Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thymic and extrathymic selection processes are responsible for the shape of the T-cell repertoire. T-cell receptor (TCR) variable (V) chain usage, holding a place in tolerance, autoimmunity and response to external agents, was analyzed in 41 patients maintained on chronic hemodialysis treatment. Leukocyte (mean: 6444 +/- 2277 cells/microliters), lymphocyte (mean: 1457 +/- 707 cells/microliters) and T-cell (mean: 67 +/- 16%) counts were within expected limits, but hemodialysis patients showed an impressive increase of TCR V beta 6.7 positive peripheral blood lymphocytes (PBL) and a massive deletion of TCR V beta 8 positive PBL. V beta 6.7 positive PBL were detectable in all hemodialysis patients (n = 41, mean: 2.47 +/- 1.61% PBL) in contrast to a healthy population, where only 45% of subjects expressed V beta 6.7 on PBL (n = 9, mean: 3.50 +/- 1.83% PBL). Only 27% of our hemodialysis patients expressed V beta 8 on PBL (n = 11, mean: 1.00 +/- 1.94% PBL) in contrast to healthy subjects, who presented V beta 8 positive PBL (n = 20, mean: 2.89 +/- 1.23% PBL) in every case. Neither primary kidney disease, nor response to vaccination for hepatitis-B, nor dialyzer membranes used, were associated with these alterations of the TCR V beta-pool. It is likely, that the well-known impairment of the cytokine network in chronic renal failure, uremic toxins or response to infectious agents, may contribute to these different and possibly independent T-cell selection mechanisms in uremia.
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PMID:T-cell selection and T-cell receptor variable beta-chain usage in chronic hemodialysis patients. 153 37

Earlier studies revealed defective concanavalin A-stimulated proliferation and cytokine production by spleen cells derived from BALB/cByJ mice acutely infected with mouse hepatitis virus (MHV), strain JHM. Based on those observations, assays of in vitro antigen-presenting cell (APC) function were undertaken. APC function of unfractionated spleen cells from individual MHV-infected mice was highly variable. Experiments using pooled spleen cells derived from MHV-infected mice revealed that adherent spleen cell APC function was impaired to a much greater degree than B cell APC function. Adherent cells derived from peritoneal exudates of infected mice exhibited an APC defect that was similar in magnitude to that observed for splenic adherent cells. Splenic B cells derived from acutely infected BALB/cByJ mice harbored infectious MHV. In contrast, lysates of adherent spleen cells from acutely infected mice did not kill intracerebrally inoculated neonatal mice, but did induce seroconversion among all survivors. Despite impairment of APC function of cells derived from MHV-infected donors, neither indomethacin nor accessory cells from uninfected control mice restored concanavalin A-induced proliferative responses of spleen cells collected from acutely infected mice. These results and those of earlier studies suggest that, although APC function is impaired, in vitro T cell dysfunction exhibited by spleen cells from MHV-JHM-infected donors is probably related to an inherent proliferative defect subsequent to T cell activation. Defective concanavalin A-stimulated proliferation does not appear to be secondary to accessory cell function suppression or to inhibitory factors secreted by accessory cells.
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PMID:Characterization of accessory cell function during acute infection of BALB/cByJ mice with mouse hepatitis virus (MHV), strain JHM. 165 37

Infection of BALB/c mice with mouse hepatitis virus, strain JHM (MHV-JHM), at any of several intervals relative to ovalbumin (OVA) administration resulted in elevated OVA-specific IgG 2 a titers. Since gamma interferon (IFN) has been implicated as an up-regulator of IgG 2 a production, attempts were made to determine whether levels of this cytokine were modified in sera of infected mice. Serum IFN-gamma was not detected, but treatment of MHV-JHM-infected mice with monoclonal anti-IFN-gamma antibody resulted in high mortality with decreased survival times, enhanced virus titers in liver and spleen, and more severe virus-associated pathology, compared to mock-treated, infected mice. Immunotherapy with recombinant IFN-gamma ameliorated disease as reflected by mortality rates and virus titers in target organs.
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PMID:The role of gamma interferon in infection of susceptible mice with murine coronavirus, MHV-JHM. 166 41

