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)

Background: Rebound hepatitis is a potentially life-threatening complication of withdrawal from immunosuppressive therapy in patients with chronic Hepatitis B viral (HBV) infections. Objectives: To document the incidence of rebound hepatitis and determine whether the hepatitis is associated with serologic evidence of immunological rebound or the appearance of specific mutations in the HBV genome. Methods: Serum cytokines (IL-6, IL-10, TNF-alpha and INF-gamma) were documented by enzyme linked immunoassays and previously described HBV mutants (surface, core, pre-core and basal core promoter) by signal probe hybridization analysis in chronic HBV carriers treated with either 6 weeks of prednisone followed by 6 weeks of acyclovir (PR/AC, n = 20) or placebo/placebo (PL/PL, n = 20). Results: Rebound hepatitis (serum ALT > 2X baseline) occurred in 6/20 (30%) PR/AC patients versus 2/20 (10%) PL/PL recipients (P = 0.24). Serum cytokine levels were similar in those who developed rebound hepatitis compared to those who did not. HBV mutants were absent prior to and during treatment but developed in the follow-up period in three patients. All three patients were PR/AC recipients and in each case, the HBV mutation was in the basal core promoter gene. In two of the three patients, the mutant appeared just prior to the onset of rebound hepatitis while in the third, rebound hepatitis did not occur. Conclusions: The results of this study indicate an association exists between some cases of rebound hepatitis and the development of HBV mutants.
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PMID:Rebound hepatitis following withdrawal of immunosuppressive therapy in patients with chronic Hepatitis B viral infections. 1534 68

In contrast to BALB/c mouse macrophages (Mphi), Mphi from the A/J mouse strain, upon activation by exogenous interferon gamma (IFNgamma), develop an anti-mouse hepatitis virus 3 (MHV3) state which correlates with resistance to virus infection. To investigate the autocrine activation of BALB/c and A/J Mphi, we activated them with interleukin-12 (IL-12) and/or IL-18, and quantified IFNgamma production, the anti-MHV3 state and arginine metabolism. Synergistic activation by IL-12/IL-18 induced the expression of the IFNgamma gene in Mphi from both mouse strains. In bone marrow (BM) or peritoneal (P) Mphi of specific pathogen-free (spf) mice of both strains, IFNgamma synthesis occurred only with a synergistic IL-12/IL-18 activation and showed increasing levels from 24 to 72 h of activation. In contrast, when non-spf mice were used in the assay, their PMphi synthesized higher IFNgamma levels upon activation with only IL-12 or only IL-18 or both. The BALB/c Mphi were always capable of synthesizing higher amounts of IFNgamma than the A/J Mphi. An anti-MHV3 state was observed only in A/J Mphi upon activation with IL-12/IL-18 or IFNgamma regardless of their origin from the peritoneum or bone marrow. Arginine metabolism in activated and/or virus infected BMMphi was investigated through nitric oxide (NO) and arginase induction as well as the consumption of arginine and synthesis of citrulline, ornithine and spermine. The results showed that both BALB/c and A/J BMMphi populations released NO only after activation with IL-12/IL-18 or IFNgamma. Arginase was not induced in BMMphi from both strains by IL-12/IL-18 or IFNgamma but only by IL-4/IL-10. Higher arginine consumption was observed in BMMphi from both strains upon activation with IL-4 or IFNgamma which further increased, in this case, when the cells were infected with MHV3. As a consequence of nitric oxide synthase synthesis and arginine consumption in IFNgamma activated BMMphi, we observed a higher synthesis of citrulline. High levels of ornithine were induced only upon IL-4 activation. Polyamine synthesis was higher in A/J BMMphi than in BALB/c ones, which correlated with the slightly lower levels of ornithine observed. Upon infection with MHV3, we observed a higher synthesis of spermine. IL-12/IL-18 or IFNgamma activation, mainly in MHV3 infected cells, led to a decreased synthesis of polyamines, notably spermine, only in A/J BMMphi. Difluoromethylornithine treatment, which leads to inhibition of polyamine synthesis, induced a decreased MHV3 multiplication in both BALB/c and A/J BMMphi. Altogether these data show the relevance of IFNgamma, from the autocrine or paracrine pathway, and arginine metabolism for the control of MHV3 replication in Mphi of a resistant mouse strain.
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PMID:Arginine metabolism during macrophage autocrine activation and infection with mouse hepatitis virus 3. 1563 27

