated replication of HBV and the constitutive expression of functional HLA-A2. These cells were recognized by HBV-specific T cells. When mixed with Huh-7 cells containing an HCV replicon, HCV RNA replication was inhibited by HBV-specific T cell responses. By contrast, HCVspecific T cell responses efficiently inhibiting HCV RNA replication did not suppress HBV replication under the same co-culture conditions. Interestingly however, HCV-specific T cells inhibited HBV replication when HBV and HCV epitopes are presented by the same cell, likely by a cytotoxic effect, as indicated by increased AST levels in culture supernatants. Conclusions: Non-cytolytic and cytolytic T cell-mediated immune responses likely contribute to viral interference during HBVHCV coinfection. Our observations yield new insights into the pathogenesis of HBV-HCV coinfection and may contribute to current efforts aimed at better managing this challenging clinical condition. 793 KUPFFER CELL DERIVED INTERLEUKIN (IL)-18 INDUCES HEPATIC INFLAMMATION BY PROMOTING LYMPHOCYTE SUBSETS RECRUITMENT ON HEPATIC ENDOTHELIAL CELLS E. Liaskou1 , D.R. Withers2 , E.H. Humphreys1 , J.C. Shaw1 , L. Tuohey1 , D.H. Adams1 , Y.H. Oo1 . 1 Centre for Liver Research & NIHR BRU, 2 Immunity and Infection, University of Birmingham, Birmingham, UK E-mail: [email protected] Background/aims: IL-18, known as interferon-g inducing factor, is a potent pro-inflammatory cytokine implicated in liver allograft rejection, viral hepatitis and hepatocellular carcinoma progression, where it plays an important role in cell-mediated immune responses and inflammatory injury. In this study, we investigated the expression and cellular regulation of IL-18 secretion in the human liver and demonstrated a role in regulating T cell recruitment to the liver. Methods: IL-18 mRNA expression levels were measured in normal and diseased human livers using QRT-PCR and tissue localization assessed by immunohistochemistry and confocal microscopy. Human hepatic sinusoidal endothelial cells were treated with Il-18 in vitro and flow cytometry used to assess induction of adhesion molecules. The functional significance of these responses to IL-18 was investigated in flow based adhesion assays using IL-18 treated HSEC and CD4 and CD8 T cell subsets under physiological flow. Results: IL-18 mRNA expression was significantly higher in liver tissue form patients with ALD (19-fold), PBC (7.6 fold) and seronegative hepatitis (30.6 fold) (p < 0.05) compared with normal liver. IL-18 protein expression was restricted to hepatic sinusoids where it colocalized with CD68+ Kupffer cells, whereas CD31+ endothelial cells were IL-18− . HSEC stimulated with IL-18 lead upregulation of cell adhesion molecules ICAM-1 and VCAM-1 which translated into a 2.5 fold increase in their functional ability to recruit CD4 and CD8 T cells in flow-based adhesion assays. Total adhesion of CD4 and CD8 T cells was significantly (p < 0.05) reduced when ICAM-1, VCAM-1, and CXCR3 molecules were blocked or if G protein coupled receptors were inhibited with pertussis toxin (PTX). CD8T cell adhesion was also dependent on vascular adhesion protein-1. Conclusion: We report high IL-18 expression by kupffer cells in inflammatory liver disease. The ability of IL-18 to enhance T cell recruitment via sinusoidal endothelium suggests it acts to promote lymphocyte recruitment during the development of chronic hepatitis and is thus a novel therapeutic target in inflammatory liver disease.
Journal of Hepatology 2012 vol. 56 | S225–S388