Integrating the Patient Perspective to Validate a Measure of Disease Severity in Inflammatory Bowel Disease: Online Survey of Patients and Their Physicians.

BACKGROUND: The patient perspective is essential for assessing disease severity, but it is not always adequately considered. We describe how a comprehensive clinical disease severity index (DSI) for inflammatory bowel disease (IBD) correlates with patient global self-assessment (PGSA). METHODS: In an individually linked parallel online survey, physicians provided the DSI, and patients provided self-assessed severity using a global question and visual analog scale (0-100) (PGSA). Mean DSI values by PGSA were calculated with 95% confidence intervals. Pearson correlation (r) and the intraclass correlation coefficient were calculated for PGSA vs DSI. Positive predictive values for identifying severe disease with PGSA categories as a reference were based on a threshold >22 points. RESULTS: The primary analysis included 89 pairs (46 Crohn's disease [CD], 43 ulcerative colitis [UC]) with strict criteria and 147 pairs when less stringent. Common reasons for exclusion were missing values for albumin or colonoscopy. Mean DSI values showed no clear trend with increasing PGSA in CD but good discrimination between moderate, severe, and very severe PGSA in UC. For PGSA on the visual analog scale, r was 0.54 for CD and 0.59 for UC (difference in means: CD 27.7, UC 13.8; intraclass correlation coefficient: CD 0.48, UC 0.58). A high DSI predicted severe disease in 76.2% of CD and 65.2% of UC. CONCLUSIONS: The DSI showed good discrimination for patient-reported disease severity in UC but performed unsatisfactorily in CD. Correlations were moderate. Further refinement of the DSI is suggested to better reflect the patient perspective.

The performance of an inflammatory bowel disease severity score was compared with self-perceived severity based on an individually linked online survey of patients and their physicians. Agreement and prediction of severe disease were moderate and should be improved by integrating the patients' perspective.

German guideline diverticular disease/diverticulitis: Part II: Conservative, interventional and surgical management.

Diverticulosis and diverticular disease are ranked among the most common gastroenterological diseases and conditions. While for many years diverticulitis was found to be mainly an event occurring in the elder population, more recent work in epidemiology demonstrates increasing frequency in younger subjects. In addition, there is a noticeable trend towards more complicated disease. This may explain the significant increase in hospitalisations observed in recent years. It is not a surprise that the number of scientific studies addressing the clinical and socioeconomic consequences in the field is increasing. As a result, diagnosis and conservative as well as surgical management have changed in recent years. Diverticulosis, diverticular disease and diverticulitis are a complex entity and apparently an interdisciplinary challenge. To meet theses considerations the German Societies for Gastroenterology and Visceral Surgery decided to create joint guidelines addressing all aspects in a truely interdisciplinary fashion. The aim of the guideline is to summarise and to evaluate the current state of knowledge on diverticulosis and diverticular disease and to develop statements as well as recommendations to all physicians involved in the management of patients with diverticular disease.

German guideline diverticular disease/diverticulitis: Part I: Methods, pathogenesis, epidemiology, clinical characteristics (definitions), natural course, diagnosis and classification.

Diverticulosis and diverticular disease are ranked among the most common gastroenterological diseases and conditions. While for many years diverticulitis was found to be mainly an event occurring in the elder population, more recent work in epidemiology demonstrates increasing frequency in younger subjects. In addition, there is a noticeable trend towards more complicated disease. This may explain the significant increase in hospitalisations observed in recent years. It is not a surprise that the number of scientific studies addressing the clinical and socioeconomic consequences in the field is increasing. As a result, diagnosis and conservative as well as surgical management have changed in recent years. Diverticulosis, diverticular disease and diverticulitis are a complex entity and apparently an interdisciplinary challenge. To meet theses considerations the German Societies for Gastroenterology and Visceral Surgery decided to create joint guidelines addressing all aspects in a truely interdisciplinary fashion. The aim of the guideline is to summarise and to evaluate the current state of knowledge on diverticulosis and diverticular disease and to develop statements as well as recommendations to all physicians involved in the management of patients with diverticular disease.

