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

Our previous reports, both experimental and human studies, have shown the importance of fibrinogen-like protein-2 (fgl2) prothrombinase in the development of fulminant viral hepatitis, a disease with a mortality of more than 80% in cases lacking immediate organ transplantation. To interfere with this potentially effective target, a 322-bp mouse fgl2 (mfgl2) antisense plasmid complementary to the exon 1 sequence of the gene, including the translation initiation site AUG, was successfully constructed. A dose-dependent inhibitory effect on mfgl2 expression by mfgl2 antisense plasmid was observed in interferon-gamma-treated RAW 264.7 cells. On hydrodynamic delivery, mfgl2 antisense plasmid significantly reduced mfgl2 expression in vivo; markedly ameliorated inflammatory cell infiltration, fibrin deposition, and hepatocyte necrosis; prolonged the survival time period; and elevated the survival rate among BALB/cJ mice with murine hepatitis virus type 3-induced fulminant hepatitis. This study may provide an effective way to interfere with the potential therapeutic target fgl2 gene for fulminant viral hepatitis and other diseases with similar pathological characteristics of microcirculation disorders, including acute rejection of xeno- or allograft transplantation and fetal loss syndrome, in which studies show fgl2 plays an important role.
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PMID:Novel mfgl2 antisense plasmid inhibits murine fgl2 expression and ameliorates murine hepatitis virus type 3-induced fulminant hepatitis in BALB/cJ mice. 1677 68

The effects of combined antiviral therapy on the apoptosis of peripheral blood mononuclears (PBM) were investigated in 54 patients with chronic hepatitis C (CHC), including patients with chronic viral-and-alcohol hepatitis (CVAH). Simultaneously, serum concentrations of cytokines (tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and interleukins 10 and 12) using flow cytofluorimetry were taken. The results demonstrate an increase in the intensity of PBM apoptosis in patients with CHC and CVAH vs. controls; there was a tendency of lesser apoptosis intensity in the CVAH subgroup. In both groups IFN-gamma and TNF-alpha concentrations were increased, and there was a direct correlation between the level of apoptosis and TNF-alpha concentration. The study found an increase in the intensity of apoptosis in CHC patients with primary virological response to antiviral therapy with IFN-alpha and riboflavin, which can be considered an additional prognostic factor of the effectiveness of treatment.
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PMID:[Apoptosis of peripheral blood mononuclears and evaluation of the effectiveness of antiviral therapy of chronic C hepatitis]. 1720 46

Several autoimmune diseases are thought to be mediated in part by interleukin (IL)-18. Many are those with associated increased interferon-gamma (IFNgamma) levels such as systemic lupus erythematosus, macrophage activation syndrome, rheumatoid arthritis, Crohn's disease, psoriasis, and graft-versus-host disease. In addition, ischemia, including acute renal failure in human beings, appears to involve IL-18. Animal studies also support the concept that IL-18 is a key player in models of lupus erythematosus, atherosclerosis, graft-versus-host disease, and hepatitis. Unexpectedly, IL-18 plays a role in appetite control and the development of obesity. IL-18 is a member of the IL-1 family; IL-1beta and IL-18 are related closely, and both require the intracellular cysteine protease caspase-1 for biological activity. The IL-18 binding protein, a naturally occurring and specific inhibitor of IL-18, neutralizes IL-18 activities and has been shown to be safe in patients. Other options for reducing IL-18 activities are inhibitors of caspase-1, human monoclonal antibodies to IL-18, soluble IL-18 receptors, and anti-IL-18 receptor monoclonal antibodies.
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PMID:Interleukin-18 and the pathogenesis of inflammatory diseases. 1733 92

The underlying mechanisms for earlier hepatitis B e antigen (HBeAg) seroconversion in patients with chronic hepatitis B virus (HBV) genotype B when compared with genotype C are unknown. We aimed to determine whether there were any differences in the T helper (Th) responses during hepatitis flares in HBeAg-positive patients with genotypes B and C. Proliferative response measured by (3)H-thymidine uptake and Th responses measured by Enzyme-Linked Immunosorbent Spot assays for interleukin (IL)-2, interferon-gamma (IFN-gamma), IL-4, IL-5 and IL-10 were performed in 10 patients with genotype B and 10 with genotype C with hepatitis flares. HBV genotypes, core promoter, precore mutations, sequence of HBV core region and HBV DNA levels were determined. There was no difference in the HBV DNA levels during hepatitis flares between patients with genotypes B and C. Patients with genotype B had a significantly higher number of IFN-gamma producing cells [with hepatitis B core antigen (HBcAg) stimulation] and lower number of IL-10 producing cells (with HBcAg and HBeAg stimulation) compared with patients with genotype C (P = 0.011, =0.043, <0.001 respectively). There was a trend (P = 0.058) that patients with genotype B had a higher cumulative rate of HBeAg seroconversion. Patients with precore mutants also had a significantly higher number of IFN-gamma producing cells (with HBcAg stimulation) and lower number of IL-10 producing cells (with HBeAg stimulation) compared to patients without precore mutant (P = 0.038, =0.016 respectively). HBV genotype B induces a greater Th1 and lesser Th2 response than genotype C. This provides immunologic evidence for the higher chance of HBeAg seroconversion in patients with genotype B.
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PMID:Difference in T helper responses during hepatitis flares in hepatitis B e antigen (HBeAg)-positive patients with genotypes B and C: implication for early HBeAg seroconversion. 1738 19

