Hepatitis: Rosenberg WM

Rosenberg WM. · University of Southampton, Southampton General Hospital, Southampton, UK. · Eur J Gastroenterol Hepatol. · Pubmed #12072592 No free full text.

Abstract: Limited knowledge of the natural history of chronic hepatitis C suggests that patients with mild histological changes on liver biopsy are at low risk of developing liver related morbidity or mortality. Patients with mild disease have been excluded from the large trials of treatment for hepatitis C and consequently guidelines recommend that they are excluded from treatment. However, as the probability of a beneficial response to treatment increases with improvements in antiviral therapy so the threshold for treatment falls. Trials reporting good responses to treatment in patients with mild disease support the case for widening access to treatment. Increasing recognition that chronic hepatitis C infection can lead to impairment of quality of life that is independent of liver histology is likely to result in more patients with mild hepatitis seeking treatment, more clinical trials that include patients with milder stages of liver disease, and greater enthusiasm for their inclusion in treatment guidelines.

Brooks CL, Rosenberg WM. · Queen Alexandra Hospital, Portsmouth. · Clin Med. · Pubmed #12195854 No free full text.

This publication has no abstract.

Libri NA, Barker SJ, Rosenberg WM, Semper AE. · iQur Ltd, Southampton General Hospital, Southampton, UK. · J Viral Hepat. · Pubmed #19243499 links to  free full text

Abstract: Immunomodulators that induce local endogenous interferon-alpha (IFN-alpha) production by plasmacytoid dendritic cells (pDCs) may offer new strategies for the treatment of patients chronically infected with the hepatitis C virus (HCV). However, such an approach may be compromised if reports are true that IFN-alpha production by pDCs from patients with chronic HCV (cHCV) is profoundly impaired. To address the question of pDC dysfunction in cHCV more definitively, in the present study a panel of four prototypic synthetic agonists of toll-like receptor 7 (TLR7) or TLR9 were administered in vitro to pDCs purified from cHCV patients and from normal uninfected donors and their responses compared in terms of not only IFN-alpha production but also the global expression of other cytokines and phenotypic maturation. Plasmacytoid DCs from uninfected donors produced substantial levels of IFN-alpha in response to three of the four agonists and yet only one TLR9 agonist, a class C CpG oligodeoxynucleotide (ODN), induced robust IFN-alpha production by pDCs from cHCV patients. Proinflammatory cytokine production and phenotypic maturation in response to all four agonists was equivalent in infected and uninfected pDCs. These data point to a profound but selective defect in IFN-alpha production by pDCs from cHCV donors. Nonetheless, a class C CpG ODN successfully induced robust IFN-alpha production, suggesting that this class of TLR9 agonist may have utility as a future immunotherapeutic for the treatment of chronic HCV infection.

Fowell AJ, Sheron N, Rosenberg WM. · Liver Research Group, Division of Infection, Inflammation and Repair, Southampton General Hospital, University of Southampton, Southampton, UK. · Liver Int. · Pubmed #18647143 No free full text.

Abstract: We report an apparently unique case where hepatitis C virus (HCV) RNA was identified in renal tissue from a patient with membranoproliferative glomerulonephritis and treated chronic hepatitis C, despite the absence of detectable virus in the serum or liver (COBAS Amplicor qualitative assay, lower limit of detection 50 IU/ml). The implications of this finding are discussed, with particular reference to current concepts regarding 'occult' hepatitis C infection.

MacDonald AJ, Libri NA, Lustigman S, Barker SJ, Whelan MA, Semper AE, Rosenberg WM. · iQur Ltd, Mailpoint 811, Southampton General Hospital, Southampton, UK. · Clin Exp Immunol. · Pubmed #18341617 links to  free full text

Abstract: We have described previously an immunostimulant derived from Onchocerca volvulus, the helminth parasite that causes onchocerciasis. Recombinant O. volvulus activation-associated secreted protein-1 (rOv-ASP-1) was a potent adjuvant for antibody and cellular responses to protein, polypeptide and small peptide antigens. Our aims were to determine whether rOv-ASP-1 is immunostimulatory for human peripheral blood mononuclear cells (PBMC) and, if so, whether it could augment cellular responses against human pathogen antigens in vitro. Cytokines from rOv-ASP-1-stimulated human PBMC were measured by a fluorescence activated cell sorter-based multiplex assay. Recall responses of normal healthy donor (NHD) and chronic hepatitis C virus (c-HCV)-infected patient PBMC to tetanus toxoid (TT) or HCV core (HCVco) antigen, respectively, were measured by interferon-gamma enzyme-linked immunospot assays. Interferon-gamma was the predominant cytokine induced by rOv-ASP-1. 77.3% of NHD anti-TT and 88.9% of c-HCV anti-HCVco responses were enhanced by rOv-ASP-1. The immunostimulant effect was dependent upon contact between CD56+ and CD56- fractions of PBMC. We have described a helminth-derived protein that can act as an immunostimulant for human recall responses in vitro to TT and, perhaps more importantly, HCV antigens in patients with chronic HCV infection. Our longer-term goal would be to boost anti-viral responses in chronic infections such as HCV.