[The gastroenterology during the first and second wave of corona pandemic - two surveys by the working group of the guiding gastroenterologic clinicians (ALGK)]. / Die Gastroenterologie in der ersten und zweiten Corona-Welle ­ zwei Umfragen der Arbeitsgemeinschaft Leitender Gastroenterologischer Krankenhausärzte (ALGK).

BACKGROUND: An evaluation of the non-university hospitals in Germany with regard to the actual and follow-up working condition, alterations and perspectives during the Corona-crisis is missing. The working group of the guiding gastroenterologic clinicians (ALGK) comprises more than 70% of the head physicians of gastroenterological units leading to representative informations. METHODS: The ALGK conducted two surveys among its members in 2020 during the first and 2021 during the second Corona-wave. 369 members with correct email adresses were contacted. The first survey included 17 and the second survey 21 questions. RESULTS: 58 % of the respondent represented primary and standard care hospitals, 36 % secondary care hospitals, 6 % tertiary hospitals of maximum care, 43 % communal, 38 % confessional and 18 % private hospitals. 87 % of the respondent reported about cancellation of the hospital appointments by the patients (87 %/85 %). In the second survey, appointment cancellation by the physican (58 % vs. 84 %), reduction of emergency cases (16 % vs. 29 %), postponement of diagnostic or therapeutic appointments (85 % vs. 99 %) and reduction of programmed inpatient (65 vs. 91 %) or outpatient treatment (15 % vs. 84 %) were lesser compared to the first survey. Mean reduction of endoscopic procedures per unit were 337/month to 151/month (55 %) for diagnostic endoscopy, 174/month to 84/month (52 %) for therapeutic endoscopy and 56/month to 7/month (87,5 %) for prevention colonoscopy. The comparison between hospital operators revealed more reports on staff to be under quarantine, more very strong or strong feeling of psychological stress, more fear of corona-infection and more suspicion of ambulatory maintenance in gastroenterology in private hospitals. Willingness for vaccination was very high among physicians and nursing staff (92 %/89 %) and not different between the hospital operators. 38 % of the repsondent reported on the fear of existential risk of their hospital because of the Corona-crisis. CONCLUSION: The two ALGK surveys give a reprensentative picture of the situation of non-university gastroenterological units during Corona-pandemic in Germany.

German Guidelines.

Because of its frequency, diverticular disease is a burden on health care systems. Only few formal guidelines covering all aspects of the disease exist. Here, some selected statements from the German guidelines are given. The guidelines include significant recommendations for the diagnosis and management of diverticular disease. Both diagnosis and management depend definitely on clear definitions of the situation of an individual patient. Therefore, a new classification is proposed that is based on earlier suggestions. An internationally established classification would not only enable better patient care but could also lead to studies with comparable results.

White-Light or Narrow-Band Imaging Colonoscopy in Surveillance of Ulcerative Colitis: A Prospective Multicenter Study.

BACKGROUND & AIMS: Early detection of neoplastic lesions is essential in patients with long-standing ulcerative colitis but the best technique of colonoscopy still is controversial. METHODS: We performed a prospective multicenter study in patients with long-standing ulcerative colitis. Two colonoscopies were performed in each patient within 3 weeks to 3 months. In white-light (WL) colonoscopy, stepwise random biopsy specimens (4 biopsy specimens every 10 cm), segmental random biopsies (2 biopsy specimens in 5 segments), and targeted biopsy specimens were taken. In NBI colonoscopy, segmental and targeted biopsy specimens were taken. The sequence of WL and NBI colonoscopy was randomized. RESULTS: In 36 of 159 patients enrolled (22.6%), 54 lesions with intraepithelial neoplasia (IN) were found (51 low-grade, 3 high-grade). In WL colonoscopy we found 11 IN in stepwise biopsy specimens, 4 in segmental biopsy specimens, and 15 in targeted biopsy specimens. In NBI colonoscopy 7 IN were detected in segmental biopsy specimens and 24 IN were detected in targeted biopsy specimens. Almost all IN were found with one technique alone (κ value of WL vs NBI, -0.86; P < .001). Statistically equivalent numbers of IN were found in NBI colonoscopy with targeted and segmental biopsy specimens as in WL colonoscopy with targeted and stepwise biopsy specimens, but with fewer biopsy specimens (11.9 vs 38.6 biopsy specimens, respectively; P < .001), and less withdrawal time was necessary (23 vs 13 min, respectively; P < .001). CONCLUSIONS: Stepwise biopsy specimens are indispensable in WL colonoscopy. The combination of targeted and segmental biopsy specimens in the NBI technique is as sensitive as targeted together with stepwise biopsy specimens in WL colonoscopy, but requires fewer biopsy specimens and less time. The highest sensitivity should be reached by combining the WL and NBI techniques by switching between the modes.