The genes for interferon (IFN) alpha, IFN gamma, IL-1 beta, IL-6, and TNF alpha were transcribed at readily detectable levels both in liver biopsies from individuals with normal liver function and in samples of normal viable liver taken for transplantation. These results provided evidence for the concept that such multifunctional cytokines play a role in homeostasis in normal human tissues. In normal human liver, in situ hybridization studies showed that, in the absence of a detectable inflammatory response, both hepatocytes and mononuclear cells exhibited a similar degree of expression of IL-6 mRNA in keeping with the finding that IL-6 is produced by cells of different lineages. The levels of IL-1, IL-6, and TNF mRNA were found to be markedly reduced in extracts of the livers of patients with primary biliary cirrhosis and other forms of autoimmune liver disease at a time when extensive liver lesions were apparent, compared to the levels of expression of these cytokines in the livers of normal individuals. The reduced expression of IL-1, IL-6, and TNF mRNAs appeared to be a specific effect and not due to a general reduction in RNA synthesis as the IFN alpha, IFN gamma and actin mRNAs were expressed at similar levels in both normal and diseased livers. The levels of IL-1 beta, IL-6, and TNF mRNAs were also reduced in samples of liver from a patient with a drug induced fulminant hepatitis suggesting that this specific pattern of altered cytokine gene expression was characteristic of the advanced stage of severe liver disease.
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PMID:Genes for interleukin-1, interleukin-6, and tumor necrosis factor are expressed at markedly reduced levels in the livers of patients with severe liver disease. 177 64

Although the shock syndrome is recognized as a form of "mediator poisoning", a plethora of details is hardly converging into a coherent concept of chronological and molecular order. As a model for organ failure in septic shock, three alternative experimental approaches with a common pathology are presented: When galactosamine-sensitized mice receive either lipopolysaccharide or leukotriene D4 or tumor necrosis factor alpha they develop fulminant hepatitis within few hours with a lethal outcome within one day. Detailed pharmacological intervention studies allow to conclude that endotoxin-induced leukotriene D4 release induces a transient ischemia by the known vasoconstrictive action of this eicosanoid. A following reperfusion/reoxygenation phase gives rise to superoxide formation which inactivates alpha 1 proteinase inhibitor. Thus a serine protease becomes active which is responsible for the processing of a monocytic tumor necrosis factor alpha precursor to be released into the circulation after proteolytic cleavage. By this sequence the final central mediator of shock and sepsis becomes systematically abundant. The concept arising from these studies reconciles previously known findings and provides a link between the role of reactive oxygen species in inflammation, the balance of proteases and antiproteases in the extracellular space and the release of the cytokine tumor necrosis factor in sepsis and shock.
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PMID:Reactive oxygen species, antiproteases, and cytokines in sepsis. 179 93

The effect of tumor necrosis factor (TNF)-alpha and interleukin-1 (IL-1) alpha, which are thought to be principal mediators inducing homeostatic abnormalities during endotoxemia, were investigated on cultured hepatocytes in an attempt to understand their role in the pathogenesis of fulminant hepatitis. Both TNF and IL-1 had no direct cytotoxicity on cultured adult rat hepatocytes as assessed by their effects on protein synthesis and also cytosolic enzyme activity released into the culture medium in the presence of 5 mM D-galactosamine (Ga1N). However, IL-1 caused a dose-dependent inhibition of DNA synthesis in cultured adult rat hepatocytes. Moreover, the serum from TNF-treated rats, prepared after intravenous administration of TNF (5 X 10(4) U per rat), caused a significant increase of enzyme release into culture medium in contrast to control rat serum. The cytotoxicity disappeared when the serum from TNF-treated rats was pretreated by heating at 56 degrees C for 30 min, and was decreased by the addition of the protease inhibitor, aprotinin. In vivo, gabexate mesilate, a serine-type protease inhibitor, prevented GalN/TNF-induced fulminant hepatitis, whereas MX-1, an anti-complement agent, had no such effect. These results strongly suggest that IL-1 has a inhibitory effect on hepatocytes in terms of DNA synthesis and that TNF indirectly induces hepatocellular damage through the serine proteases which are possibly activated by the cytokine in vivo.
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PMID:Significance of tumor necrosis factor (TNF) and interleukin-1 (IL-1) in the pathogenesis of fulminant hepatitis: possible involvement of serine protease in TNF-mediated liver injury. 191 53

