pyrimidinones and Hepatitis--Viral--Animal

Telbivudine is an orally bioavailable L-nucleoside with potent and specific anti-hepatitis B virus activity. The higher rate of hepatitis B e antigen (HBeAg) seroconversion during telbivudine treatment than other potent anti-HBV agents suggests a potential immunomodulatory effect. We sought to determine the effects of telbivudine on the immune system, particularly on cytokine production and T-cell response, using an animal model with mouse hepatitis virus strain 3 (MHV-3)-induced hepatitis. The effects of telbivudine on virus replication and cytokine production were investigated in vitro using MHV-3-infected macrophages, and the effects on T-cell response were investigated in vivo in an MHV-3-induced viral hepatitis model. Telbivudine had no effect on MHV-3 replication in macrophages. However, the production of tumour necrosis factor-alpha and interleukin-12 was increased significantly in MHV-3-induced macrophages treated with telbivudine. In vivo survival was enhanced in telbivudine-treated mice, with marked normalization in clinical conditions and histological lesions. Serum levels of interferon-gamma were elevated significantly after telbivudine treatment in MHV-3-infected C3H mice. In contrast, serum interleukin-4 levels were decreased significantly. Furthermore, telbivudine treatment enhanced the ability of T cells to undergo proliferation and secrete cytokines but did not affect cytotoxicity of infected hepatocytes. Of note, we found that telbivudine treatment suppressed programmed death ligand 1 expression on T cells. The results demonstrate the immunomodulatory properties of telbivudine, independent of its antiviral activity, in a mouse model of MHV-3-induced hepatitis.

Topics: Animals; Antiviral Agents; B7-H1 Antigen; Cells, Cultured; Cytokines; Female; Hepatitis, Viral, Animal; Immunologic Factors; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Murine hepatitis virus; Nucleosides; Pyrimidinones; Survival Analysis; Telbivudine; Th1 Cells; Thymidine

At least three marked differences were noted in the results compared from two parallel experiments using identical protocols with virus-free mice and mouse hepatitis virus (MHV) infected mice inoculated with P388 leukemia. First, the therapeutic effect of cyclophosphamide (CY), a cytotoxic antitumor drug, was apparently augmented in MHV-infected mice. A 162% increase of life span (ILS) was obtained in MHV-infected mice compared to a 100% ILS in uninfected mice. Second, the experimental error in terms of the range of animal survival time was much larger with MHV-infected mice than with uninfected mice. In MHV-infected mice, the therapeutic effect of the combination treatment with CY and pyrimidinone was not statistically different from that of the treatment with CY alone. In uninfected mice, the effects of the combination therapy at all doses of pyrimidinone were statistically more effective than that of CY treatment alone.

Topics: Animals; Antineoplastic Agents; Cyclophosphamide; Cytosine; Drug Therapy, Combination; Female; Hepatitis, Viral, Animal; Leukemia P388; Leukemia, Experimental; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Murine hepatitis virus; Pyrimidinones