Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L(d)- and K(b)-binding epitopes processed by murine dendritic cells (DC) pulsed with exogenous, particulate hepatitis B surface antigen (HBsAg) are presented to cytotoxic T lymphocytes (CTL). The specific and dose-dependent induction of IFN-gamma release and cytotoxicity in CTL by metabolically active DC did not depend on antigenic peptides contaminating the particles, was cytochalasin D resistant, independent of the maturation state of DC, and blocked by primaquine, amiloride and NH(4)Cl (indicating involvement of acid proteolysis). The specific immunostimulatory phenotype of pulsed DC was maintained for about 3 h after the end of the pulse but rapidly decayed thereafter. Processing of L(d)- and K(b)-binding epitopes from exogenous HBsAg particles by pulsed DC for presentation was TAP independent. Surface-associated 'empty' (presentation-deficient) 64(+) L(d) molecules (defined by the mAb 64-3-7), but not trimeric (presentation-competent) 30(+) L(d) molecules (defined by the mAb 30-5-7) had to be available during the pulse of DC with exogenous HBsAg particles to generate 30(+) L(d)molecules that present the antigenic S(28-39) peptide. Exogenous beta2-microglobulin present during the pulse of DC with HBsAg particles facilitated presentation of L(d)- and K(b)-restricted epitopes. DC generated from bone marrow progenitors in vitro, as well as splenic and liver DC (generated in vivo) presented epitopes to specific CTL. HBsAg particles thus efficiently enter an alternative processing pathway in DC that leads to presentation of epitopes to MHC class I-restricted CTL.
 ...
PMID:Dendritic cells pulsed with exogenous hepatitis B surface antigen particles efficiently present epitopes to MHC class I-restricted cytotoxic T cells. 1192 May 77

Dendritic cell (DC)-dependent activation of liver NKT cells triggered by a single i.v. injection of a low dose (10-100 ng/mouse) of alpha-galactosyl ceramide (alphaGalCer) into mice induces liver injury. This response is particularly evident in HBs-tg B6 mice that express a transgene-encoded hepatitis B surface Ag in the liver. Liver injury following alphaGalCer injection is suppressed in mice depleted of NK cells, indicating that NK cells play a role in NK T cell-initiated liver injury. In vitro, liver NKT cells provide a CD80/86-dependent signal to alphaGalCer-pulsed liver DC to release IL-12 p70 that stimulates the IFN-gamma response of NKT and NK cells. Adoptive transfer of NKT cell-activated liver DC into the liver of nontreated, normal (immunocompetent), or immunodeficient (RAG(-/-) or HBs-tg/RAG(-/-)) hosts via the portal vein elicited IFN-gamma responses of liver NK cells in situ. IFN-beta down-regulates the pathogenic IL-12/IFN-gamma cytokine cascade triggered by NKT cell/DC/NK cell interactions in the liver. Pretreating liver DC in vitro with IFN-beta suppressed their IL-12 (but not IL-10) release in response to CD40 ligation or specific (alphaGalCer-dependent) interaction with liver NKT cells and down-regulated the IFN-gamma response of the specifically activated liver NKT cells. In vivo, IFN-beta attenuated the NKT cell-triggered induction of liver immunopathology. This study identifies interacting subsets of the hepatic innate immune system (and cytokines that up- and down-regulate these interactions) activated early in immune-mediated liver pathology.
 ...
PMID:Activating immunity in the liver. II. IFN-beta attenuates NK cell-dependent liver injury triggered by liver NKT cell activation. 1193 27

Vaccination of healthy adults with recombinant hepatitis B (rHB) vaccine fails to induce a protective antibody response in a proportion of individuals. Imbalanced T-helper (Th)1/Th2 response has been attributed to the lack of specific antibody response to rHB vaccine. In this study, in vitro production of interleukin (IL)-2, interferon (IFN)-gamma and IL-10 was investigated in Iranian healthy adults vaccinated with rHB vaccine. Peripheral blood mononuclear cells (PBMC) were isolated from 18 high responders and eight nonresponders and stimulated with rHB antigen or phytohaemaglutinin (PHA) mitogen. The cytokines were quantitated in culture supernatants by sandwich enzyme-linked immunosorbent assay (ELISA). Our results demonstrated a significant decrease in the production of IL-2, IFN-gamma and IL-10 (P < 0.005) in response to rHB antigen. The levels of all cytokines induced by PHA were similarly represented in both groups of vaccinees. These findings suggest that unresponsiveness to rHB vaccine may be owing to inadequate Th1- and Th2-like cytokine production.
 ...
PMID:Diminished Th1 and Th2 cytokine production in healthy adult nonresponders to recombinant hepatitis B vaccine. 1194 Feb 38

