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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis C virus (HCV)-related liver failure is the leading indication for liver transplantation worldwide. After transplantation, virological recurrence is the rule, but the spectrum of histological injury is wide, ranging from the development of allograft cirrhosis within a few years to minimal hepatitis despite long-term follow-up. The immunological correlates of this variable natural history are poorly understood. Here, we studied the kinetics of the cellular immune responses, viral replication, and allograft histology in 24 patients who had undergone liver transplantation for HCV-related liver failure. Using direct ex vivo methodologies (i.e., interferon-gamma ELISPOT and major histocompatibility complex class I-peptide tetrameric complexes), we found that patients who experienced viral eradication after antiviral therapy showed restoration of HCV-specific T-cell responses, whereas patients with progressive HCV recurrence that failed to respond to therapy showed declining frequencies of these viral-specific effector cells. The cytotoxic T lymphocytes that peripherally reconstituted after transplantation were clonotypically identical to those present within the recipient explant liver, defined at the level of the T-cell receptor beta chain (one epitope/one clone). Moreover, the subset of patients who spontaneously demonstrated minimal histologic recurrence had more vigorous CD4+ T-cell responses in the first 3 months, particularly targeting nonstructural proteins. We provide evidence that T-cell responses emerge after liver transplantation, and their presence correlates with improved histological and clinical outcomes. In conclusion, these results may help identify patients more likely to develop severe HCV recurrence and therefore benefit from current antiviral therapy, as well as provide a rationale for the future use of novel immunotherapeutic approaches. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience. wiley.com/jpages/0270-9139/suppmat/index.html).
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PMID:Reconstitution of hepatitis C virus-specific T-cellmediated immunity after liver transplantation. 1561 26

Clearance of acute hepatitis C virus (HCV) infection is associated with strong and multi-specific cellular immune responses which are often weak in chronic hepatitis C. We here report a case of spontaneous and sustained resolution of chronic hepatitis C virus infection in the absence of apparent HCV-specific immunity. The patient received standard antiviral therapy for chronic HCV infection and was HCV-RNA negative at the end of treatment but relapsed between follow-up week 4 and 12. Surprisingly, from follow-up week 28 on, he persistently was HCV-RNA negative in serum, even when being tested with the highly sensitive TMA-assay (cut-off 5-10IU/ml). ALT levels were within the normal range throughout follow-up. Virus-specific CD4+ T cell responses were prospectively analysed during the relapse period and during spontaneous resolution by interferon-gamma ELISPOT assays. Importantly, no HCV-specific cellular immune responses were detectable at any time-point. The patient suffered from an acute respiratory tract infection before HCV clearance and serum IL-8 levels were significantly increased during this period. Thus, spontaneous resolution of hepatitis C after antiviral treatment and relapse may occur even in the absence of hepatitis flares and apparent HCV-specific immune responses in single cases. The role of heterologous infections for HCV clearance requires further investigation.
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PMID:Spontaneous resolution of chronic hepatitis C virus infection after antiviral treatment and relapse. 1565 66

Transfer of B6 T cells to major histocompatibility complex (MHC) class I disparate bm1 x B6 F1 mice leads to the development of hepatic graft-versus-host disease (GVHD) characterized by an active hepatitis with portal and lobular inflammation as well as bile duct inflammation and venulitis. The present studies determined the role of tumor necrosis factor (TNF) in hepatic GVHD. B6 responder cells were cultured with irradiated MHC class I disparate bm1 or syngeneic spleen cells (SpC) in the presence or absence of TNF receptor inhibitor [TNFR-immunoglobulin (Ig)]. Recipient bm1 x B6 F1 mice were irradiated (600 cGy) and reconstituted with 5 x 10(6) T cell-depleted B6 bone marrow cells and 1 x 10(7) B6 SpC. Mice were injected with an adenovirus encoding TNFR-Ig [TNF inhibitor-encoding adenovirus (Adv-TNFi)] or beta-galactosidase (Adv-betagal). Severity of liver GVHD was assessed by a composite histopathological score consisting of the sum of scores for venulitis, lobular hepatitis, and bile duct inflammation. Addition of TNFR-Ig reduced cell proliferation in mixed lymphocyte cultures using B6 responder SpC by 71% +/- 12.8% and interferon-gamma responses by 78% +/- 18%. GVHD-induced "wasting disease" was reduced in Adv-TNFi recipients [4.4%+/-5.2% weight loss (n=11)] compared with Adv-betagal recipients [16.1%+/-7.6% weight loss (n=11; P=0.0004)] 9 days post-transplant. Composite histopathological scores and individual venulitis scores were reduced with the addition of Adv-TNFi. Hepatic CD8+ T cells in the recipients of Adv-TNFi were reduced as compared with recipients of Adv-betagal. In conclusion, Adv-TNFi reduces MHC class I disparate alloproliferative responses and hepatic GVHD.
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PMID:The role of TNF in hepatic histopathological manifestations and hepatic CD8+ T cell alloresponses in murine MHC class I disparate GVHD. 1608 94

