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.

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.

SUMMARY BackgroundNewer therapies are needed for patients with primary biliary cirrhosis and incomplete response to ursodeoxycholic acid (UDCA). Fenofibrate is a fibric acid postulated to regulate immune response and cell proliferation.