Diverticular disease: guidelines of the german society for gastroenterology, digestive and metabolic diseases and the german society for general and visceral surgery.

BACKGROUND: Diverticular disease is one of the most common disorders of the gastrointestinal tract. 28-45% of the population develop colonic diverticula, while about 25% suffer symptoms and about 5% complications. AIM: To create formal guidelines for diagnosis and management. METHODS: Six working groups with 44 participants analyzed key questions in subject areas assigned to them. Following a systematic literature search, 451 publications were included. Consensus was obtained by agreement within the working groups, two Delphi processes and a guideline conference. RESULTS: Targeted management of diverticular disease requires a classificatory diagnosis. A new classification was created. In addition to the clinical examination, intestinal ultrasound or computed tomography is the determining factor. Interval colonoscopy is recommended to exclude comorbidities. A low-fiber diet, obesity, lack of exercise, smoking and immunosuppression have an adverse impact on diverticulosis. This can lead to diverticulitis. Antibiotics are no longer recommended in uncomplicated diverticulitis if no risk factors such as immunosuppression are present. If close monitoring is ensured, uncomplicated diverticulitis can be treated on an outpatient basis. Complicated diverticulitis should be treated in hospital, involving broad-spectrum antibiotic therapy, where necessary abscess drainage, and surgery, if possible laparoscopically. In the case of chronic relapsing diverticulitis, the risk of perforation decreases with each episode, so that surgery is no longer recommended after the second episode but only following individual assessment. CONCLUSIONS: New findings on diverticular disease call into question the overuse of antibiotics and excessive indications for surgery. Targeted treatment requires a precise diagnosis and intensive interdisciplinary cooperation.

Influence of the CXCL1 rs4074 A allele on alcohol induced cirrhosis and HCC in patients of European descent.

BACKGROUND AND AIMS: CXCL1 (CXC chemokine-ligand-1) is a ligand for CXC chemokine receptor 2 expressed on hepatic stellate cells (HSC). Thus, CXCL1 might contribute to HSC activation and fibrogenesis. In the present study, we investigated the influence of the CXCL1 rs4074 polymorphism on the occurrence of alcohol induced liver cirrhosis and hepatocellular carcinoma (HCC). METHODS: The study involved 458 patients with alcoholic cirrhosis (170 with HCC), 115 alcoholics without liver disease and 342 healthy controls. All subjects were genotyped for the CXCL1 rs4074 polymorphism and CXCL1 serum levels of 132 patients were measured. In vitro CXCL1 secretion in TLR-transfected cell lines were studied by ELISA. RESULTS: Distribution of the CXCL1 genotypes (GG/GA/AA) was 159/219/80 in patients with alcoholic cirrhosis, 52/44/19 in alcoholic controls and 158/140/44 in healthy controls. Patients with alcohol-induced cirrhosis were significantly more often carriers of the CXCL1 rs4074 A allele (65.3%) than alcoholics without liver disease (54.8%, OR=1.55; 95%CI=1.025-2.350; p=0.04) and healthy controls (53.8%, OR=1.62; 95%CI=1.212-2.151; p=0.001). Accordingly, the frequency of the CXCL1 rs4074 A allele was significantly higher in the cirrhotic patients than in the subjects without cirrhosis (41.4% vs. 33.9%, OR=1.38, 95% CI:1.14-1.66, p=0.001). Furthermore cirrhotic carriers of the CXCL1 rs4074 A allele had significantly higher CXCL1 serum levels than carriers of the GG genotype. In contrast to sera from healthy controls, sera from patients with alcoholic cirrhosis induced CXCL1 secretion in TLR2- (p=0.016) and TLR4- (p=0.008) transfected HEK293 cells. This finding indicates that sera from patients with alcoholic cirrhosis contain soluble ligands that can induce CXCL1 production via stimulation of TLRs. CONCLUSION: The enhanced CXCL1 serum levels in carriers of the rs4074 A allele together with their increased frequency in patients with alcohol induced cirrhosis suggest the CXCL1 rs4074 A allele as a genetic risk factor for alcoholic cirrhosis.