Expression of costimulatory molecules is significantly upregulated in various organs in an animal model of severe hepatitis induced by injection of Propionibacterium acnes (P. acnes) and lipopolysaccharide (LPS). In the present study, we examined whether blockade of costimulatory signals by CTLA-4Ig can suppress the liver injury in this model. We injected an adenovirus encoding CTLA-4Ig (AdCTLA-4Ig) into mice 7 days before, on the same day, or 3 days after P. acnes priming. The virus was found to infect the liver preferentially, and CTLA-4Ig was detected in the serum as early as 2 days after viral injection. After injection of LPS, liver injury and survival rates were examined. Most of the mice not injected with AdCTLA-4Ig died within 12 hours after injection of LPS. In contrast, all the AdCTLA-4Ig-injected mice survived when the virus was injected 7 days before or on the same day as P. acnes priming. Importantly, hemorrhagic liver injury and serum alanine aminotransferase levels were significantly reduced after LPS injection even when AdCTLA-4Ig was injected 3 days after P. acnes priming. Immunological analyses showed that CTLA-4Ig inhibited the activation and expansion of P. acnes-specific CD4+ T cells in the hepatic lymph nodes, leading to a reduction in the recruitment of the cells to the liver. The total amounts of interferon-gamma, interleukin-12, and various chemokines in the liver were then decreased, resulting in inhibition of the secondary recruitment of not only T cells but also macrophages. In conclusion, CTLA-4Ig could be useful for treatment of severe liver injury.
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PMID:CTLA-4Ig suppresses liver injury by inhibiting acquired immune responses in a mouse model of fulminant hepatitis. 1617 5

Concanavalin A-induced hepatitis is often used as a model of liver injury. In this model, plasma tumor necrosis factor-alpha (TNF-alpha) level increased in concanavalin A-injected mice. Prophylactic treatment with Y-40138, N-[1-(4-[4-(pyrimidin-2-yl)piperazin-1-yl]methyl phenyl)cyclopropyl] acetamide.HCl, significantly suppressed the increase in plasma TNF-alpha level. In this study, we compared the effect of Y-40138 with those of pentoxifylline and anti-TNF-alpha antibody on concanavalin A-induced hepatitis. Prophylactic treatment with pentoxifylline, anti-TNF-alpha antibody and Y-40138 reduced plasma alanine aminotransferase level. Therapeutic treatment with Y-40138 significantly reduced plasma alanine aminotransferase level, but pentoxifylline and anti-TNF-alpha antibody did not. Therapeutic treatment with Y-40138 significantly reduced plasma interferon-gamma (IFN-gamma) and monokine induced by interferon-gamma levels. From these results, Y-40138 may be expected as a new class of therapeutic drug for treatment of TNF-alpha, IFN-gamma and/or chemokine-related liver diseases such as alcoholic liver disease.
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PMID:Therapeutic administration of Y-40138, a multiple cytokine modulator, inhibits concanavalin A-induced hepatitis in mice. 1623 80

