768 differences in ip-10 levels between patients with chronic hbv and hcv infectionstaining might be a useful additional criterion to predict likelihoodof post-transplant tumor recurrence.
05. LIVER IMMUNOLOGY
INCLUDING VIRAL HEPATITIS
ASSOCIATION BETWEEN THE PSC SUSCEPTIBILITY VARIANT
IN THE MST1 LOCUS AND CHOLANGIOCARCINOMA RISK:
CASE-CONTROL ANALYSIS OF A LARGE EUROPEAN COHORT
M. Krawczyk1, A. H ¨oblinger2, F. Mihalache3, M. Acalovschi3,
F. Lammert1, V. Zimmer1. 1Department of Medicine II, Saarland DO THE INITIAL SERUM LEVEL CHANGES OF SCD26 HAVE
University Medical Center, Homburg, 2Department of Medicine I, ABILITY TO PREDICT SUCCESSFUL TREATMENT WITH IFN-ALPHA
University Hospital Bonn, Bonn, Germany; 3Department of Medicine AMONG NAIVE CHRONIC HEPATITIS B PATIENTS?
III, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, M. Alavi-Moghaddam1, S.M. Alavian2, S.H. Aalaei-Andabili2.
1 Research Institute of Gastroenterology and Liver Diseases, Shahid Beheshti University M.C., 2Research Center for Gastroenterology andLiver Disease (BRCGL), Baqiyatallah University of Medical Sciences, Background: Individuals with primary sclerosing cholangitis (PSC)
Tehran, Iran are at an increased cholangiocellular carcinoma (CCA) risk. Lately, the single nucleotide variant (SNV) rs3197999 in the gene encodingmacrophage stimulating 1 (MST1), a potent tumor suppressor Introduction: Hepatitis B is a major health problem with serious
, has been linked to PSC . Here we aim to test this MST1 consequences. In hepatitis B treatment host cellular immune polymorphism as genetic determinant of CCA in a large cohort of responses have a determinant role and T helper cells are the main European patients.
active members of immune system against virological infection.
Patients and Methods: We genotyped 226 patients with diagnosed
The aims of this study are to investigate response rate of patients CCA (126 males, age 28–90 years; PSC prevalence <2%) from to INF-Alpha therapy and evaluation of sCD26 and sCD30 roles as Germany (n = 170) and Romania (n = 56). The control group presenters of T cellls activities in predicting the outcome of therapy consisted of 359 CCA-free individuals (160 males, age 22–90 years).
in chronic hepatitis B patients.
The MST1 SNV rs3197999 was genotyped using a PCR-based assay Methods and Materials: Fifty three chronic hepatitis B patients
with 5-nuclease and ﬂuorescence detection. Consistency with received IFN-9 MU S.C three times weekly for 24 weeks, and were Hardy-Weinberg equilibrium (HWE) was checked by exact tests; followed up for 24 weeks. Serum levels of sCD26 and sCD30, before, associations were tested in contingency tables (alleles: chi2 tests; 1 and 3 months after treatment commencement were evaluated in genotypes: Armitrage's trend test) and regression analyses.
53 chronic hepatitis B patients and 30 healthy individuals as control Results: The cases (P = 0.04), but not controls (P > 0.05) deviated
from HWE, providing a hint for a possible association between the Results: Normal level of ALT was seen in 64.1% (34/53) of patients
SNV and CCA. A trend for a higher frequency of the [G] allele in cases and undetectable DNA was observed in 39.6% (21 out of 53) of (31% vs. 26%, P = 0.09) was detected. Carriers of the [GG] genotype them. Finally, 33.9% (18/53) of patients obtained sustain virological were at higher CCA risk as compared to [AA] individuals (OR = 1.95, response. CD26 levels changes was correlated with response 95% CI 1.08–3.52, P = 0.02). In the whole cohort, gender (OR = 1.53, to treatment and signiﬁcantly (p < 0.001) increased during ﬁrst 95% CI 1.10–2.14, P = 0.12) and age (P = 0.03) were associated with 3 months of treatment among patients with successful response CCA development. In a multivariate model, including solely carriers of the genotypes [GG] and [AA], gender (OR = 1.59, 95% CI 1.04– Conclusion: Interferon is an effective and safe treatment for chronic
2.45, P = 0.03) and the [GG] genotype (OR = 1.95, 95% CI 1.07–3.56, hepatitis B patients and sCD26 serum level changes might be useful P = 0.03) proved to be independent risk factors for CCA.
in predicting the outcome of therapy in naïve chronic hepatitis B Conclusions: The previously indentiﬁed PSC risk variant of the
patients undergoing treatment with IFN-, as it can help clinicians MST1 tumor suppressor gene involved in the Hippo signalling for withdrawing non-responder patients for prevention of adverse cascade increases the odds of developing CCA. This variant may events and economical burden.
increase the CCA risk irrespective of PSC status.