Expression of urotensin II and its receptor in human liver cirrhosis and fulminant hepatic failure.

OBJECTIVES: Urotensin II [U-II] plasma levels are increased in liver cirrhosis [LC] and are discussed as an important mediator of portal hypertension since the U-II antagonist palosuran has beneficial effects on portal hypertension by increasing splanchnic resistance. Nevertheless, no data are available on the intrahepatic expression of U-II and its receptor [UT] in humans. METHODS: U-II and UT expression were analyzed in the livers of patients with LC, fulminant hepatic failure [FHF], and normal controls [NC] using immunohistochemistry. RESULTS: Both U-II and UT were expressed in the liver on endothelial cells from arteries, veins, and bile ducts as well as on Kupffer cells. In LC, the total number of U-II-expressing cells was 20% lower compared to NC (P < 0.001), while expression of UT did not differ between LC and NC. In contrast, significant enhanced number of U-II and UT positive cells were found in FHF compared to LC and NC (P < 0.001). U-II and UT expression was also found in portal veins, without differences between LC and NC. CONCLUSIONS: Our data demonstrate that U-II and UT are not elevated in human cirrhotic livers but are in livers of patients with FHF.

Hepatitis C virus-induced secretion of inflammatory chemokines preferentially recruits NKG2A+CD8+ T cells.

In patients with hepatitis C, a loss-of-function mutation of chemokine receptor CCR5 (CCR5Delta32) has been shown to be associated with spontaneous viral clearance and lower levels of hepatic inflammation. In the present study, we show that CCR5 is coexpressed with the inhibitory NKG2A receptor on CD8(+) T cells. Consequently, CCR5(+) T cells were highly susceptible to NKG2A-mediated inhibition of cytotoxic activity and NKG2A(+) lymphocytes were preferentially attracted by CCR5 ligands induced by hepatitis C virus E2 antigen. Thus, CCR5 is likely to exert immunoregulatory effects in hepatitis C virus infection by preferentially recruiting CD8(+) T cells bearing the inhibitory NKG2A receptor to the liver.

Plasminogen fragment K1-5 improves survival in a murine hepatocellular carcinoma model.

BACKGROUND: The prognosis of patients with hepatocellular carcinoma (HCC) remains poor, and new alternative treatments are needed. AIMS: To comparatively test the angiostatic and antitumour effects of adenoviral gene transfer of angiostatin (PlgK1-4, amino acids 1-440) and full kringles 1-5 (PlgK1-5, amino acids 1-546) in a model of subcutaneously transferred HCC in mice. METHODS: PlgK1-4 and PlgK1-5 were generated from human WtPlg cDNA and used for adenovirus construction. Vector function and angiostatic effects were confirmed in vitro and in vivo. Antitumoral efficacies of intratumoral vector injections were studied in a model of subcutaneously transferred HCC model. RESULTS: Cell supernatants containing PlgK1-4 and PlgK1-5 reduced endothelial tube formation in vitro by about 30%, whereas WtPlg exerted no inhibitory effect. Endothelial cell infiltration in vivo was decreased by about 60%, but not in AdWtPlg-treated animals. Intratumoral treatment of subcutaneous HCC tumours inhibited growth by 40% for AdPlgK1-4 and 63% for AdPlgK1-5 in surviving mice 12 days after initiation of treatment, whereas treatment with AdWtPlg even led to accelerated growth. Although PlgK1-4 and PlgK1-5 have similar inhibitory effects on intratumoral microvessels, PlgK1-5 markedly improved the survival time compared with PlgK1-4. CONCLUSION: PlgK1-5 and PlgK1-4 effectively inhibited HCC growth. As PlgK1-5 could also prolong the survival time, inducing complete tumour elimination in half of the AdPlgK1-5-treated mice, PlgK1-5 might be the most potential plasminogen fragment for treatment of experimental HCC.

