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)

The release of lymphotoxin (LT) from peripheral blood lymphocytes of patients with isoniazid (INH)-induced hepatitis was studied, using L929 fibroblast target cells, as was the cytotoxic effect of these lymphocytes on murine hepatoma cells (L1469) and L929 fibroblasts, using a 3H-proline cytotoxicity assay. Evidence for LT release was found in five out of six patients, following stimulation of the peripheral blood lymphocytes with INH or isonicotinic acid (INA) conjugated to human serum albumin. In the direct cytotoxicity assay, cytotoxic effects on the hepatoma cells were enhanced by preincubation of the target cells with INH in five out of six patients tested. Although specificity with regard to the drug was demonstrable, tissue specificity was less certain in that enhanced killing of the fibroblast cell line was also found to occur following preincubation of the L929 cells with INH.
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PMID:Lymphocyte-mediated cytotoxicity in isoniazid-associated hepatitis. 31 34

Methisoprinol (Isoprinosine), a purine derivative, has been shown to exert a number of immunopharmacological effects, both in vitro and in vivo, in animal and human studies. The agent, somehow mimicking the effects of thymic factors, induces the appearance of phenotypic markers of differentiation on immature precursor T cells; enhances the proliferative response of murine and human lymphocytes to mitogens or antigens, augments helper or suppressor T cell functions and increases the production of lymphotoxin a lymphokine. It has also been shown that this drug can potentiate the effects of macrophage activating factor to stimulate macrophage, and of interferon to protect mice against experimental viral and tumor challenges. In humans, beneficial results have been reported from clinical trials testing the effects of methisoprinol in a variety of diseases including subacute sclerosing panencephalitis (SSPE), acute viral encephalitis, recurrent mucocutaneous infections due to type I and II Herpes viruses as well as in immune restoration of cancer patients with immunodepression following radiotherapy. The drug is also being studied in immunopathological disorders such as rheumatoid arthritis, systemic lupus erythematosus. Sjogren's disease and type A hepatitis. The large spectrum of effects of methisoprinol on a number of immune parameters, the increasing evidence of its therapeutic value in several pathological conditions and its safety of use qualifies this drug as an interesting immunoregulating agent.
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PMID:A recent overview on in vitro and in vivo immunological activities of methisoprinol. 617 7

T lymphocytes from 7 (21%) of 34 patients with chronic hepatitis showed positive cytotoxicity against HBsAg-coated Chang cells. This positivity was observed in HBsAg-negative patients having positive blast transformation responses to HBsAg, as well as in patients convalescing and recovered from acute B hepatitis. Levels of S-GPT in these patients were not different from those showing no cytotoxicity. T cell-mediated cytotoxicity against HBsAg-coated hepatocytes in HBsAg-negative patients thus may have no significant pathogenetic role in destruction of hepatocytes and may represent anamnestic response of sensitized T lymphocytes to HBsAg. Positive cytotoxicity against HBsAg-coated Chang cells was also found in 3 of 17 patients with HBsAg-positive chronic hepatitis. All positive cases exhibited blast transformation responses to HBsAg and low HBsAg titers in their sera. Levels of S-GPT in these patients were significantly higher than in those showing no cytotoxicity, suggesting possible presence of T cell-mediated liver cell damage in these patients. T lymphocytes from asymptomatic HBsAg carrier showed no cytotoxicity to HBsAg-coated hepatocytes and no blast transformation responses of lymphocytes to HBsAg. From the results of the parallel occurrence of T cell-mediated cytotoxicity and blast transformation responses to HBsAg, and of presence of lymphotoxin in the supernatant co-cultured HBsAg and cytotoxicity-positive lymphocytes, it seemed likely that T cell-mediated cytotoxicity in our system might be mediated by lymphokine produced by T cells as a result of delayed hypersensitivity reaction in vitro.
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PMID:T cell-mediated cytotoxicity against HBsAg-coated Chang cells in patients with chronic hepatitis: evidence for cytotoxicity mediated by delayed hypersensitivity T cell reaction. 698 42