Guha IN, Parkes J, Roderick P, Chattopadhyay D, Cross R, Harris S, Kaye P, Burt AD, Ryder SD, Aithal GP, Day CP, Rosenberg WM. · Liver group, University of Southampton, Southampton, UK. · Hepatology. · Pubmed #18038452 No free full text.

Abstract: The detection of fibrosis within nonalcoholic fatty liver disease (NAFLD) is important for ascertaining prognosis and the stratification of patients for emerging therapeutic intervention. We validated the Original European Liver Fibrosis panel (OELF) and a simplified algorithm not containing age, the Enhanced Liver fibrosis panel (ELF), in an independent cohort of patients with NAFLD. Furthermore, we explored whether the addition of simple markers to the existing panel test could improve diagnostic performance. One hundred ninety-six consecutively recruited patients from 2 centers were included in the validation study. The diagnostic accuracy of the discriminant scores of the ELF panel, simple markers, and a combined panel were compared using receiver operator curves, predictive values, and a clinical utility model. The ELF panel had an area under the curve (AUC) of 0.90 for distinguishing severe fibrosis, 0.82 for moderate fibrosis, and 0.76 for no fibrosis. Simplification of the algorithm by removing age did not alter diagnostic performance. Addition of simple markers to the panel improved diagnostic performance with AUCs of 0.98, 0.93, and 0.84 for the detection of severe fibrosis, moderate fibrosis, and no fibrosis, respectively. The clinical utility model showed that 82% and 88% of liver biopsies could be potentially avoided for the diagnosis of severe fibrosis using ELF and the combined panel, respectively. The ELF panel has good diagnostic accuracy in an independent validation cohort of patients with NAFLD. The addition of established simple markers augments the diagnostic performance across different stages of fibrosis, which will potentially allow superior stratification of patients with NAFLD for emerging therapeutic strategies.

MacDonald AJ, Semper AE, Libri NA, Rosenberg WM. · iQur Ltd, Southampton General Hospital, Southampton, UK. · Clin Exp Immunol. · Pubmed #17362265 links to  free full text

Abstract: Monocyte-derived dendritic cells (MoDCs) are a promising cellular adjuvant for effector immune responses against tumours and chronic viral infections, including hepatitis C virus (HCV). If autologous DC therapeutic approaches are to be applied in persistent HCV infections in patients, it is important to have an unambiguous understanding of the functional status of the cell type used, namely MoDCs from patients with chronic hepatitis C (CHC) infection. Because of conflicting published reports of either impaired or normal MoDC function in CHC infection, we re-examined the ability of MoDCs from CHC and normal healthy donors (NHD) to mature to an inflammatory stimulus [tumour necrosis factor (TNF)-alpha] and their subsequent functional capabilities. Expression of maturation-associated phenotypic markers [human leucocyte antigen (HLA)-DR, CD83, CD86, CD40], allostimulatory capacity in mixed lymphocyte reactions (MLRs) and CD40-ligand-induced cytokine and chemokine generation were compared in CHC- versus NHD-MoDCs. TNF-alpha-stimulated CHC-MoDCs up-regulated phenotypic markers, but to significantly lower levels than NHD-MoDCs. At physiological ratios of DCs to T cells, CHC-MoDCs were less allostimulatory than NHD-MoDCs, but not when DC numbers were substantially increased. CHC- and NHD-MoDCs generated equivalent amounts of cytokines [TNF-alpha, interleukin (IL)-1beta, IL-6, IL-12p70, IL-15, IL-10] and chemokines [interferon-inducible protein (IP)-10, macrophage inflammatory protein (MIP)-1alpha, regulated upon activation, normal T expressed and secreted (RANTES)] after CD40 ligation. Because the functional defect was not apparent at high MoDC : T cell ratios, autologous MoDC therapy with sufficiently high numbers of DCs could, in theory, overcome any impairment of MoDC function in CHC.

Khakoo SI, Thio CL, Martin MP, Brooks CR, Gao X, Astemborski J, Cheng J, Goedert JJ, Vlahov D, Hilgartner M, Cox S, Little AM, Alexander GJ, Cramp ME, O'Brien SJ, Rosenberg WM, Thomas DL, Carrington M. · Liver Group, Division of Infection, Inflammation, and Repair, Southampton University, Southampton 5016 6YD, UK. · Science. · Pubmed #15297676 links to  free full text

Abstract: Natural killer (NK) cells provide a central defense against viral infection by using inhibitory and activation receptors for major histocompatibility complex class I molecules as a means of controlling their activity. We show that genes encoding the inhibitory NK cell receptor KIR2DL3 and its human leukocyte antigen C group 1 (HLA-C1) ligand directly influence resolution of hepatitis C virus (HCV) infection. This effect was observed in Caucasians and African Americans with expected low infectious doses of HCV but not in those with high-dose exposure, in whom the innate immune response is likely overwhelmed. The data strongly suggest that inhibitory NK cell interactions are important in determining antiviral immunity and that diminished inhibitory responses confer protection against HCV.