Hepatitis C virus E2 and CD81 interaction may be associated with altered trafficking of dendritic cells in chronic hepatitis C.

Dendritic cells (DC) are crucially involved in the induction of immune responses; however, reports on DC functions in chronic hepatitis C are controversial. Function of DC includes proper cell trafficking between sites of infection and lympho-cellular compartments. Thus, we analyzed DC compartmentalization and changes in DC migration in hepatitis C virus (HCV)-infected patients. We found significantly lower numbers of circulating BDCA1+ and BDCA2+ DC in HCV(+) patients (n = 20) than in healthy controls (n = 12) (P < .05). Analyzing liver samples from HCV(+) patients (n = 15), HCV(-) controls (n = 15), and disease controls (n = 10), we demonstrated chronic hepatitis C to be associated with intrahepatic DC enrichment (P < .05). In vitro studies indicated that HCV E2-induced secretion of RANTES efficiently attracts CCR5(+) immature DC. Incubation of DC with sera derived from HCV(+) patients made DC unresponsive to CCL21, the chemokine recruiting DC to lymphoid tissues for T cell priming. Unlike attraction of CCR5+ DCs via RANTES, direct inhibition of DC migration in response to CCL21 was specific for patients with chronic hepatitis C and could be attributed to interaction of HCV E2 with CD81 on DC. In conclusion, migration of DC is markedly affected by interaction of HCV E2 with CD81. Failure of DC to recirculate to lymphoid tissue may be critically involved in impaired T cell priming during HCV infection.

Induction of murine liver damage by overexpression of CD40 ligand provides an experimental model to study fulminant hepatic failure.

Previously, we demonstrated that intrahepatic upregulation of the immunoactivating molecules CD40 and CD40 ligand (CD40L) are early mechanisms for liver cell damage in human and murine fulminant hepatic failure (FHF). In the present study, we investigated the functional effects of intrahepatic overexpression of CD40L by adenoviral-mediated gene transfer (AdCD40L) in mice. AdCD40L injection induced severe liver cell damage, which was associated with increased alanine aminotransferase (ALT) levels peaking at day 5 after vector administration (AdCD40L, 1,707 +/- 279 U/L; AdLacZ, 213 +/- 25 U/L) and with lethality in half of the mice. Except for mild splenomegaly, no organs other than the liver were involved in inflammatory reactions. CD40-CD40L interaction was mandatory for liver damage, because CD40(-/-) mice were completely protected. Furthermore, CD40L-induced FHF depended on competent lymphocytes, because inflammatory reactions were strongly decreased in SCID and Rag1(-/-) mice. In contrast, neither natural killer T (NKT) cells nor Kupffer cells relevantly influenced histology as shown in NKT cell-deficient CD1d(-/-) mice and by gadolinium depletion of Kupffer cells. Furthermore, immunosuppression by dexamethasone and cyclosporin A was not sufficient to block CD40L damage. In conclusion, we present a model of FHF with strong similarities to human FHF with respect to time course and histological changes. This model suggests involvement of the CD40-CD40L system in FHF and might have important implications for future pathophysiological studies of this condition.

Anti-apoptotic function of gelsolin in fas antibody-induced liver failure in vivo.