DIFFERENCES IN IP-10 LEVELS BETWEEN PATIENTS WITH
 Avruch J, et al. Br J Cancer 2010.
CHRONIC HBV AND HCV INFECTION
 Melum E, et al. Nat Genet 2011.
K. Antonov, A. Ivanova, D. Jelev, Z. Krastev. Clinic of Gastroenterology,University Hospital ‘St. Ivan Rilski', Soﬁa, BulgariaE-mail: [email protected] Introduction: The level of IP-10 in patients with chronic HCV
infection was shown as predictor of viral response. It wasn't known
about patients with chronic HBV infection. There were data for
connection between of IP-10 levels with liver disease and HCV RNA
levels but it was little known about IP-10 levels and chronic HBV
Aim: Of the study was to compare IP-10 levels in patients with
chronic HBV and HCV infection and their connection with viral
replication, liver disease and viral response on treatment.
Material and Methods: 17 patients with chronic HCV infection and
14 with chronic HBV infection were involved in the study. In all
patients liver biopsies, measuring of viral load and IP-10 were done.
The HCV genotype 1 was proved in all patients with hepatitis C.
HBeAg was positive in 5 patients with hepatitis B. Treatment with
PEG-IFN a and Ribavirin was initiated in patients with chronic HCV
infection and Tenofovir in patients with chronic HBV infection.
Journal of Hepatology 2012 vol. 56 S225–S388
ELISA test Quantikine® was used for quantiﬁcation of IP-10. HBV DNA and HCV RNA were measured by real-time PCR.
THE HCV NS3/4A-MEDIATED IMPAIRMENT OF THE HEPATIC
Results: The levels of IP-10 were signiﬁcant lower in patients with
ANTIVIRAL IMMUNE RESPONSE IS REVERSED BY PROTEASE
HBV infection than in HCV infected patients (p 0.044). It was INHIBITION OR RIBAVIRIN IN VIVO
found correlation between base IP-10 levels and HBV DNA (r 0.635; E.D. Brennd ¨orfer1, A. Brass1, J. S ¨oderholm2, L. Frelin1, J.G. Bode3, p 0.015). There was connection between IP-10 and HCV RNA only M. S ¨allberg1. 1Department of Laboratory Medicine, Division of in patients without viral response (r 0.925; p 0.024). The levels Clinical Microbiology, Karolinska Institutet, Stockholm, 2Department of of IP-10 did not correlate with sex, age, ALT, histology activity Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, and liver ﬁbrosis in both groups of patients. There was connection Gothenburg, Sweden; 3Department of Gastroenterology, Hepatology between basal IP-10 levels and virological response – rapid and and Infectiology, University Hospital, Heinrich-Heine-University of early (r −0.611; p 0.009), in patients with chronic HCV infection, usseldorf, D¨ but not in HBV infected patients.
Conclusion: The patients with chronic HBV infection had lower
Background: Hepatitis C virus (HCV) has evolved mechanisms to
plasma levels of IP-10 than those with HCV infection. The IP- evade elimination by both innate and adaptive immunity resulting 10 levels correlated with HBV replication and with HCV RNA in in HCV persistence. The HCV NS3/4A protease/helicase is known to special group of patients. IP-10 could predict virological response modulate signaling pathways in the infected hepatocyte by cleaving in patients with chronic HCV infection on treatment with PEG-IFN MAVS, TC-PTP and TRIF. However, the global effects exerted by a and Ribavirin but not in HBV infected patients on nucleotide NS3/4A in vivo still remain unclear. This is currently of a particular analogs therapy.
interest since new antiviral therapies are being introduced basedon inhibitors blocking the NS3/4A protease. Thus, these therapies may exert effects beyond the viral replication.
IMPAIRED T-CELL GLUCOSE METABOLISM DURING CHRONIC
Objectives: We aimed to understand how NS3/4A affects
HEPATITIS C VIRUS INFECTION
intercellular signaling and immune cell function in vivo and to B. Baharuddin, A. Zekry, D. Simar, C. Palmer, A. Lloyd. Inﬂammation study the effects of ribavirin or NS3/4A protease inhibition on the and Infection Research Centre, University of New South Wales, NS3/4A-mediated modulation of the host's immune system.