Natural killer (NK) cells are innate immune cells that are enriched in the liver, but the processes underlying NK cell trafficking to the liver and cellular activation within the liver of patients with T cell-mediated liver diseases remain poorly defined. Concanavalin A (Con A) hepatitis is a murine model mimicking many aspects of human T cell-mediated liver diseases. Here we demonstrate that severe hepatitis in CCR5-deficient (KO) mice is associated with increased hepatic NK cell recruitment driven by enhanced hepatic production of CCL5 acting via CCR1 and by enhanced hepatic NK cell activation relative to that observed in wild-type mice after Con A administration. Furthermore, NK cell depletion ameliorated severe hepatitis in CCR5 KO mice but did not alter hepatitis in wild-type mice after Con A treatment. We propose that in the setting of CCR5 deficiency NK cells assume a profound effector role in Con A hepatitis via enhanced CCL5-CCR1 driven hepatic recruitment in addition to augmented cytokine-driven NK cell activation to produce interferon-gamma. These results highlight the potential profound impact of altered chemokine receptor expression on the innate immune response in the setting of T cell-mediated hepatitis.
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PMID:CCR5 deficiency drives enhanced natural killer cell trafficking to and activation within the liver in murine T cell-mediated hepatitis. 1752 65

The authors studied the levels of cytokines (interleukin (IL)-1, IL-2, IL-4, IL-6, and interferon-gamma (IFN-gamma)) and cell response to HBV and HCV in the dynamics in patients with acute mixed hepatitis (B+C) who recovered or became chronically ill, as well as before and after treatment of hepatitis C. Patients who later recovered had high levels of IL-2 and IFN-gamma during the acute phase of the disease, and displayed T-lymphocyte sensitization to HbeAg, Hbcore Ag, and the non-structural protein HCV NS3. A significant elevation of IL-2 level and, especially, IFN-gamma level, as well as the appearance of T-lymphocyte response to HCV NS3, HCVcore Ag, and HCV NS4 was observed during antiviral therapy.
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PMID:[Clinical significance of cytokine level and T-cell lymphocyte response to B and C hepatic viral antigens in patients with type C and B+C hepatitis receiving antiviral therapy]. 1788 15

The histological hallmark of autoimmune hepatitis (AIH) is a dense portal mononuclear cell infiltrate that invades the surrounding parenchyma and comprises T and B lymphocytes, macrophages, and plasma cells. An unknown but powerful stimulus must be promoting the formation of this massive inflammatory cellular reaction that is likely to initiate and perpetuate liver damage. An autoimmune attack can follow different pathways to inflict damage on hepatocytes. Liver damage is likely to be orchestrated by CD4(+) T lymphocytes recognizing an autoantigenic liver peptide. To trigger an autoimmune response, the peptide must be embraced by an HLA class II molecule and presented to naive CD4(+) T helper (Th0) cells by professional antigen presenting cells, with the co-stimulation of ligand-ligand fostering interaction between the two cells. Th0 cells become activated, differentiate into functional phenotypes according to the cytokines prevailing in the microenvironment and the nature of the antigen, and initiate a cascade of immune reactions determined by the cytokines produced by the activated T cells. Th1 cells, arising in the presence of the macrophage-derived interleukin (IL) -12, secrete mainly IL-2 and interferon-gamma (IFN-gamma), which activate macrophages, enhance expression of HLA class I (increasing liver cell vulnerability to a CD8(+) T cell cytotoxic attack), and induce expression of HLA class II molecules on hepatocytes. Th2 cells, which differentiate from Th0 if the microenvironment is rich in IL-4, produce mainly IL-4, IL-10, and IL-13 which favour autoantibody production by B lymphocytes. Physiologically, Th1 and Th2 antagonize each other. Th17 cells, a recently described population, arise in the presence of transforming growth factor beta (TGF-beta) and IL-6 and appear to have an important effector role in inflammation and autoimmunity. The process of autoantigen recognition is strictly controlled by regulatory mechanisms, such as those exerted by CD4(+)CD25(+) regulatory T cells, which derive from Th0 in the presence of TGF-beta, but in the absence of IL-6. If regulatory mechanisms fail, the autoimmune attack is perpetuated. Over the past three decades different aspects of the above pathogenic scenario have been investigated. In particular, a defect in immunoregulation affecting CD4(+)CD25(+) regulatory T cells (T-regs) has been demonstrated in AIH, particularly at diagnosis or during relapse. Advances in the study of autoreactive T cells have occurred mostly in AIH type 2, since the knowledge that CYP2D6 is the main autoantigen has enabled the characterization of both CD4 and CD8 T cells targeting this cytochrome. CD4 T cells from patients with type 2 AIH positive for the predisposing HLA allele DRB1*0701 recognize seven regions of CYP2D6, five of which are also recognized by CD8 T cells. High numbers of IFN-gamma producing CD4 T cells and CD8 T cells are associated with biochemical evidence of liver damage, suggesting a combined cellular immune attack.
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PMID:Aetiopathogenesis of autoimmune hepatitis. 1852 28