Apoptosis is a key mechanism underlying fulminant hepatic failure. The role of gelsolin in such apoptotic pathways is not well understood because both pro-apoptotic and anti-apoptotic effects have been reported in vitro, depending on the cell type and in vitro expression model used. Therefore, we studied an in vivo model of hepatic failure by analyzing expression of gelsolin; intrahepatic activation of caspase-3, -8, and -9; and the extent of apoptosis in gelsolin knockout (gsn(-/-)) versus wild-type mice (gsn(+/+)) after exposure to stimulatory Fas antibody Jo-2. Gelsolin was expressed exclusively in sinusoidal lining cells, including sinusoidal endothelial cells and Kupffer cells, of gsn(+/+) mice. Compared with wild-type mice, Jo2-exposed gsn(-/-) mice showed significantly higher numbers of apoptotic cells in the liver (22 +/- 9 versus 5 +/- 4% terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells, P = 0.002); shorter survival (P = 0.037); and enhanced activation of caspase-3 (P = 0.009), -8 (P = 0.004), and -9 (P = 0.004). Furthermore, inhibition of caspase-3 with z-DEVD-fmk blocked Jo2-induced liver failure in all mice. Thus, our data on Jo2-induced hepatic failure suggest that gelsolin exerts an overall anti-apoptotic effect in vivo. Moreover, selective expression of gelsolin in sinusoidal endothelial cells indicates a pivotal role for interactions between sinusoidal endothelial cells and liver parenchymal cells in Fas ligand-mediated liver failure.

Effective angiostatic treatment in a murine metastatic and orthotopic hepatoma model.

Vascular endothelial growth factor (VEGF) activity is correlated with a progressive tumor disease in patients with hepatocellular carcinoma (HCC). In spite of the well-recognized role of VEGF in HCC, there are few data available regarding therapeutic strategies to block VEGF activity. Therefore, we employed a recombinant adenoviral vector encoding a soluble dominant negative fragment of VEGF receptor 2 (Flk-1), AdsFlk-1, to control pre-established murine orthotopic and metastatic hepatomas. Vector function was confirmed via reverse-transcriptase polymerase chain reaction and ELISA, and angiostatic effects were analyzed in vitro and in vivo. Antitumoral effects of systemic AdsFlk-1 application were studied in a subcutaneous and orthotopic Hepa129 HCC model. Cell supernatant containing the truncated form of Flk-1 had no direct effect on cell proliferation of Hepa129 cells in vitro but reduced endothelial tube formation on matrigel matrix by approximately 80% in vitro. Endothelial-like cell infiltration into matrigel plugs in vivo was also decreased by 80%. Systemic treatment of tumor-bearing mice inhibited tumor growth by 84% compared with the corresponding control group within 16 days after vector application. Likewise, the survival rate was significantly improved in the AdsFlk-1 group compared with control. Orthotopic tumor growth was reduced by 82%, and development of malignant ascites was also retarded. In conclusion, systemic adenoviral-mediated gene transfer of an Flk-1 fragment significantly inhibited tumor growth in orthotopic and metastatic murine HCC. The data support the value of VEGF blockade as an effective target for HCC treatment.

Serum antibodies against the hepatitis C virus E2 protein mediate antibody-dependent cellular cytotoxicity (ADCC).

BACKGROUND/AIMS: The role of antibody dependent cellular cytotoxicity (ADCC) in HCV infection is unclear at present. Antibodies mediating ADCC are usually directed against viral envelope proteins. As cell surface expression of the HCV envelope E2 protein has been shown, the HCV E2 protein is an especially promising candidate target for ADCC. METHODS: Sera from patients with acute (n=6), self-limited (n=11) and chronic (n=19) HCV infection were analyzed in this study. Sera reacting with cell-bound HCV antigens were examined in a flowcytometric cytotoxicity assay using antigen-coated JOK-1 cells as targets. RESULTS: We found that sera from all stages of HCV infection reacted with cells loaded with HCV E2. E2-specific ADCC was observed in patients with acute (n=3/6), self-limited (n=5/11) and chronic (n=13/19) hepatitis C and was closely related to fluorescence intensity in the E2-binding assay (r=0.67, P<0.001). CONCLUSIONS: We conclude that E2-antibodies from all stages of HCV infection can mediate ADCC. Thus, the role of this process in the pathogenesis of chronic hepatitis C should be further elucidated.

The HLA-A2 restricted T cell epitope HCV core 35-44 stabilizes HLA-E expression and inhibits cytolysis mediated by natural killer cells.

