Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis B virus (HBV) infection is thought to be controlled by virus-specific cytotoxic T lymphocytes (CTL). We have recently shown that HBV-specific CTL can abolish HBV replication noncytopathically in the liver of transgenic mice by secreting tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) after antigen recognition. We now demonstrate that hepatocellular HBV replication is also abolished noncytopathically during lymphocytic choriomeningitis virus (LCMV) infection, and we show that this process is mediated by TNF-alpha and IFN-alpha/beta produced by LCMV-infected hepatic macrophages. These results confirm the ability of these inflammatory cytokines to abolish HBV replication; they elucidate the mechanism likely to be responsible for clearance of HBV in chronically infected patients who become superinfected by other hepatotropic viruses; they suggest that pharmacological activation of intrahepatic macrophages may have therapeutic value in chronic HBV infection; and they raise the possibility that conceptually similar events may be operative in other viral infections as well.
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PMID:Viral cross talk: intracellular inactivation of the hepatitis B virus during an unrelated viral infection of the liver. 864 48

The immune responses to hepatitis B vaccine were studied in 11 hepatitis B surface antigen (HBsAg) carrier children who had cleared HBsAg but failed to develop hepatitis B surface antigen antibodies (anti-HBs) in sera (group 1), 5 HBsAg carrier children who had cleared HBsAg and developed detectable anti-HBs in sera (group 2), and 5 healthy subjects seronegative for all hepatitis B virus (HBV) markers (group 3). After receiving three doses of HB vaccine, group 1 subjects failed to develop detectable anti-HBs. Subsequently, each subject of the three groups was given one dose of the same vaccine for a cellular immunity study, and a measurable proliferation of peripheral blood mononuclear cells (PBMC) to HBsAg was detected in 1 of 8 (12.5%), 0 of 5, and 4 of 5 (80%) of the cases in each group, respectively, after vaccination. The removal of CD8+ cells enhanced the HBsAg blastogenic response in group 3 but did not reverse the unresponsiveness in group 1 and group 2 subjects. The addition of interleukin (IL)-2 in culture reversed unresponsiveness in all cases except one case in group 1. Compared with before vaccination, PBMC from group 2 subjects produced significantly less interferon gamma (IFN-gamma) and more IL-4 in response to HBsAg after vaccination, a cytokine response not observed in group 1 subjects. HLA typing indicated that 3 of 10 patients in group 1 (30%) and 1 of 5 patients in group 2 (20%) had HLA-DRw14-DRw52, a marker previously linked to low anti-HBs response to hepatitis B vaccine in Taiwan. We conclude that the underlying causes of poor anti-HBs response in group 1 subjects are multifactorial, including specific failure of antigen presentation or T-cell activation, or the lack of T helper (Th)2 cell-like response to HBsAg. HLA-DRw14-DRw52 does not confer absolute nonresponsiveness to HBsAg. These patients are not benefited by hepatitis B immunization.
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PMID:Humoral and cellular immune responses to hepatitis B vaccination in hepatitis B surface antigen-carrier children who cleared serum-hepatitis B surface antigen. 893 61

The cytokine pattern secreted by T cells on viral antigen recognition is believed to exert a profound influence on both the type of disease caused by the infecting agent and the final outcome of the viral infection. To characterize the cytokine pattern associated with spontaneous resolution of acute hepatitis B, we analyzed interferon gamma (IFN-gamma), interleukin (IL)-4, and IL-5 production by a wide series of hepatitis B virus (HBV) nucleocapsid-specific T-cell lines (34 lines) and T-cell clones (71 clones) derived from the peripheral blood of 13 patients during the acute or recovery phase of hepatitis B (2 and 7 of them were studied only in the recovery or the acute phase, respectively, and 4 during both). Most T-cell lines (67%) and clones (77%) isolated during the acute phase of infection expressed a T-helper (Th) 1 cytokine profile dominated by the production of IFN-gamma. A larger proportion (74%) of T-cell lines produced several years after resolution of hepatitis was able to secrete not only IFN-gamma, but also IL-4 and IL-5 (Th0-like cells). Results indicate that the antigen-specific fraction of peripheral blood T cells in acute self-limited hepatitis B selectively secrete Th1-type eytokines, suggesting that Th1-mediated effects may contribute not only to liver cell injury, but probably also to recovery from disease and successful control of infection.
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PMID:Predominant T-helper 1 cytokine profile of hepatitis B virus nucleocapsid-specific T cells in acute self-limited hepatitis B. 909 14