Skipper C, Guy JM, Parkes J, Roderick P, Rosenberg WM. · HMP Parkhurst, Isle of Wight, UK. · Gut. · Pubmed #12970145 links to  free full text

Abstract: BACKGROUND: Hepatitis C virus (HCV) infection is a major public health problem recognised by the UK National Strategy that proposes that a care pathway for assessment, diagnosis, and treatment be established in all prisons, integrated within managed clinical networks. A prison sentence provides the opportunity to focus on traditionally hard to reach patients. AIMS: To evaluate the prevalence of HCV infection in a UK prison cluster and to assess the effectiveness of a prison outreach service for hepatitis C. SUBJECTS: Male prisoners. METHODS: A nurse specialist led clinic within a cluster of adult prisons was established, offering health education on hepatitis C, advice on harm minimisation, and HCV testing. Infected prisoners were offered access to a care pathway leading to treatment. Outcome measures were uptake of the service, and diagnosis and treatment of hepatitis C. RESULTS: A total of 8.5% of 1618 prisoners accepted testing: 30% had active infection with HCV. Most were ineligible for treatment due to psychiatric illness or did not receive treatment for logistic reasons. Injecting drug use was the major risk factor in all cases. Only 7% of HCV polymerase chain amplification positive inmates received treatment in prison. CONCLUSION: There is a large pool of HCV infected prisoners at risk of complications, constituting a source of infection during their sentence and after discharge. A prison outreach clinic and care pathway was perceived as effective in delivering health education, reducing the burden on prison and hospital services. It provided an opportunity for intervention but had a limited effect in eradicating HCV in prisoners and it remains unclear how this might be achieved.

Lancaster T, Sanders E, Christie JM, Brooks C, Green S, Rosenberg WM. · Liver Group, Division of Infection, Inflammation and Repair, University of Southampton, Southampton, UK. · J Viral Hepat. · Pubmed #11851899 No free full text.

Abstract: CD8+ T lymphocyte responses are important in the clearance of viral infections. In chronic infections they may contribute to pathogenesis. To investigate the role of CD8+ T lymphocyte responses in viral clearance and chronic hepatitis C we have compared hepatitis C virus (HCV) specific cytotoxicity and interferon-gamma (IFN-gamma) production in patients with resolved-acute, and chronic HCV infection. CD8+ T cell responses to a panel of 13 HCV T cell peptide epitopes were studied using Elispot assays of IFN-gamma production and chromium release cytotoxicity assays. Responses of seven patients with resolved acute HCV infection were compared with those of 14 chronically infected patients. HCV-specific cytotoxicity differentiated the two populations of patients. The majority (71%) of patients with resolved acute infection tested positive to 42% of relevant peptides compared with the minority (28%) of patients with chronic hepatitis C (P=0.03) who responded to only 8% of relevant peptides (P=0.0009). In contrast, HCV-specific IFN-gamma production was detected in 86% of patients with either resolved or chronic infection in response to 42% and 35%, respectively, of relevant peptides tested (not significant). In patients with chronic infection the magnitude of the HCV-specific IFN-gamma production was inversely correlated to viral load (R2=0.52; P=0.042). Failure to clear HCV infection may be attributable to the presence of noncytolytic IFN-gamma producing CD8+ T lymphocytes in chronically infected patients. However these CD8+ T cells may play a beneficial role in contributing to the control of viral load in chronic hepatitis C.

Christie JM, Chapel H, Chapman RW, Rosenberg WM. · Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK. · Hepatology. · Pubmed #10498657 No free full text.

Abstract: How Hepatitis C Virus (HCV) causes persistent infection is unknown. One hypothesis is that HCV evades the host immune response through mutation in immune epitopes. We have investigated mutations in the HCV genome to see if they cluster within immune epitopes; and we have studied the effect of antibody deficiency on mutation rates. We studied patients with chronic hepatitis C, 3 with antibody deficiency and 3 with normal immunity. Regions of the core and envelope genes of HCV, encoding cytotoxic (CTL), and B cell epitopes were sequenced at 2 time points, 2 years apart. The diversity of quasispecies increased with time. The HCV genetic mutation rate was higher than previously predicted. The cryptic nucleotide mutation rate in core was similar to that observed in envelope, suggesting that the error rate of the HCV RNA polymerase is similar in both regions. In contrast, the coding mutation rate was decreased in core and increased in envelope. No genetic mutation was seen in any of the core CTL epitopes despite detectable cellular responses. All patients had mutations within a previously described envelope CTL epitope but did not exhibit immune responses to either index or mutated peptides. There was no difference in mutation rates in any cellular or humoral epitopes between patients with antibody deficiency and normal immunity. Thus we have found no evidence that mutations were selected by T-lymphocytes or antibodies. These findings implicate alternative virus-host interactions in the selection of HCV mutations.

Guha IN, Rosenberg WM. · No affiliation provided · Gut. · Pubmed #16344584 links to  free full text

This publication has no abstract.