Cellular immune responses to hepatitis B virus (HBV) play an important role in the resolution of acute infection. They also influence the course of chronic infection and disease but are inadequate to completely clear the infection. Woodchuck hepatitis virus (WHV) infection of the woodchuck can provide a model to study these processes. Lymphocyte responses of woodchucks were assessed by in vitro proliferation and/or interleukin (IL)-2 assays using mitogen (Concanavalin A [ConA]), cytokine (IL-2), superantigen (Staphylococcus aureus enterotoxin B [SEB]), major histocompatibility complex (MHC) allo-antigen (mixed lymphocyte reaction [MLR]), and viral antigens (woodchuck hepatitis virus core antigen [WHcAg] and woodchuck hepatitis virus surface antigen [WHsAg]). ConA-stimulated woodchuck lymphocytes underwent cell division based on cell counting experiments and produced IL-2 as detected using an IL-2-dependent murine cell line but failed to incorporate sufficient tritiated thymidine; however, they did incorporate sufficient tritiated adenosine and deoxyadenosine to permit development of a meaningful proliferation assay. The IL-2 assay was sensitive and specific for detection of woodchuck IL-2 induced by mitogen, superantigen, and MLR, as shown by quantitative titration analysis and anti-body neutralization of ConA-supernatant activity. Cyclosporin A and FK506 specifically inhibited ConA- and SEB-induced IL-2 production by woodchuck lymphocytes. Positive two-way MLRs were detected by IL-2 production and proliferation assay between woodchucks from different geographic regions, thus indicating divergence among MHC molecules; however, occasional negative MLR reactions among indigenous pairs of woodchucks indicated that some woodchucks were mutually immunocompatible to some degree. The radioadenosine proliferation assay was sensitive for detecting peripheral blood lymphocyte responses to WHcAg and WHsAg in adult woodchucks with recently resolved acute infections. The above systems should facilitate the design of adoptive therapy and liver transplantation experiments in the woodchuck, and also enable modeling of immune responses that promote and maintain chronic hepadnavirus infection.
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PMID:In vitro activation of woodchuck lymphocytes measured by radiopurine incorporation and interleukin-2 production: implications for modeling immunity and therapy in hepatitis B virus infection. 754 55

It should be apparent from the foregoing that the transgenic mouse model system has contributed substantially to our understanding of many aspects of HBV biology, immunobiology, and pathogenesis in the past several years. We have learned that HBV can replicate within the mouse hepatocyte, as well as other mouse cell types, suggesting that there are probably no strong tissue or species-specific constraints to viral replication once the viral genome enters the cell. However, the failure thus far to detect viral cccDNA in the hepatocyte nucleus in several independently derived transgenic lineages suggests that other, currently undefined, constraints on host range and tissue specificity may also be operative. Thanks to the transgenic mouse model, we now understand the pathophysiological basis for HBsAg filament formation and "ground glass" cell production, and we have learned that at least this viral gene product can be toxic for the hepatocyte, first by compromising its ability to survive the hepatocytopathic effects of lipopolysaccharide and gamma interferon, and eventually by causing it to die in the absence of any obvious exogenous stimulus. In recent studies, it has been shown that preformed nucleocapsid particles do not cross the nuclear membrane, in either direction, at least in the mouse hepatocyte. If this is confirmed, it will have two important implications: first, that nucleocapsid disassembly must occur in the cytoplasm before the nascent viral genome can enter the nucleus; second, that the intranuclear nucleocapsid particles are empty, and therefore serve no currently defined purpose in the viral life cycle. This should stimulate new interest in the analysis of the function of these particles that are a prominent feature of mammalian hepadnavirus infection. The transgenic mouse model has also established definitively that HBV-induced liver disease has an immunologic basis, and that the class I restricted CTL response plays a central role in this process. Additionally, the mouse studies have taught us that when the CTL recognize their target antigen on the hepatocyte they cause them to undergo apoptosis, forming the acidophilic Councilman bodies that are characteristic of viral hepatitis. Further, we have learned that although the CTL initiate the liver disease, they actually contribute more to disease severity indirectly by recruiting antigen nonspecific effector cells into the liver than by directly killing the hepatocytes themselves; and that by releasing gamma interferon when they recognize antigen, the CTL can destroy enough of the liver to cause fulminant hepatitis in mice whose hepatocytes overproduce the large envelope protein and are hypersensitive to the cytopathic effects of this cytokine.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hepatitis B virus transgenic mice: insights into the virus and the disease. 755 87