Genetic immunization is a potentially useful strategy to prevent or treat hepatitis B virus (HBV) infection. We have previously shown that HBV envelope proteins are highly immunogenic using this technique. The large envelope protein (LHBs), however, induced significantly weaker humoral and cellular immune responses when compared with the middle envelope protein (MHBs). We studied the effect of co-immunizations with cytokine DNA expression constructs encoding for interleukin (IL)-2 and (GM-CSF) on the immunogenicity of LHBs at the B-and T-cell level. Co-immunizations of mice with plasmids encoding for MHBs and IL-2 or GM-CSF increased anti-HBs responses, helper T-cell proliferative activity, and cytotoxic T lymphocyte (CTL) killing. In contrast, co-immunizations of plasmids encoding for LHBs and IL-2 or GM-CSF had no effect on humoral and cellular immune responses. LHBs did not inhibit the production or secretion of IL-2 and GM-CSF. In addition, IL-2, tumor necrosis factor alfa (TNF-alpha), and interferon gamma (IFN-gamma) had no suppressive effect on HBV envelope protein expression in vitro. Based on these data, MHBs, but not LHBs, genetic immunization can be augmented by IL-2 or GM-CSF cytokines.
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PMID:Cytokine and hepatitis B virus DNA co-immunizations enhance cellular and humoral immune responses to the middle but not to the large hepatitis B virus surface antigen in mice. 965 13

Because cellular and humoral immune responses against the hepatitis B virus (HBV) surface antigen (HBs) might be crucial to overcome HBV infection, HBs-specific B- and T-cell responses of HBV patients and HBs vaccine recipients were analyzed quantitatively and functionally. In patients with acute hepatitis B (AHB), transient high anti-HBs-secreting B-cell frequencies were observed early after clinical onset, whereas 1 patient who probably developed chronic infection and chronic HBV carriers had absent or weak B- and T-cell responses. In HBs vaccine recipients, maximal HBs-specific B- and T-cell responses were detected after the first injection that decreased gradually before anti-HBs antibodies appeared in serum. Years after vaccination, anti-HBs-secreting B cells were enriched in the bone marrow. After in vitro stimulation with HBsAg, peripheral blood mononuclear cells (PBMC) of only 1 of 5 acute and 1 of 6 chronic HBV patients, but of all 6 vaccine recipients, secreted varying amounts of interferon gamma (IFN-gamma), but no interleukin-4 (IL-4) or IL-5. Furthermore, the addition of IFN-gamma, but not of IL-2, -4, -12, or IFN-alpha, resulted in strong increases of anti-HBs-secreting B cells in vaccine recipients and chronic carriers. In conclusion, circulating anti-HBs-secreting B cells were significantly higher in early acute hepatitis B or early after HBs vaccination than in chronic hepatitis B and decreased in the follow-up as a result of compartmentalization to lymphoid tissues. Release of IFN-gamma by antigen-stimulated T cells might be critical for anti-HBs formation.
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PMID:Kinetics of hepatitis B surface antigen-specific immune responses in acute and chronic hepatitis B or after HBs vaccination: stimulation of the in vitro antibody response by interferon gamma. 986 72