Impaired activity of natural killer cells has been proposed as a mechanism contributing to viral persistence in hepatitis C virus (HCV) infection. Natural cytotoxicity is regulated by interactions of HLA-E with inhibitory CD94/NKG2A receptors on natural killer (NK) cells. Here, we studied whether HCV core encodes peptides that bind to HLA-E and inhibit natural cytotoxicity. We analyzed 30 HCV core-derived peptides. Peptide-induced stabilization of HLA-E expression was measured flow cytometrically after incubating HLA-E-transfected cells with peptides. NK cell function was studied with a (51)chromium-release-assay. Intrahepatic HLA-E expression was analyzed by an indirect immunoperoxidase technique and flow cytometry of isolated cells using a HLA-E-specific antibody. We identified peptide aa35-44, a well-characterized HLA-A2 restricted T cell epitope, as a peptide stabilizing HLA-E expression and thereby inhibiting NK cell-mediated lysis. Blocking experiments confirmed that this inhibitory effect of peptide aa35-44 on natural cytotoxicity was mediated via interactions between CD94/NKG2A receptors and enhanced HLA-E expression. In line with these in vitro data we found enhanced intrahepatic HLA-E expression on antigen-presenting cells in HCV-infected patients. Our data indicate the existence of T cell epitopes that can be recognized by HLA-A2 and HLA-E. This dual recognition may contribute to viral persistence in hepatitis C.

Interleukin 6/gp130-dependent pathways are protective during chronic liver diseases.

The contribution of the acute phase inducer interleukin 6 (IL-6) in the pathogenesis of liver diseases is yet unclear. Our analysis showed enhanced expression of IL-6 in livers derived from patients with acute and chronic liver diseases. Additionally, IL-6 plasma levels were significantly increased in patients with chronic liver diseases and showed an inverse correlation with biochemical markers of liver function and a positive correlation with inflammatory markers, signs of portal hypertension, and the degree of liver fibrosis. To prove the relevance of these clinical findings, we applied the tetrachlorcarbonide (CCl(4)) model to conditional knockout animals (Cre/loxP system) for gp130, the common signal transducer of IL-6 family cytokines. Cre recombinases were expressed through a hepatocyte (AlfpCre) and a ubiquitous (MxCre) control element. Gp130 deleted mice had a totally abolished STAT3 activation and acute phase response induction, but gp130 deletion had no effect on the degree of acute liver injury and subsequent hepatocyte proliferation. In contrast, during chronic liver injury induced by biweekly application of CCl(4), deletion of the gp130 receptor in nonparenchymal liver cells and not hepatocytes resulted in fibrosis progression. In conclusion, our experiments indicate an involvement of IL-6 in the pathogenesis of liver diseases and suggest a protective role of IL-6/gp130-dependent pathways in nonparenchymal liver cells during fibrosis progression in chronic liver diseases. (Hepatology 2003;38:218-229).

Heterogeneous expression and regulation of CD40 in human hepatocellular carcinoma.

OBJECTIVE: CD40, a member of the tumour necrosis factor receptor family, plays a major role in adaptive immune responses and contributes to cancer surveillance. Conflicting results have been reported recently on the expression and function of CD40 in carcinomas. The aim of the present study was to investigate the role of CD40 in human hepatoma. DESIGN/METHODS: CD40 expression was examined in hepatomas and derived cell lines by immunohistochemistry, flow cytometry and reverse transcriptase polymerase chain reaction. We investigated in hepatoma cell lines the regulation of CD40 by pro-inflammatory cytokines and the effects of its ligation with soluble CD40L on the expression of co-stimulatory and pro-apoptotic cell-surface molecules and survival. RESULTS: CD40 was detected with a similar frequency of about 40% in hepatoma specimens and derived cell lines but not in normal hepatocytes. Tumour necrosis factor alpha and its combination with interferon gamma upregulated CD40 only in intrinsically positive cell lines. CD40 ligation had no effect on cell viability or surface expression of CD54, CD80, CD86 or CD95. CONCLUSIONS: CD40 is expressed variably in human hepatoma and enhanced by distinct pro-inflammatory cytokines. The lack of detectable effects of CD40 ligation does not support a major role of this molecule in hepatocellular carcinoma biology.