To investigate the mechanism by which viruses are cleared from neurons in the central nervous system, we have utilized a mouse model involving infection with a neurotropic variant of mouse hepatitis virus (OBLV60). After intranasal inoculation, OBLV60 grew preferentially in the olfactory bulbs of BALB/c mice. Using in situ hybridization, we found that viral RNA localized primarily in the outer layers of the olfactory bulb, including neurons of the mitral cell layer. Virus was cleared rapidly from the olfactory bulb between 5 and 11 days. Athymic nude mice failed to eliminate the virus, demonstrating a requirement for T lymphocytes. Immunosuppression of normal mice with cyclophosphamide also prevented clearance. Both CD4+ and CD8+ T-cell subsets were important, as depletion of either of these subsets delayed viral clearance. Gliosis and infiltrates of CD4+ and CD8+ cells were detected by immunohistochemical analysis at 6 days. The role of cytokines in clearance was investigated by using an RNase protection assay for interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, tumor necrosis factor alpha (TNF-alpha), TNF-beta, and gamma interferon (IFN-gamma). In immunocompetent mice there was upregulation of RNA for IL-1 alpha, IL-1 beta, IL-6, TNF-alpha, and IFN-gamma at the time of clearance. Nude mice had comparable increases in these cytokine messages, with the exception of IFN-gamma. Induction of major histocompatibility complex class I (MHC-I) molecules on cells in infected brains was demonstrated by immunohistochemical analyses in normal and nude mice, suggesting that IFN-gamma may not be necessary for induction of MHC-I on neural cells in vivo.
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PMID:Cytokine induction during T-cell-mediated clearance of mouse hepatitis virus from neurons in vivo. 805 31

To investigate the relationship between intrahepatic cytokine expression and interferon (IFN) response in chronic hepatitis C [CH(C)], interleukin (IL)-1 beta, -2, -4, -6, -8, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha and TNF-beta mRNAs were investigated semiquantitatively by reverse transcription polymerase chain reaction using serial liver biopsies taken before and after IFN-alpha treatment from 24 patients with CH(C), including 12 responders and 12 non-responders. Before IFN treatment, IL-2, TNF-beta, IFN-gamma and IL-8 mRNA were associated with severe hepatitis activity whereas IL-4 mRNA was associated with weak hepatitis activity, regardless of IFN response. IL-2, TNF-beta and IFN-gamma mRNAs were significantly greater in IFN non-responders. After IFN treatment a complete response to IFN was significantly associated with the disappearance of these pro-inflammatory cytokines, whereas non-responders retained the expression of cytokine mRNA as before IFN treatment. Our results indicated that IFN-alpha treatment may modulate the intrahepatic cytokine network, and this may be one mechanism of IFN-alpha that reduces hepatitis activity, aside from an anti-viral effect. A difference in cytokine network may be involved in IFN response in CH(C).
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PMID:Intrahepatic expression of pro-inflammatory cytokine mRNAs and interferon efficacy in chronic hepatitis C. 902 19