Clinical evidence suggests that idiosyncratic hepatitis following administration of halogenated volatile anesthetics is mediated by autoimmune responses. No murine model to study mechanisms of anesthetic-induced or any other form of drug-induced idiosyncratic hepatitis exists. Anesthetics are believed to trigger hepatitis by covalently linking a trifluoroacetyl (TFA) chloride hapten to hepatic proteins, forming haptenated self-proteins. To test this hypothesis, we developed a hapten-induced model of hepatitis by immunization with syngeneic S100 liver proteins covalently coupled to TFA (TFA-S100). We found that TFA-S100 induced hepatitis was more severe than disease induced by S100 plus adjuvants or by the adjuvant alone and was characterized by neutrophil, mast cell, and eosinophil infiltration. TFA-specific IgG1 antibodies directly correlated with hepatitis, whereas S100 autoantibodies did not. TNF-alpha, IL-1beta, and IL-6 released from splenocytes collected 2 weeks after TFA-S100 inoculation were increased resembling the elevated serum cytokines reported in patients with autoimmune hepatitis (AIH). Three weeks after inoculation, the peak of hepatitis, we noted decreased numbers of Kupffer cells and lower levels of IL-6 and IL-10 in the liver, cytokines produced by Kupffer cells. This is the first report, to our knowledge, of a hapten-induced model of hepatitis with immune and autoimmune features.
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PMID:A novel model of drug hapten-induced hepatitis with increased mast cells in the BALB/c mouse. 1571 33

Extracellular heat shock protein 60 (HSP60) has been considered a proinflammatory danger signal. Yet, HSP60 can also down-regulate experimental immune arthritis and diabetes models by specific inhibition of Th1-like responses. We now report that HSP60 in vitro differentially modulates the expression of Th1/Th2 transcription factors in human T cells: HSP60 down-regulates T-bet, NF-kappaB, and NFATp and up-regulates GATA-3, leading to decreased secretion of TNF-alpha and IFN-gamma and enhanced secretion of IL-10. These effects depended on TLR2 signaling and could not be attributed to LPS or to other contaminants. In BALB/c mice, HSP60 in vivo inhibited the clinical, histological, and serological manifestations of Con A-induced hepatitis associated with up-regulated T cell expression of suppressor of cytokine signaling 3 and GATA-3 and down-regulated T-bet expression. These results provide a molecular explanation for the effects of HSP60 treatment on T cell inflammation via innate regulation of the inflammatory response.
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PMID:Heat shock protein 60 inhibits Th1-mediated hepatitis model via innate regulation of Th1/Th2 transcription factors and cytokines. 1574 53

Hepatitis C virus (HCV) induces chronic liver disease in hosts which can eventually progresses to liver cirrhosis and hepatocellular carcinoma. However, progression of liver disease is slower in patients with persistently normal levels of alanine aminotransferase (ALT) than in those with active hepatitis. Although distinct immune responses against HCV have been proposed in asymptomatic infection, the role of circulating dendritic cells (DC) in the pathogenesis of these patients remains obscure. To address this issue, we compared the number and function of myeloid DC (MDC) and plasmacytoid DC (PDC) between uninfected individuals and HCV-infected patients with or without elevated ALT levels. Numbers of DC and DC progenitors were significantly lower in patients with chronic active hepatitis than in control subjects. However, no differences were found in the number of DC between normal controls and HCV-infected patients with persistently normal ALT levels. MDC from patients with active hepatitis were less able to polarize naive CD4 T cells into the Th1 phenotype, while their MDC and PDC primed more CD4 T cells producing IL-10 than those from normal controls. Such dysfunction of DC was also observed in patients with persistently normal ALT levels. In conclusion, circulating DC decrease in number predominantly in HCV-infected patients with active hepatitis, and the function of DC is impaired even in those with normal ALT levels.
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PMID:Impaired function of dendritic cells circulating in patients infected with hepatitis C virus who have persistently normal alanine aminotransferase levels. 1616 90

