Magnitude of activity in chronic hepatitis C is influenced by apoptosis of T cells responsible for hepatitis C virus.

BACKGROUND: The mechanisms of hepatitis C virus (HCV) persistence are unknown, but down-regulation of immune response in a host is likely to play a major role in it. METHODS: To investigate whether T cell apoptosis contributes to such down-regulation, we compared peripheral T cell apoptosis in patients with chronic hepatitis C (CHC) with the serum titre of HCV-RNA, serum alanine aminotransferase (sALT) levels and its change, or peripheral T cell proliferation to the recombinant core antigen of HCV, JCC-1. RESULTS: The percentage of apoptosis in T cells was 0.30 +/- 0.31% (mean +/- SD) in 44 patients with CHC and 0.10 +/- 0.05% in 10 normal volunteers (P < 0.05). In patients with CHC there was no statistical correlation between apoptosis in T cells and sALT levels, titre of HCV-RNA or T cell proliferation to JCC-1 antigen. But, in patients showing relatively more apoptosis in T cells (more than mean + 2SD of apoptosis in T cells from normal volunteers), sALT levels decreased. CONCLUSIONS: Thus, T cell apoptosis in patients with CHC is considered to cause a reduction in sALT, contributing to HCV persistence in patients with CHC.

Unresponsiveness of peripheral T cells induced by apoptotic bodies derived from autologous T cells.

Several reports described the dose-dependent effect of Staphylococcus aureus enterotoxin B (SEB) regarding both levels of apoptosis and anergy of T cells. We investigated here whether T-cell apoptosis induced with SEB causes unresponsiveness of naive T cells. Apoptotic bodies were isolated from human T cells stimulated with antigen-presenting cells (APCs) and SEB by the continuous density gradient centrifugation method. When naive T cells were stimulated with APCs and SEB in the presence of apoptotic bodies, their proliferation was dose dependently suppressed and their TCRs were less downregulated than those of T cells stimulated without apoptotic bodies. Furthermore, those T cells were predisposed not to respond to restimulation with fresh APCs and SEB in the absence of apoptotic bodies. These results, taken together with the observation of tight binding of apoptotic bodies to APCs, imply that T cells stimulated in the presence of apoptotic bodies may undergo unresponsiveness due to interruption of contact with APCs.

An analysis of T cell antigen receptor variable beta genes during the clinical course of patients with chronic hepatitis B.

BACKGROUND: The degree of hepatocyte injury in patients with chronic hepatitis B appears consistent with the number of T cells that respond to hepatitis B virus-related antigens. METHODS: By using a polymerase chain reaction (PCR)-based approach, we monitored a ratio of the T cell antigen receptor (TcR) variable (V) beta gene families against a total TcR V beta gene expression in the peripheral T cells obtained from five patients and four healthy controls. RESULTS: In the healthy controls, there was no significant change in the ratios at an interval of four or eight weeks. In contrast, several TcR V beta families showed the significant changes in the ratios of their gene expression during the follow-up period in all patients. No common highly fluctuated TcR V beta, however, was found among the patients. Furthermore, there was no correlation between their changes and serum levels of alanine aminotransferase. CONCLUSIONS: These findings suggest that the skewing of the TcR family with multiclone is the result of T-cell responses to viral antigens in peripheral blood.

Analysis of human T-cell antigen receptor variable beta gene usage following vaccination with recombinant HBsAg.

We analyzed the TcR Vbeta gene usage before and after vaccination with the hepatitis B vaccine since changes in the TcR Vbeta gene families would be considered to provide preliminary evidence of a mechanism to prevent HBV infection. Six healthy adult volunteers received immunizations. TcR Vbeta usage, T-cell proliferation, and HLA class II alleles were examined in peripheral blood mononuclear cells (PBMC) both before and after vaccination. Furthermore, TcR Vbeta usage in postimmunization PBMC was also compared with PBMC cultured with recombinant HBsAg (rHBsAg). The level of in vitro T-cell proliferation in the presence of rHBsAg increased significantly (P < 0.01) in PBMC isolated after vaccinations. Increases in the different TcR Vbeta genes were also observed in each individual following vaccinations, regardless of the similarity in their HLA alleles. Specific HBV-related antigen-responsive T cells were induced after HB vaccination, without any common restriction for the TcR Vbeta gene families. The mechanism that helps prevent HBV infection was thus found to involve multiclonal alterations in the TcR Vbeta repertoire.

Apoptosis observed in peripheral T lymphocytes from patients with chronic hepatitis B.

BACKGROUND & AIMS: Activation-induced cell death is involved in regulating peripheral T-cell function. Understanding the kinetics of these T cells is important to elucidate the pathogenesis of chronic hepatitis B, which is mediated by cellular immune mechanisms. METHODS: Subtle apoptotic cells in CD3+ cells were discriminated by flow-cytometric assay using freshly obtained and in vitro recombinant hepatitis B core antigen-stimulated peripheral lymphocytes from patients with chronic hepatitis. RESULTS: The ratio of apoptotic cells in freshly obtained CD3+ cells was significantly higher during the decreasing phase than increasing phase of serum alanine aminotransferase activity in each patient, and apoptosis of CD3+ cells was induced by stimulation with recombinant hepatitis B core antigen. CONCLUSIONS: Activation-induced cell death in peripheral T cells was found in chronic hepatitis B virus infection, similar to some other viral infections. The apoptosis in T cells during the decreasing phase of serum alanine aminotransferase activity results in a vast amount of T-cell deletion that may weaken T-cell function of cytotoxicity over hepatitis B virus-infected hepatocytes. Thus, activation-induced cell death is considered an important modulator in down-regulating the "burst" of responding T cells in patients with chronic hepatitis B.