It is well known that hepatitis B virus infections can be transient or chronic, but the basis for this dichotomy is not known. To gain insight into the mechanism responsible for the clearance of hepadnavirus infections, we have performed a molecular and histologic analysis of liver tissues obtained from transiently infected woodchucks during the critical phase of the recovery period. We found as expected that clearance from transient infections occurred subsequent to the appearance of CD4(+) and CD8(+) T cells and the production of interferon gamma and tumor necrosis factor alpha in the infected liver. These events were accompanied by a significant increase in apoptosis and regeneration of hepatocytes. Surprisingly, however, accumulation of virus-free hepatocytes was delayed for several weeks following this initial influx of lymphocytes. In addition, we observed that chronically infected animals can exhibit levels of T-cell accumulation, cytokine expression, and apoptosis that are comparable with those observed during the initial phase of transient infections. Our results are most consistent with a model for recovery predicting replacement of infected hepatocytes with regenerated cells, which by unknown mechanisms remain protected from reinfection in animals that can be cured.
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PMID:Apoptosis and regeneration of hepatocytes during recovery from transient hepadnavirus infections. 1062 61

Hepatitis delta virus (HDV) superinfection is one of the major causes of fulminant hepatitis in endemic areas of hepatitis B virus (HBV) infection. Currently, there is no effective treatment or vaccine against HDV superinfection. DNA-based immunization is a promising antiviral strategy to prevent or treat persistent viral infections. In this study, we investigated the immunological effects of DNA vaccines against HDV in BALB/c mice. Plasmid (pD) encoding large hepatitis D antigen (L-HDAg), or plasmid (pS/pD) coexpressing hepatitis B surface antigen (HBsAg) and L-HDAg, were injected into mice intramuscularly. The seroconversion rate, anti-HBs levels, anti-HDV titers, T-cell proliferation responses, and T-helper (Th)-release cytokine profiles were analyzed. Mice immunized with plasmids, pS/pD or pD, produced low, but significant, titers of anti-HDV antibodies. In contrast, pS/pD induced much stronger anti-HBs titers in the immunized animals. Interestingly, splenic lymphocytes derived from pS/pD-inoculated mice demonstrated significant proliferation responses to recombinant HBsAg and HDAg, and resulted in a Th1-like immune response as suggested by the production of interferon gamma (INF-gamma) and interleukin-2 (IL-2), but not IL-4. The splenic lymphocyte derived from the pD-inoculated mice showed a similar Th1 response to the stimulation of HDAg, but not to HBsAg. In conclusion, our results suggest that DNA vaccines against HDV can induce significant cellular immune responses with a Th1 preference. HBV and HDV coimmunization can be performed by DNA vaccines. These results are promising for the future development of prophylactic and therapeutic HDV vaccines.
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PMID:DNA-Based immunization produces Th1 immune responses to hepatitis delta virus in a mouse model. 1086 96

Hepatitis B virus (HBV) infection can elicit a variety of clinical sequelae ranging from acute self-limited hepatitis to hepatocellular carcinoma, which are not attributable to a direct cytopathic effect of the virus but rather to the individual host's immune response. Cytokines, low-molecular-weight proteins with a broad range of activity, have been shown to be involved in the regulation of hepatocyte functions, as well as in the pathogenesis leading to liver damage. In the present study, we investigated the correlation between serum interleukin 6 (IL-6) and interferon gamma (IFN-gamma) in altogether 75 patients chronically infected with HBV. They comprised 15 asymptomatic carriers, 15 chronic persistent hepatitis (CPH) and 15 chronic active hepatitis (CAH) patients, 15 cases of cirrhosis and 15 patients with hepatocellular carcinoma (HCC) previously diagnosed by serology and histology, respectively. IL-6 and IFN-gamma levels in their sera were determined using a commercially available kit. Our results showed various concentrations of serum IL-6 detectable in 6.7% of asymptomatic carriers, 13.3% of patients with CPH, 20% of patients with CAH, 33.3% in cirrhotic patients and 66.7% in HCC. In contrast, serum IFN-gamma was only found in 13.3% of asymptomatic carriers and CAH, but could not be detected in the other groups. Our data demonstrated a positive correlation between serum IL-6 and clinical severity of chronic HBV infection, whereas the IFN-gamma levels appeared not to be correlated. From this we conclude that among chronic hepatitis patients IFN-gamma is mostly not expressed at a level detectable by serology, whereas according to other authors it is involved in the immediate immune response triggered by acute hepatitis. IL-6 on the other hand, might rather be responsible for liver inflammation and regeneration in chronic liver disease.
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PMID:Serum interleukin-6 and interferon-gamma levels in patients with hepatitis B-associated chronic liver disease. 1092 24

