The CD4 ؉ CD25 ؉ regulatory T lymphocytes have been implicated in suppressing T cell immune responses. Our aim was to characterize the frequency, phenotype, function, and specificity of CD4 ؉ CD25 ؉ T cells in hepatitis C virus (HCV) infection. Peripheral CD4 ؉ CD25 ؉ cells from recovered (n ‫؍‬ 15), chronic infected (n ‫؍‬ 30), and normal control (n ‫؍‬ 15) subjects were analyzed ex vivo for quantitation, phenotype, and effect on HCVspecific interferon gamma production and proliferation. CD4 ؉ CD25 ؉ specificity was determined by intracellular cytokine staining for interleukin 10 (IL-10). A higher proportion of CD4 ؉ CD25 ؉ were found in chronic infection (mean, 3.02%) when compared with recovered (1.64%, P ‫؍‬ .001) and normal controls (2.27%, P ‫؍‬ .02). CD4 ؉ CD25 ؉ cells display CD45RO high , CD45RA low , CD28 high , CD62L high , and CD95 high phenotype. HCVspecific interferon gamma activity was enhanced in peripheral blood mononuclear cells depleted of CD4 ؉ CD25 ؉ and suppressed in peripheral blood mononuclear cells enriched with CD4 ؉ CD25 ؉ . Depletion of CD4 ؉ CD25 ؉ cells also enhanced HCV-specific CD4 ؉ and CD8 ؉ T cell proliferation. Cytokine analysis suggested CD4 ؉ CD25 ؉ cells secrete transforming growth factor beta (TGF-␤ 1 ) and IL-10. The inhibitory role for TGF-␤ 1 was confirmed by anti-TGF-␤ 1 . Transwell studies showed CD4 ؉ CD25 ؉ mediated suppression to be dose dependent and requiring cell contact. CD4 ؉ CD25 ؉ cells showed HCV-specificity through IL-10 production, with a frequency ranging from 1.9% to 5.3%. A positive correlation was detected between CD4 ؉ CD25 ؉ T cell frequency and HCV RNA titer, whereas an inverse relation was found with liver inflammatory activity. In conclusion, CD4 ؉ CD25 ؉ T lymphocytes constitute a highly differentiated population and appear to play a role in viral persistence by suppressing HCV-specific T cell responses in a cell-cell contact manner.

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Cyclosporine is an immunosuppressive agent widely used in the management of liver transplant recipients. Cyclosporine has been shown to have antiviral activities against HIV, herpes simplex, and vaccinia viruses. The aim of this study was to determine the effect of Cyclosporine in viral clearance in the liver transplant recipients during therapy with combination of interferon and ribavirin, and to determine the anti-viral potential of Cyclosporine in vitro. Immunosuppression consisted of either Cyclosporine or Tacrolimus-based therapy. Both groups received therapy with interferon and ribavirin for 48 weeks when evidence of progressive histologic disease was determined. We found that subjects on Cyclosporine-based immunosuppression (n ϭ 56) had a higher sustained virological response of 46% compared to 27% in the patients on Tacrolimus-based therapy (nϭ59, P ϭ 0.03). In vitro studies were performed to evaluate the antiviral effect of Cyclosporine in the replicon system. These studies showed that Cyclosporine inhibits hepatitis C viral replication in a dose-dependent manner. Combination of Cyclosporine with interferon showed additive effect, and its function is independent of interferon signaling pathways. In conclusion, Cyclosporine may offer an advantage to Tacrolimus in those patients undergoing interferon-based therapy and should be studied in a prospective randomized trial. Liver Transpl 12: 51-57, 2006.

Aliment Pharmacol Ther 31, 461–476 Summary Background  Hepatocellular carcinoma is the leading cause of death in cirrhosis. A majority of patients present at an advanced stage with poor prognosis. Aim  To review the current screening, diagnosis and management strategies involved in hepatocellular carcinoma. Methods  A literature search was performed using PubMed for publications with a predetermined search string to identify relevant studies. Results  Hepatocellular carcinoma is dramatically increasing in incidence that is mostly attributed to chronic hepatitis C and non‐alcoholic fatty liver disease/non‐alcoholic steatohepatitis and its clinical phenotype diabetes and obesity. Cirrhosis is the major predisposing risk factor and its presence necessitates close surveillance for hepatocellular carcinoma with serial imaging studies. Hepatocellular carcinoma can be diagnosed by its unique radiological behaviour of arterial enhancement and washout on delayed images. The Barcelona Clinic Liver Cancer staging classification system is a clinically useful algorithm for the management of patients with hepatocellular carcinoma. The simultaneous presence of cirrhosis in the patients complicates their management and monitoring for cirrhosis‐related complications is important. Conclusions  Early diagnosis and definitive treatment remains the key to long‐term outcome. A multidisciplinary approach is critical to the successful management of hepatocellular carcinoma. Studies combining sorafenib with locoregional or other targeted molecular therapies are likely to improve responses and outcome.

Hepatocellular carcinoma (HCC) is a common malignancy in developing countries and its incidence is on the rise in the developing world. The epidemiology of this cancer is unique since its risk factors, including hepatitis C and B, have been clearly established. The current trends in the shifting incidence of HCC in different regions of the world can be explained partly by the changing prevalence of hepatitis. Early detection offers the only hope for curative treatment for patients with HCC, hence effective screening strategies for high-risk patients is of utmost importance. Liver transplantation and surgical resection remains the cornerstone of curative treatment. But major advances in locoregional therapies and molecular-targeted therapies for the treatment of advanced HCC have occurred recently. In this review, current trends in the worldwide epidemiology, surveillance, diagnosis, standard treatments, and the emerging therapies for HCC are discussed.