Randwick, NSW, Australia Methods: The intrahepatic immune response of naive and
lipopolysaccharide (LPS)/D-galactosamine (D-galN) treated NS3/4A- Background and Aims: A powerful and sustained T-cell immune
transgenic (Tg) mice was determined by western blot, ELISA, Real response is dependent on glucose metabolism within the T-cell Time PCR, Flow cytometry, ALT levels, and survival. Ribavirin itself, essential for the provision of energy to sustain and maintain pretreatment or NS3/4A protease inhibition was performed to T-cell function, so called, fuel for energy. In chronic hepatitis C (CHC) analyze the inﬂuence of antivirals on the NS3/4A-mediated effects.
infection, the immune response is a key determinant to outcome to Results: Hepatic IL10 expression is enhanced in NS3/4A-Tg mice
antiviral therapy. The aims of this study are to determine alterations both basally and after LPS/D-galN treatment, while IFNg secretion in glucose metabolism in T-cells in HCV infected patients and its is impaired. Furthermore, the chemokine proﬁle (CCL2, CCL17, effect on the immune response.
CXCL9) is altered towards an anti-inﬂammatory state. As result, Methods: Longitudinal peripheral blood mononuclear cells (PBMCs)
the intrahepatic number of Th1 cells as well as IFNg-positive CD4+ from patients with CHC were examined at baseline – prior to and CD8+ T cells in NS3/4A-Tg mice is decreased, while the amount antiviral therapy (n = 25), at week 12 during treatment (n = 10) and of Th2 cells is increased. Interestingly, the NS3/4A-mediated effects 6 months post end-treatment (n = 10). As a control group, PBMCs could be reversed by both ribavirin treatment and inhibition of from 8 healthy controls and 6 subjects with non-alcoholic fatty the NS3/4A protease. This is of particular importance since recent liver disease (NAFLD) were also examined. PBMCs from subjects are clinical trials suggest that ribavirin is essential for a functional stimulated with CD3/CD28 Dyanbeads for 24 hrs. Flow cytometry therapy with only directly acting antiviral (DAAs) compounds.
was used to measure speciﬁc metabolic markers such as pAKT Conclusions: NS3/4A induces a shift of the intrahepatic immune
(a key molecule in glucose transport and metabolism) and glucose response towards a non-antiviral Th2-dominated immunity. This uptake (2-NBDG) in T-cells (CD4/CD8), while CD8 cytolytic function may impair the host response to the infection and promote was assessed by examining granzyme B.
viral persistence. Importantly, both ribavirin treatment and the Results: Compared to healthy subjects and NAFLD, CD8 T-cells
inhibition of the NS3/4A protease can block the effects mediated from patients with CHC had signiﬁcantly reduced expression of pAKT (p = 0.0001 and p = 0.02 respectively) and exhibited lessglucose uptake (p = 0.0001 and p = 0.007 respectively). At baseline, compared to healthy controls there was reduced CD8 T-cell cytolytic TLR3-DEPENDENT IMMUNOLOGICAL PROPERTIES OF LIVER
function (p = 0.04) and this correlated with reduced glucose uptake CELLS ARE CONTROLLED BY ANTI-INFLAMMATORY CYTOKINES
(p = 0.02). After viral clearance with antiviral therapy, pAKT and THROUGH MODULATION OF MIR-155 EXPRESSION
glucose uptake recovered to levels comparable to those of healthy M. Jiang1, M. Trippler1, R. Broering1, J. Wu1, E. Zhang2, X. Zhang2, G. Gerken1, M. Lu2, J.F. Schlaak1. 1Department of Gastroenterology Conclusion: In patients with CHC, there is impaired T-cell glucose
and Hepatology, University Hospital of Essen, 2Institute of Virology, metabolism as assessed by pAKT and glucose uptake. Reduction in University Hospital of Essen, Essen, Germany glucose uptake in particular correlated with reduced CD8 cytolytic function. Clearance of HCV with antiviral therapy restores pAKTand glucose uptake to normal levels, indicating a viral medicated Background and Aims: The hepatitis C virus (HCV) can establish
impairment of T-cell glucose metabolism.
a persistent infection despite a strong activation of the innate
immune system through TLR3 and other sensors, the so-called "IFN-
paradox". We analyzed regulatory mechanisms of TLR3-mediated
immune responses in human liver and in murine non-parenchymal
liver cells (NPC).
Methods: Hepatic expression of Interleukin 10 (IL-10) and
transforming growth factor beta (TGF-b) in biopsies of HCV patients
Journal of Hepatology 2012 vol. 56 S225–S388
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