Activation of innate immunity is critical for vaccine development and immunotherapy, through triggering antigen specific immune responses. Natural killer T (NKT) cells are a unique type of innate immune cells which exert potent anti-viral and anti-metastasis function, through producing interferon-gamma and activating dendritic cells to present tumor antigens to CD8 T cells. alpha-Galactosylceramide, a synthetic antigen for NKT cells, is an adjuvant for protein antigens which can induce protective immunity against cancer and viral diseases, and has been proven to be safe and immune stimulatory in human cancer and hepatitis patients. Current existing problem for alpha-galactosylceramide is its induction of anergy of NKT cells, due to the non-selective presentation of alpha-galactosylceramide antigen by B cells. We hypothesized that nanoparticle formulated alpha-galactosylceramide may be selectively presented by dendritic cells and macrophages, but not B cells, thus avoiding anergy induction in NKT cells. We have prepared poly-lactic acid based nanoparticles conjugated with alpha-galactosylceramide, examined their stimulation of NKT cells in vitro and in vivo in mice, and showed that nanoparticle formulated alpha-galactosylceramide stimulates NKT cells. In contrast to soluble alpha-galactosylceramide, which caused NKT anergy after single stimulation, nanoparticle formulated alpha-galactosylceramide repeatedly stimulates NKT cells without inducing anergy. Mechanistic studies showed that nanoparticle formulated alpha-galactosylceramide is efficiently presented by mouse CD11c+population containing dendritic cells, and CD11b+population containing macrophages, but very poorly by B220+population containing B cells. Hence, nanoparticle formulated alpha-galactosylceramide is an attractive immunomodulator for immunotherapy and vaccine development. Future studies will be focused on its application as adjuvant for protein and/or peptide antigens.
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PMID:Nanoparticle formulated alpha-galactosylceramide activates NKT cells without inducing anergy. 1946 51

Vasoactive intestinal peptide (VIP) is well characterized as an endogenous anti-inflammatory neuropeptide and has a brand range of biological functions. In this study, we found increased endogenous VIP expression in mice with concanavalin A-induced hepatitis, a widely used experimental model of immune-mediated liver injury. We investigated further the effect of VIP administration on concanavalin A-induced liver injury. Compared with mice pretreated with PBS, mice pretreated with VIP exhibited much lower plasma levels of aminotransferases, less inflammatory infiltration in the liver and hepatocyte apoptosis. Meanwhile, VIP significantly inhibited the release of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in concanavalin A-injected mice, but markedly elevated the production of anti-inflammatory cytokine interleukine-10 (IL-10). Further investigation demonstrated increased intracellular cAMP concentration after VIP administration, and showed that the protective effect of VIP on concanavalin A-induced hepatitis was mediated mainly through VIP receptor 1 (VPAC(1)). These results suggest that VIP is capable of attenuating immune-mediated liver injury in vivo. This effect is associated with its downregulation of critical inflammatory mediators and its upregulation of anti-inflammatory cytokine through VPAC(1), possibly via the cAMP-dependent pathway.
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PMID:Vasoactive intestinal peptide attenuates concanavalin A-mediated liver injury. 1922 97

Complexes of cationic liposomes and non-coding DNA (CLDC) have shown promise as vaccine adjuvant. Using the woodchuck animal model of hepatitis B virus (HBV) infection, the immunogenic effects of CLDC were evaluated following vaccination with three doses of woodchuck hepatitis virus surface antigen (WHsAg) adjuvanted with either CLDC or conventional alum and administered intramuscularly (im) or subcutaneously (sc). IM vaccination with WHsAg and CLDC elicited antibodies earlier, in more woodchucks, and with higher titers than WHsAg and alum. After two vaccine doses, antibody titers were higher following im than sc administration. Woodchucks administered two vaccine doses sc received the third vaccine dose im, and antibody responses reached titers comparable to those elicited by im administration. Following the second vaccine dose, im vaccination with WHsAg and CLDC induced T cell responses to WHsAg and selected WHs peptides and expression of the leukocyte surface marker CD8 and of the Th1 cytokines interferon-gamma and tumor necrosis factor alpha in woodchucks. T cell responses and CD8/cytokine expression were diminished in woodchucks from the other groups suggesting that this vaccine regimen induced a skew toward Th1 immune responses. The present study in woodchucks demonstrates that CLDC-adjuvanted WHsAg vaccine administered im resulted in a more rapid induction of humoral and cellular immune responses compared to conventional, alum-adjuvanted WHsAg vaccine. While less rapid, the immune responses following sc administration can prime the im immune responses. This adjuvant activity of CLDC over alum may be beneficial for therapeutic vaccination in chronic HBV infection.
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PMID:Rapid immunity to vaccination with woodchuck hepatitis virus surface antigen using cationic liposome-DNA complexes as adjuvant. 1969 9


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