We have previously shown that alpha/beta interferon (IFN-alpha/beta) and gamma interferon (IFN-gamma) inhibit hepatitis B virus (HBV) replication by eliminating pregenomic RNA containing viral capsids from the hepatocyte. We have also shown that HBV-specific cytotoxic T lymphocytes that induce IFN-gamma and tumor necrosis factor alpha (TNF-alpha) in the liver can inhibit HBV gene expression by destabilizing preformed viral mRNA. In order to further study the antiviral activity of IFN-alpha/beta, IFN-gamma, and TNF-alpha at the molecular level, we sought to reproduce these observations in an in vitro system. Accordingly, hepatocytes were derived from the livers of HBV-transgenic mice that also expressed the constitutively active cytoplasmic domain of the human hepatocyte growth factor receptor (c-Met). Here, we show that the resultant well-differentiated, continuous hepatocyte cell lines (HBV-Met) replicate HBV and that viral replication in these cells is efficiently controlled by IFN-alpha/beta or IFN-gamma, which eliminate pregenomic RNA-containing capsids from the cells as they do in the liver. Furthermore, we demonstrate that IFN-gamma, but not IFN-alpha/beta, is capable of inhibiting HBV gene expression in this system, especially when it acts synergistically with TNF-alpha. These cells should facilitate the analysis of the intracellular signaling pathways and effector mechanisms responsible for these antiviral effects.
 ...
PMID:Cytokine-sensitive replication of hepatitis B virus in immortalized mouse hepatocyte cultures. 1199 93

Particulate hepatitis B core Ag (C protein) (HBcAg) and soluble hepatitis B precore Ag (E protein) (HBeAg) of the hepatitis B virus share >70% of their amino acid sequence and most T and B cell-defined epitopes. When injected at low doses into mice, HBcAg particles prime Th1 immunity while HBeAg protein primes Th2 immunity. HBcAg contains 5-20 ng RNA/microg protein while nucleotide binding to HBeAg is not detectable. Deletion of the C-terminal arginine-rich domain of HBcAg generates HBcAg-144 or HBcAg-149 particles (in which >98% of RNA binding is lost) that prime Th2-biased immunity. HBcAg particles, but not truncated HBcAg-144 or -149 particles stimulate IL-12 p70 release by dendritic cells and IFN-gamma release by nonimmune spleen cells. The injection of HBeAg protein or HBcAg-149 particles into mice primes Th1 immunity only when high doses of RNA (i.e., 20-100 microg/mouse) are codelivered with the Ag. Particle-incorporated RNA has thus a 1000-fold higher potency as a Th1-inducing adjuvant than free RNA mixed to a protein Ag. Disrupting the particulate structure of HBcAg releases RNA and abolishes its Th1 immunity inducing potency. Using DNA vaccines delivered intradermally with the gene gun, inoculation of 1 microg HBcAg-encoding pCI/C plasmid DNA primes Th1 immunity while inoculation of 1 microg HBeAg-encoding pCI/E plasmid DNA or HBcAg-149-encoding pCI/C-149 plasmid DNA primes Th2 immunity. Expression data show eukaryotic RNA associated with HBcAg, but not HBeAg, expressed by the DNA vaccine. Hence, codelivery of an efficient, intrinsic adjuvant (i.e., nanogram amounts of prokaryotic or eukaryotic RNA bound to arginine-rich sequences) by HBcAg nucleocapsids facilitates priming of anti-viral Th1 immunity.
 ...
PMID:Priming Th1 immunity to viral core particles is facilitated by trace amounts of RNA bound to its arginine-rich domain. 1199 46