Imatinib exerts potent antileukemic effects in vitro and in vivo. Despite its well known antitumor activity, the potential of imatinib for the treatment of inflammatory diseases remains elusive so far. Our current report provides strong evidence that imatinib has potent antiinflammatory effects. It potently inhibits LPS- and Con A-induced TNF-alpha production by human myeloid cells in vitro (peripheral blood mononuclear cells, CD14-selected monocytes, and monocyte-derived macrophages). Of note, the production of the antiinflammatory cytokine IL-10 was not significantly regulated by imatinib. In line with this observation, phosphorylation of IkappaB and subsequent DNA binding of NF-kappaB, which is critically involved in TNF-alpha, but not IL-10 expression, was reduced by imatinib. Using several murine models of acute hepatitis, we could corroborate our in vitro findings, as imatinib prevented macrophage- and TNF-alpha-dependent inflammatory damage of the liver induced by injection of either Con A or d-galactosamine/LPS by inhibition of hepatic TNF-alpha production. Of note, d-galactosamine/TNF-induced hepatitis was not affected, showing that imatinib does not directly inhibit TNF-alpha-induced hepatocellular cell death. These findings suggest a potent antiinflammatory role of imatinib by modulation of TNF-alpha production in monocytes/macrophages. This observation might be of therapeutic value for the treatment of TNF-mediated diseases.
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PMID:The kinase inhibitor imatinib mesylate inhibits TNF-{alpha} production in vitro and prevents TNF-dependent acute hepatic inflammation. 1617 51

N-[1-(4-[4-(pyrimidin-2-yl)piperazin-1-yl]methyl phenyl)cyclopropyl] acetamide . HCl (Y-40138) suppresses liver injury in concanavalin A- and D-galactosamine/lipopolysaccharide (LPS)-induced mouse hepatitis models. However, the mechanism of action of Y-40138 has not been fully investigated. In this study, we examined the effect of Y-40138 on cytokine production in mice. Cytokine production was induced by intraperitoneal injection of LPS (0.5 mg kg(-1)) or intravenous injection of recombinant mouse tumour necrosis factor (TNF)-alpha (10 mug mouse(-1)) in BALB/c mice. TNF-alpha and interleukin (IL)-10 reached maximum levels 1.5 h after the LPS injection. IL-12 and interferon-sigma (IFN-sigma) reached maximum levels 3 to 9 h after the injection. When Y-40138 was orally administered 30 min prior to the injection, it inhibited TNF-alpha, IL-12 and IFN-sigma production and augmented IL-10 production. Y-40138 also inhibited IL-12 production and augmented IL-10 production in TNF-alpha-stimulated mice. In IL-10 knockout mice, Y-40138 inhibited TNF-alpha and IL-12 production 1.5 h after the LPS injection but not after 3 h or later, unlike in wild mice. In addition, TNF-alpha production was inhibited by Y-40138 at concentrations that could not augment IL-10 production. These data suggest that Y-40138 modulates pro-inflammatory cytokine production by both IL-10-dependent and -independent mechanisms.
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PMID:Treatment with Y-40138, a multiple cytokine production modulator, inhibits lipopolysaccharide- or tumour necrosis factor-alpha-induced production of pro-inflammatory cytokines and augments interleukin-10. 1625 79

The study demonstrates significant changes of cytokine-producing ability of mononuclear blood leucocytes in type 'hepatitis, correlating with the degree of hepatic lesion. The results showed that various morphologic types of chronic virus type C hepatitis were associated with disbalance in production of pro- and antiinflammatory cytokines, i.e. decrease of tumor necrosis factor (TNF)-alpha concentration and a significant rise of interleukin (IL)-4 and IL-10 concentations, which were the most prominent in cases of severe hepatic fibrosis and high histologic activity of hepatitis. The study established a direct correlation between increase of the ability of mononuclear blood leucocytes to synthesize IL-4, and the progress of the pathologic process.
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PMID:[Immunoregulatory cytokines and chronization of type C hepatitis: matching of clinical and immunological manifestations]. 1627 39