We cloned and characterized the woodchuck tumor necrosis factor (TNF) and lymphotoxin-alpha, -beta (LT-alpha, -beta) cDNAs, genes and proteins to facilitate study of the functions of these cytokines during the course of woodchuck hepatitis virus (WHV) infection. Woodchuck cDNA and genomic DNA libraries were screened with woodchuck-specific DNA probes to isolate the cDNA and gene clones for TNF, LT-alpha and LT-beta. The cDNAs for woodchuck TNF, LT-alpha and LT-beta code for proteins of 233, 205 and 310 amino acids respectively. The polypeptide encoded by each gene among woodchucks, humans and mice can differ: the human TNF, LT-alpha and LT-beta genes encode polypeptides of 233, 205 and 244 amino acids respectively, whereas the mouse TNF, LT-alpha and LT-beta genes encode polypeptides of 235, 202 and 306 amino acids respectively. In the woodchuck, there are four exons for TNF, four exons for LT-alpha and three exons for LT-beta. The RNA splicing patterns for TNF, LT-alpha and LT-beta genes are identical among woodchucks, humans and mice, except that the human LT-beta gene contains four exons. The woodchuck TNF gene promoter contains consensus sequences for binding of AP-1, AP-2, C/EBPbeta, CRE, Egr-1, Ets, NF-AT, NF-kappaB and SP-1 transcription factors. LT-alpha has AP-2, Ets, NF-kappaB, SP-1 and STAT binding sites, and LT-beta has Egr-1/SP-1, Ets and NF-kappaB binding sites. The bacterially expressed woodchuck TNF and LT-alpha proteins exhibited cytotoxic activities on both mouse L929B and woodchuck A2 cells in the presence of actinomycin D. The specific activities of TNF and LT-alpha were 2.62x10(8) units/mg and 2.22x10(3) units/mg respectively for L929B cells, and 1.05x10(9) units/mg and 3.56x10(4) units/mg respectively for A2 cells. However, only woodchuck TNF showed cytotoxic activity on human HepG2 cells, with a specific activity of 6.55x10(7) units/mg in the presence of actinomycin D. The data obtained from this study will be useful to future investigations of the TNF and LT antitumor and anti-viral activities, and their therapeutic potential in the woodchuck model for human hepatitis B virus (HBV).
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PMID:Woodchuck lymphotoxin-alpha, -beta and tumor necrosis factor genes: structure, characterization and biological activity. 1072 23

Upper respiratory tract febrile illnesses caused by various viruses, mycoplasma, chlamydia infections, and/or inflammatory diseases are usually observed a few days to a few (several) weeks before the onset of Reye's syndrome, Stevens-Johnson syndrome, autoimmune hepatitis (hepatotropic virus infections), or hepatotoxicity associated with therapeutic administration of acetaminophen in persons with varying degrees of deficits of important enzymatic activity. Activation of systemic host defense mechanisms by inflammatory component(s) results in depression of various induced and constitutive isoforms of cytochrome P-450 mixed-function oxidase system superfamily enzymes in the liver and most other tissues of the body. Because several cytochrome P-450 enzymes activities important for biotransformation of many endogenous and egzogenous substances show considerable variability between individuals, in some genetically predisposed persons, even the administration of therapeutic doses of a drug may result in serious clinical mishaps, if an important concomitant risk factor (eg, acute viral infection) is involved. Several inflammatory cytokines, such as interleukins, transforming growth factor beta1, human hepatocyte growth factor, and lymphotoxin, downregulate gene expression of major cytochrome P-450 enzymes with the specific effects on mRNA levels, protein expression, and enzyme activity observed with a given cytokine varying for each P-450 studied, thus eventually leading to metabolite-mediated adverse drug reactions and immunometallic diseases which sometimes result in tissue injury beyond the site(s) where metabolic bioactivation takes place. On the other hand, it must be emphasized that inhibition of metabolism of several drugs, as well as influence on the concentration and/or ratio of various cytokines in inflamed tissues, may exert beneficial effects in patients with different diseases, thus opening new therapeutic possibilities. Clinically relevant interactions may be exemplified by the effects of some fluoroquinolone antibiotics, such as pefloxacin and ciprofloxacin, which probably have a steroid-sparing effect in some patients with frequently relapsing nephrotic syndrome, and an increased bioavailability of several drugs following concomitant intake with freshly pressed grapefruit juice, eventually caused by inhibition of their metabolism, mediated mainly by CYP3A and specifically inhibited by naturally occurring flavonoids.
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PMID:Important role of prodromal viral infections responsible for inhibition of xenobiotic metabolizing enzymes in the pathomechanism of idiopathic Reye's syndrome, Stevens-Johnson syndrome, autoimmune hepatitis, and hepatotoxicity of the therapeutic doses of acetaminophen used in genetically predisposed persons. 1189 29