The pathogenic mechanisms involved in viral hepatitis are not completely understood. Evidence suggests that the pathology associated with hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are a result of the immune response in the liver to these viruses. The livers of patients with viral hepatitis have been shown to contain elevated numbers of T cells expressing the gamma/delta form of the T-cell receptor for antigen (TCRgammadelta). In this study, we investigated whether liver biopsy specimens obtained from individuals with viral (HCV and/or HBV) or nonviral hepatitis contained TCRgammadelta(+) T cells that could be expanded in vitro by cytokines. A high percentage of liver biopsy specimens obtained from HCV- and/or HBV-infected individuals contained high numbers of TCRgammadelta(+) T cells. In contrast, T-cell lines generated from liver biopsy tissues obtained from individuals with nonviral hepatitis or from normal controls had no preferential expansion of TCRgammadelta(+) T cells. Liver TCRgammadelta(+) T-cell lines from HCV-infected individuals had high levels of non-major histocompatibility complex (MHC)-restricted cytotoxic activity against different targets including primary hepatocytes and produced interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin 8 (IL-8) following activation by anti-CD3. Surprisingly, none of these liver TCRgammadelta(+) T-cell lines could recognize any of the structural or nonstructural proteins of HCV and had no cytotoxic activity against cells infected with recombinant vaccinia viruses expressing different HCV proteins. However, the crosslinking of CD81, which has been shown to bind HCV particles and E2, resulted in significant levels of IFN-gamma and TNF-alpha production by liver TCRgammadelta(+) T cells. These results suggest that TCRgammadelta(+) T cells may play a role in the liver pathology of HCV infections.
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PMID:Characterization of liver T-cell receptor gammadelta T cells obtained from individuals chronically infected with hepatitis C virus (HCV): evidence for these T cells playing a role in the liver pathology associated with HCV infections. 1134 61

Woodchucks infected with woodchuck hepatitis virus (WHV) have profiles of liver disease and age-dependent rates of progression to chronic hepatitis (CH) comparable with those seen in human hepatitis B. The mechanism of recovery from acute hepadnaviral infection or its evolution to chronicity remains unknown, although the liver immune responses are expected to play an important role. To determine the dynamics of intrahepatic cytokine expression and T-cell involvement, and to assess their value in predicting the outcome of acute hepatitis (AH) in the adult onset of WHV infection, we evaluated liver transcription of interferon gamma (IFN-gamma); tumor necrosis factor alpha (TNF-alpha); interleukins (IL)-2, -4, and -6; and the T-cell influx in relation to disease histologic severity and virus load in serial liver biopsies collected during the life span of experimentally infected woodchucks. Our results show that recovery from viral AH in adulthood is preceded by a significantly greater hepatic expression of IFN-gamma and CD3, an increased TNF-alpha transcription, lower hepatic WHV load, and a greater degree of liver inflammation than those in acute infection with CH outcome. Furthermore, we have learned that the elevated IFN-gamma, TNF-alpha, and CD3 expression in the liver endures for years not only in CH, but also, although to a lesser extent, in apparently completely resolved infection. This is consistent with our previous findings that residual WHV replication and remnant liver inflammation continue for life after recovery from AH. This study indicates that antiviral cytokines, in particular IFN-gamma, may play a central role in the long-term control of occult hepadnavirus persistence in the liver.
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PMID:Augmented hepatic interferon gamma expression and T-cell influx characterize acute hepatitis progressing to recovery and residual lifelong virus persistence in experimental adult woodchuck hepatitis virus infection. 1167 78


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