Regulatory CD4(+)CD25(+) T cells (Tregs) are defective numerically and functionally in autoimmune hepatitis (AIH). We have investigated and compared the mechanism of action of Tregs in healthy subjects and in AIH patients using Transwell experiments, where Tregs are cultured either in direct contact with or separated from their targets by a semipermeable membrane. We also studied Treg FOXP3 expression and effect on apoptosis. Direct contact is necessary for Tregs to suppress proliferation and IFN-gamma production by CD4(+)CD25(-) and CD8(+) T cells in patients and controls. Moreover, in both, direct contact of Tregs with their targets leads to increased secretion of regulatory cytokines IL-4, IL-10, and TGF-beta, suggesting a mechanism of linked immunosuppression. Tregs/CD4(+)CD25(-) T cell cocultures lead to similar changes in IFN-gamma and IL-10 secretion in patients and controls, whereas increased TGF-beta secretion is significantly lower in patients. In contrast, in patients, Tregs/CD8(+) T cell cocultures lead to a higher increase of IL-4 secretion. In AIH, Treg FOXP3 expression is lower than in normal subjects. Both in patients and controls, FOXP3 expression is present also in CD4(+)CD25(-) T cells, although at a low level and not associated to suppressive function. Both in patients and controls, addition of Tregs does not influence target cell apoptosis, but in AIH, spontaneous apoptosis of CD4(+)CD25(-) T cells is reduced. In conclusion, Tregs act through a direct contact with their targets by modifying the cytokine profile and not inducing apoptosis. Deficient CD4(+)CD25(-) T cell spontaneous apoptosis may contribute to the development of autoimmunity.
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PMID:Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis. 1654 87

Vaccines are for healthy people, to prevent them from becoming ill. Such prophylactic vaccines have been a great success. Therapeutic vaccines become more and more important, especially as life expectancy increases. Efforts to develop vaccines against such diseases as cancer, AIDS, hepatitis, tuberculosis, Alzheimer disease, and mad cow disease have not yet reached the stage where they can be successfully used on a daily basis. However, significant progress has been made in the realm of autoimmune diseases, resulting (at least in one case) in an immunomodulatory vaccine against multiple sclerosis that was developed in the author's laboratory, and that is in daily use by about 100,000 patients. The drug or therapeutic vaccine against the exacerbating-remitting type of multiple sclerosis is a copolymer of four amino acid residues, denoted Copaxone, which are related to myelin basic protein. This paper discusses Copaxone as well as a candidate immunomodulatory vaccine against myasthenia gravis, a peptide derived from the nicotinic acetylcholine receptor. Copolymer 1 (Cop 1, glatiramer acetate, Copaxone) is a synthetic amino acid random copolymer that is immunologically cross-reactive with myelin basic protein and suppresses experimental allergic encephalomyelitis in several animal species. Cop 1 slows the progression of disability and reduces the relapse rate in exacerbating-remitting multiple sclerosis patients. Cop 1 is a potent inducer of T helper 2 (Th2) regulatory cells in mice and humans; and Th2 cells are found in both the brains and spinal cords of Cop 1-treated mice and humans. MG and experimental autoimmune MG are T cell-regulated, antibody-mediated autoimmune diseases. Two peptides, representing sequences of the human AChR-alpha-subunit, p195-212 and p259-271, are immunodominant T-cell epitopes in MG patients and two strains of mice. Altered peptide ligand, composed of the randomly arranged two single amino acid analogs inhibits in vitro and in vivo MG-associated autoimmune responses. The active suppression is mediated by the CD4+ CD25+ immunoregulatory cells and is associated with the downregulation of Th1-type cytokines and upregulation of the secretion of IL-10 and the immunosuppressive cytokine transforming growth factor beta.
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PMID:Immunomodulatory vaccines against autoimmune diseases. 1660 9


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