We have previously reported several CTL epitopes derived from the hepatitis B viral X Ag (HBx). In this study, we evaluated whether HBx-specific CTLs can be effectively used in adoptive cancer immunotherapy. To validate the possibility, four peptides containing a HLA-A2.1-restricted binding consensus motif were identified from the HBx protein and tested for their ability to activate CTL from PBMCs isolated from chronic carriers of HBV (n = 12). We selected two highly potent epitopes, HBx 52-60 (HLSLRGLFV) and HBx 115-123 (CLFKDWEEL), that are capable of inducing Ag-specific cytotoxic T cells in patient PBMCs. For adoptive immunotherapy using HBx-specific CTLs, we generated CTL clones restricted to the HBx 52-60 or HBx 115-123 peptide using a limiting dilution technique. LC-46, an HBx 52-60-specific clone, is CD62L(-)CD69(+)CD45RO(+)CD45RA(-)CD25(dim) and is stained by IFN-gamma (approximately 92%), IL-2 (30%), and TNF-alpha (56%), but not by IL-5, IL-10, IL-12, or TNF-beta, indicating that the cells are fully activated T cytotoxic 1-type cells. When LC-46 cells were adoptively transferred into xenografted nude mice bearing human hepatomas expressing HLA-A2.1 molecules and intracellular HBx proteins, the tumors were eradicated. Taken together, our data provide solid evidence for the feasibility of adoptive immunotherapy with HBx-sensitized CTLs in hepatitis disease, including hepatocellular carcinoma (HCC).
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PMID:Tumor eradication by hepatitis B virus X antigen-specific CD8+ T cells in xenografted nude mice. 1253 74

LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for binding herpesvirus entry mediator on T cells) is a recently identified of the tumor necrosis factor alpha (TNF-alpha) ligand superfamily. We wanted to establish whether the presence of chronic viral hepatitis could be implicated in enhanced inflammation as well as the elevation of plasma LIGHT levels in haemodialyzed (HD) patients. The plasma levels of LIGHT, high sensitivity C-reactive protein (hs CRP) and TNF-alpha were measured in HD patients with hepatitis in comparison to subjects without hepatitis and to healthy volunteers. The values of hs CRP and TNF-alpha were significantly elevated in HD patients when compared to the controls. TNF-alpha levels were significantly higher in the hepatitis-positive relative to the hepatitis-negative group (p <0.01). LIGHT levels were significantly decreased in hepatitis-negative patients as compared to controls (p <0.001) and hepatitis-positive group (p < 0.01). Both LIGHT and TNF-alpha were directly associated with the presence of hepatitis. Multiple stepwise regression analysis identified increased iron levels as the only independent variable significantly associated with increased LIGHT (beta=0.475, p=0.003). These results suggest the presence of chronic viral hepatitis and iron levels are novel determinants of the increased LIGHT in the plasma of HD patients.
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PMID:Chronic viral hepatitis and iron affect the plasma levels of LIGHT--a new member of the TNF superfamily in uraemic haemodialyzed patients. 1782 30

Hepatitis B and C viruses (HBV and HCV) cause chronic hepatitis and hepatocellular carcinoma (HCC) by poorly understood mechanisms. We show that cytokines lymphotoxin (LT) alpha and beta and their receptor (LTbetaR) are upregulated in HBV- or HCV-induced hepatitis and HCC. Liver-specific LTalphabeta expression in mice induces liver inflammation and HCC, causally linking hepatic LT overexpression to hepatitis and HCC. Development of HCC, composed in part of A6(+) oval cells, depends on lymphocytes and IKappa B kinase beta expressed by hepatocytes but is independent of TNFR1. In vivo LTbetaR stimulation implicates hepatocytes as the major LT-responsive liver cells, and LTbetaR inhibition in LTalphabeta-transgenic mice with hepatitis suppresses HCC formation. Thus, sustained LT signaling represents a pathway involved in hepatitis-induced HCC.
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PMID:A lymphotoxin-driven pathway to hepatocellular carcinoma. 1980 May 70


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