The presence of natural killer (NK) cells contributes to early defense against murine cytomegalovirus (MCMV) infection. Although NK cells can mediate in vivo protection against MCMV, the mechanism by which they do so has not been defined. The studies presented here evaluate cytokine production by NK cells activated during MCMV infection and the role of NK cell-produced cytokines in early in vivo antiviral defenses. Experiments with normal C57BL/6, T cell-deficient C57BL/6 nude, and severe combined immunodeficient mice lacking T and B cells demonstrated that both interferon gamma (IFN-gamma) and tumor necrosis factor (TNF) production were induced at early times after infection with MCMV. Conditioned media samples prepared with cells from these mice, on day 2 after infection, produced 11-43 pg/million cells of IFN-gamma and 12-19 pg/million cells of TNF as evaluated by specific protein enzyme-linked immunosorbent assays. Studies in the NK- and T cell-deficient mouse line, E26, in mice that had been depleted in vivo of NK cells by treatment with antibodies eliminating NK cells, anti-asialo ganglio-N-tetraosylceramide or anti-NK1.1, and with populations of cells that had been depleted of NK cells by complement treatment with the anti-NK cell antibody, SW3A4, demonstrated that NK cells were solely responsible for the IFN-gamma but were not required for TNF production. The in vivo absence of NK cells was accompanied by increased viral hepatitis and viral replication in both immunocompetent and immunodeficient mice, as well as decreased survival time of immunodeficient mice. In vivo treatments with antibodies neutralizing IFN-gamma demonstrated that this factor contributed to the NK cell-mediated antiviral defense and reduced the measured parameters of viral defense to levels indistinguishable from those observed in NK cell-deficient mice. These effects appeared to be independent of cytolytic activity, as NK cells isolated from anti-IFN-gamma-treated mice mediated killing at levels comparable to those observed in control-treated mice. The consequences of interleukin 12 (IL-12) administration, a known potent inducer of IFN-gamma production by NK cells, were evaluated in MCMV-infected mice. Low IL-12 doses, i.e., 1 ng/d, increased NK cell cytotoxicity and IFN-gamma production up to twofold and resulted in improved antiviral status; virus-induced hepatitis was decreased as much as fivefold, and viral burdens were decreased to levels below detection.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Requirement for natural killer cell-produced interferon gamma in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin 12 administration. 756 78

Oxidative stress, with reactive oxygen intermediate formation, may represent a common mechanism by which liver injury is induced by diverse etiologies. Oxidative stress enhances nuclear factor kappa B (NF-kappa B) activity, and NF-kappa B activity has been shown to enhance the expression of cytotoxic cytokines. Acute hepatic injury caused by reactive oxygen intermediate production was induced by an intraperitoneal injection of CCl4 in mice. This injury was significantly inhibited by intravenous pretreatment of the mice with a water-soluble emulsion of alpha-tocopherol. Alpha-tocopherol treatment of the mice given the CCl4 also reduced the NF-kappa B binding to levels approaching those found in normal mice. In vitro treatment of a monocyte/macrophage cell line with CCl4 led to enhanced NF-kappa B binding and an increase in tumor necrosis factor-alpha (TNF-alpha) messenger RNA levels. Liver specimens taken from patients with acute fulminant hepatitis had markedly increased NF-kappa B binding activity in comparison with the binding of normal livers. These data demonstrate that abolishing acute hepatic injury with alpha-tocopherol, a free radical scavenger, also eliminated increased NF-kappa B binding. It is tempting to speculate that enhanced NF-kappa B expression caused by free radical production/oxidative stress may modulate liver injury, perhaps through an effect on cytotoxic cytokine synthesis.
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PMID:Vitamin E therapy of acute CCl4-induced hepatic injury in mice is associated with inhibition of nuclear factor kappa B binding. 759 Jun 66


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