HBV-SPECIFIC LYMPHOPROLIFERATIVE AND CYTOKINE RESPONSES IN PATIENTS WITH CHRONIC HEPATITIS-B

Background/Aims: Hepatitis B virus specific T cell reponses are crucia l for viral elimination but their nature is not fully understood. Meth ods: We studied the regulation of proliferation and cytokine productio n after antigenic stimulation in peripheral blood mononuclear cells fr om chronically HBV-infected patients and subjects with natural immunit y after recovery from an acute infection, Proliferation and production of interferon-gamma, IL-10 and tumor necrosis factor-alpha were deter mined after stimulation with HBcAg, HBeAg or HBsAg in the absence or p resence of IL-12 or neutralizing antibodies to IL-12, interferon-gamma , IL-4, IL-10 or tumor necrosis factor-alpha. Results: Upon stimulatio n with HBcAg or HBeAg, peripheral blood mononuclear cells from chronic hepatitis B virus patients displayed a clear class-II restricted prol iferative response (SI greater than 2.5), Both interferon-gamma (less than 50 IU/ml) and IL-10 levels up to 600 pg/ml were detected, Prolife rative or cytokine responses to HBsAg were very weak or absent, Additi on of IL-12 to HBeAg-stimulated cultures increased the production of i nterferon-gamma to more than 200 IU/ml in all patients and slightly in creased the production of IL-10, Neutralization of IL-10 increased the HBeAg-induced interferon-gamma production but had no effect on tumor necrosis factor-alpha production, Addition of anti-IL-4 or anti-tumor necrosis factor-alpha had no significant influence on proliferation or cytokine release, Importantly, in both chronic hepatitis B virus pati ents and naturally immune subjects, IL-12 induced proliferative and in terferon-gamma responses in peripheral blood mononuclear cells stimula ted with HBsAg. Conclusions: Our data indicate that peripheral blood m ononuclear cells from chronic hepatitis B virus patients proliferate a nd produce interferon-gamma and IL-10 upon HBeAg but not upon HBsAg st imulation, IL-12 augments the HBeAg-induced responses and, additionall y, provokes proliferation and interferon-gamma production in HBsAg-sti mulated cultures.