Our results showing that RBV prevents the conversion of naive Th cells into Tregadapt cells indicate that RBV maintains Th1 cells in the activated phase, which enhances the eradication of HCV-infected hepatocytes. This is one potential mechanism by which RBV enhances HCV elimination in combination with IFN administration. It was reported that Treg cells can be modulated by other drugs. The administration of low-dose cyclophosphamide (CPA), a chemotherapeutic reagent, enhanced cellular immune responses in mice[53] by its effects on Treg cells via induction of their apoptosis

and down-modulation of both GITR and Foxp3 expression. Other reports indicated that Ku-0059436 solubility dmso Tregadapt cells expressed high levels of cyclooxygenase-2 (COX2)

and could be enhanced in a prostaglandin-E2-dependent manner.[54, 55] Hence, COX2 inhibitors may be potential inhibitors of CD4+ CD25+ FOXP3+ Tregadapt cells.[55] Our results confirmed that RBV is a new reagent that down-modulates Treg cells through conversion of naive Th cells into Treg cells. This inhibitory activity against Treg cells was similar to that of CPA. These two reagents selectively Z-VAD-FMK nmr down-modulate Treg cells without any effect on other effector lymphocytes. However, we did not investigate whether RBV induces apoptosis in Treg cells and did not clarify in detail how RBV modulates Treg cells, Ureohydrolase and therefore could not determine whether CPA or RBV was more effective in modulating Treg cell activity. The ability of RBV to modulate Treg cells could be applied to the treatment of other diseases associated

with immunological impairment. It was reported that there is a relationship between the down-modulation of Treg cells and the disease activity of systemic lupus erythematosus.[56] The ability of RBV to inhibit Treg cells would accelerate the activation of self-reactive Th cells in patients with systemic lupus erythematosus. Autoimmune liver disease, such as autoimmune hepatitis or primary biliary cirrhosis, is also associated with excessive activation of self-reactive T cells induced by the hypo-activity of Treg cells.[57, 58] Our results suggest that the administration of RBV in combination with IFN for the treatment of patients with HCV infection complicated by autoimmune hepatitis or primary biliary cirrhosis would accelerate self-reactive T-cell activation in association with down-modulation of Treg cells. In contrast, because tumour-associated antigen (TAA) is considered to be a self-generated antigen,[59] the TAA-specific cellular immune response would be suppressed if Treg cells corresponding to TAA-specific Th cells were activated to cause the Th cells to enter anergy.