Unlike T cells, the role of natural killer (NK) cells is not well documented in the concanavalin (ConA)- induced hepatitis model. This study aimed to investigate the regulatory effect of high levels of interferon-gamma (IFN-gamma) on NK cells in ConA-induced hepatitis. The cytotoxicities of NK cells from ConA-injected mice or NK cell lines (NK92 and NKL) were detected by the 4-h 51Cr release assay. Depletion of NK cells with AsGM1 antibody was used to assess the NK cell role in ConA-induced hepatitis. Expression of NK cell receptors and cytotoxic molecules was measured by reverse transcription-polymerase chain reaction. Twelve hours after ConA injection, serum IFN-gamma was significantly increased in wild mice, but not in severe combined immunodeficiency mice, and hepatic NK cells exerted impaired cytotoxicity against YAC-l cells in wild mice. Eight hours after NK cells were incubated in serum from ConA-treated mice, NK cell cytotoxicity was down-modulated and the effect was abolished by pretreatment with neutralizing serum IFN-gamma with specific antibody in vitro. A high concentration of IFN-gamma (> 1000 U/mL) inhibited the cytotoxicities of 2 NK cell lines in vitro, accompanied with down-regulation of NKG2D transcripts and up-regulation of NKG2A/B and KIR2DL transcripts. The inhibitive role of IFN-gamma was not seen in NKG2D ligand negative cells. These results suggest that NK cell cytotoxicity was inhibited by high levels of IFN-gamma in ConA-induced hepatitis, which may relate to the dispensable role of NK cells.
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PMID:Impaired NK cell cytotoxicity by high level of interferon-gamma in concanavalin A-induced hepatitis. 1639 13

Bicyclol, a new anti-hepatitis drug, has been found to protect against liver injury induced by certain hepatotoxins. The present study was to investigate the effect of bicyclol on acute hepatic failure caused by an intraperitoneal injection of lipopolysaccharide (LPS, 15 microg/kg) and D-galactosamine (800 mg/kg) in mice. Bicyclol (150, 300 mg/kg) was given to mice orally once or three doses before the injection of LPS/D-galactosamine. The liver injury was assessed biochemically and histologically. The mortality in mice was monitored for 48 h after LPS/D-galactosamine poisoning. The expressions of cytokines, adhesion molecules and LPS receptors were determined. As a result, bicyclol showed significant protection as evidenced by the decrease of elevated aminotransferases and total bilirubin, reversion of prolonged prothrombin time and improvement of liver pathological injury in a dose-dependent manner. Pretreatment with bicyclol (300 mg/kg) also lowered the mortality after LPS/GalN intoxication. Furthermore, bicyclol inhibited the elevation of serum tumor necrosis factor-alpha, interferon-gamma and markedly enhanced interleukin-10. The expressions of intercellular adhesion molecule-1, lymphocyte function-associated antigen 1 and the transcription of CD14 and toll-like receptor 4 were also suppressed by bicyclol. These results suggest that bicyclol has remarkable hepatoprotective effects on LPS/D-galactosamine-induced liver injury and the possible mechanism is related to its anti-inflammatory action.
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PMID:Protective effect of bicyclol on acute hepatic failure induced by lipopolysaccharide and D-galactosamine in mice. 1648 63

Infection of the central nervous system (CNS) by the neurotropic JHM strain of mouse hepatitis virus (JHMV) induces an acute encephalomyelitis associated with demyelination. To examine the anti-viral and/or regulatory role of interferon-gamma (IFN-gamma) signaling in the cell that synthesizes and maintains the myelin sheath, we analyzed JHMV pathogenesis in transgenic mice expressing a dominant-negative IFN-gamma receptor on oligodendroglia. Defective IFN-gamma signaling was associated with enhanced oligodendroglial tropism and delayed virus clearance. However, the CNS inflammatory cell composition and CD8(+) T-cell effector functions were similar between transgenic and wild-type mice, supporting unimpaired peripheral and CNS immune responses in transgenic mice. Surprisingly, increased viral load in oligodendroglia did not affect the extent of myelin loss, the frequency of oligodendroglial apoptosis, or CNS recruitment of macrophages. These data demonstrate that IFN-gamma receptor signaling is critical for the control of JHMV replication in oligodendroglia. In addition, the absence of a correlation between increased oligodendroglial infection and the extent of demyelination suggests a complex pathobiology of myelin loss in which infection of oligodendroglia is required but not sufficient.
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PMID:Inhibition of interferon-gamma signaling in oligodendroglia delays coronavirus clearance without altering demyelination. 1650 95

