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Proliferative response of CD4+ T cells and hepatitis B virus clearance in chronic hepatitis with or without hepatitis B e–minus hepatitis B virus mutants



To assess the significance of cell-mediated immunity, T cells were derived from the peripheral blood and liver tissue of hepatitis B virus (HBV)-infected patients and controls. The analysis of the <3>H-thymidine-uptake in response to a panel of recombinant HBV antigens revealed that peripheral blood mononuclear cells (PBMC) of the 25 viremic patients with inflammatory active, chronic hepatitis B, 16 with wild-type and nine with HBe-minus HBV mutant infection, showed stronger proliferative responses to HBc and HBe antigens than 16 asymptomatic nonviremic HBsAg carriers with normal aminotransferase levels (HBc: SI 19.3 ± 3.9 vs. 13.0 ± 3.2 vs. 8.0 ± 1.2; P < .01 and HBe: SI 16.6 ± 4.0 vs. 10.7 ± 3.5 vs. 6.9 ± 1.5; P < .05). In 15 patients with acute self-limited hepatitis B, however, significantly stronger HBc antigen-specific T-cell responses were observed during HBV clearance and HBe/anti-HBe seroconversion, whereas in nine completely HBV-immunized patients only minor proliferative responses to HBV antigens were observed. Six HBe/HBcAg- and two HBeAg-specific CD4+ T-cell lines could be expanded from liver tissue and peripheral blood of six viremic patients with chronic hepatitis B. Irrespectively of HBV mutations the HBV-specific activation of the T-cell lines was restricted by the presence of HLA-DR molecules and resulted in the release of Th1-like cytokine patterns. Follow-up of interferon (IFN) recipients showed simultaneous short-term increase of HBc/HBe- specific T-cell reactivities in responder patients during HBV clearance and HBe/anti-HBe seroconversion, whereas in nonresponders high virus load and HBV-specific immune responses were in imbalance. In conclusion, HBe/HBc-specific CD4+ helper T cells are related to disease activity. From patients with HBe-minus HBV mutants HBeAg-specific T cells could be obtained in vitro, suggestive of viral escape from the host immune response. We speculate that HBe/HBcAg-specific T helper cells are required to mount an efficient immune response in HBV infection. (HEPATOLOGY 1995; 22:61–68.)

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