We studied inhibition of histone deacetylases (HDACs), which results in the unraveling of chromatin, facilitating increased gene expression. ITF2357, an orally active, synthetic inhibitor of HDACs, was evaluated as an anti-inflammatory agent. In lipopolysaccharide (LPS)-stimulated cultured human peripheral blood mononuclear cells (PBMCs), ITF2357 reduced by 50% the release of tumor necrosis factor-alpha (TNFalpha) at 10 to 22 nM, the release of intracellular interleukin (IL)-1alpha at 12 nM, the secretion of IL-1beta at 12.5 to 25 nM, and the production of interferon-gamma (IFNgamma) at 25 nM. There was no reduction in IL-8 in these same cultures. Using the combination of IL-12 plus IL-18, IFNgamma and IL-6 production was reduced by 50% at 12.5 to 25 nM, independent of decreased IL-1 or TNFalpha. There was no evidence of cell death in LPS-stimulated PBMCs at 100 nM ITF2357, using assays for DNA degradation, annexin V, and caspase-3/7. By Northern blotting of PBMCs, there was a 50% to 90% reduction in LPS-induced steady-state levels of TNFalpha and IFNgamma mRNA but no effect on IL-1beta or IL-8 levels. Real-time PCR confirmed the reduction in TNFalpha RNA by ITF2357. Oral administration of 1.0 to 10 mg/kg ITF2357 to mice reduced LPS-induced serum TNFalpha and IFNgamma by more than 50%. Anti-CD3-induced cytokines were not suppressed by ITF2357 in PBMCs either in vitro or in the circulation in mice. In concanavalin-A-induced hepatitis, 1 or 5 mg/kg of oral ITF2357 significantly reduced liver damage. Thus, low, nonapoptotic concentrations of the HDAC inhibitor ITF2357 reduce pro-inflammatory cytokine production in primary cells in vitro and exhibit anti-inflammatory effects in vivo.
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PMID:The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. 1655 34

(5R)-5-hydroxytriptolide (LLDT-8) exhibits strong immunosuppressive activities in vitro and in vivo. Here, we investigated the effects of LLDT-8 on concanavalin A-induced hepatitis. Liver damage was evaluated by serum alanine transaminase (ALT) level and liver histology. The effects of LLDT-8 were determined by measurement of serum cytokines, lymphocyte proliferation assay, flow cytometry analysis of splenic T cell percentage and apoptosis, reverse-transcription polymerase chain reaction (RT-PCR) analysis for gene transcriptions. In LLDT-8-treated mice, serum ALT level and histological damage were markedly attenuated. The beneficial effect of LLDT-8 was closely associated with (i) reduction of serum tumor necrosis factor-alpha, interferon-gamma (IFN-gamma), interleukin-2, interleukin-12, and interleukin-6 levels; (ii) elimination of activated T cells by increasing proapoptotic genes signal transducer and activator of transcription 1 (STAT1) and interferon regulatory factor-1 (IRF-1) expression in spleens; (iii) blockade of mRNA expressions for chemokines (monokine induced by IFN-gamma, Mig; IFN-gamma-inducible protein-10, IP-10; IFN-inducible T cell-alpha chemoattractant, I-TAC), vascular adhesion molecule-1 (VCAM-1), and chemokine receptors (C-C chemokine receptor 1, CCR1; C-C chemokine receptor 5, CCR5; C-X-C chemokine receptor 3, CXCR3) in livers. These results suggested the therapeutic potential of LLDT-8 in IFN-gamma/STAT1/IRF-1 signaling- and inflammatory cytokines-mediated immune disorders.
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PMID:Preventive effects of (5R)-5-hydroxytriptolide on concanavalin A-induced hepatitis. 1660 50


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