The chimpanzee is a critical animal model for studying cellular immune responses to infectious pathogens such as hepatitis B and C viruses, human immunodeficiency virus, and malaria. Several candidate vaccines and immunotherapies for these infections aim at the induction or enhancement of cellular immune responses against viral epitopes presented by common human major histocompatibility complex (MHC) alleles. To identify and characterize chimpanzee MHC class I molecules that are functionally related to human alleles, we sequenced 18 different Pan troglodytes (Patr) alleles of 14 chimpanzees, 2 of them previously unknown and 3 with only partially reported sequences. Comparative analysis of Patr binding pockets and binding assays with biotinylated peptides demonstrated a molecular homology between the binding grooves of individual Patr alleles and the common human alleles HLA-A1, -A2, -A3, and -B7. Using cytotoxic T cells isolated from the blood of hepatitis C virus (HCV)-infected chimpanzees, we then mapped the Patr restriction of these HCV peptides and demonstrated functional homology between the Patr-HLA orthologues in cytotoxicity and gamma interferon (IFN-gamma) release assays. Based on these results, 21 HCV epitopes were selected to characterize the chimpanzees' cellular immune response to HCV. In each case, IFN-gamma-producing T cells were detectable in the blood after but not prior to HCV infection and were specifically targeted against those HCV peptides predicted by Patr-HLA homology. This study demonstrates a close functional homology between individual Patr and HLA alleles and shows that HCV infection generates HCV peptides that are recognized by both chimpanzees and humans with Patr and HLA orthologues. These results are relevant for the design and evaluation of vaccines in chimpanzees that can now be selected according to the most frequent human MHC haplotypes.
 ...
PMID:Molecular and immunological significance of chimpanzee major histocompatibility complex haplotypes for hepatitis C virus immune response and vaccination studies. 1202 42

Real-time polymerase chain reaction (PCR) assays were developed for woodchuck leukocyte cluster of differentiation (CD) and cytokine mRNA expression. Plasmid DNA standards of each marker (CD3, CD4, CD8, IL-2, IFN-gamma, TNF-alpha, IL-4, IL-10), and RNA standards from mitogen-stimulated woodchuck peripheral blood mononuclear cells (PBMCs) were used to validate and optimize the assays for TaqMan 7700 and iCycler PCR instruments. The complementary DNAs (cDNAs) produced by reverse transcription (RT) of RNA were quantified by real-time PCR against the plasmid DNA standards (6-8 log range) with detection of as few as 10-50 copies of amplicon cDNA per reaction. Analysis of unstimulated and concanavalin A-stimulated woodchuck PBMC demonstrated increased CD and cytokine mRNA expression following mitogenic activation. A liver sample from a woodchuck hepatitis virus (WHV) infected woodchuck with histologically confirmed acute hepatitis had increased intrahepatic CD and cytokine mRNAs compared to liver from an uninfected control woodchuck. The real-time PCR assays were highly specific for the woodchuck markers in PBMC and liver samples and were equally applicable for use in alternate real-time PCR instrumentation. These assays will enable the high-throughput analyses of mRNA markers during WHV infection, and thereby facilitate continued modelling of the immunopathogenesis and immunotherapy of human hepatitis B virus (HBV) infection.
 ...
PMID:Real-time polymerase chain reaction assays for leukocyte CD and cytokine mRNAs of the Eastern woodchuck (Marmota monax). 1205 47

In murine models, overexpression of interleukin (IL)-12 and interferon (IFN)-gamma can induce severe liver damage, whereas IL-10 has anti-inflammatory and hepatoprotective properties. To analyze the potential role of these cytokines in human fulminant hepatitis B, we used immunohistochemistry to study expression of IL-12, IFN-gamma, and IL-10 in explant livers of 11 patients with fulminant hepatitis B, 5 patients with fulminant hepatitis due to other etiologies, 37 patients with chronic liver disease (CLD; hepatitis B virus, n = 15; hepatitis C virus, n = 10; primary biliary cirrhosis, n = 12), and 10 normal controls (NCs). Furthermore, cytokine messenger RNA (mRNA) levels were determined in the liver specimens by quantitative real-time polymerase chain reaction (PCR). In NCs, faint IL-12 expression was detected in only a few Kupffer cells, whereas sinusoidal endothelial cells, hepatic stellate cells, bile ducts, and lymphocytes expressed IL-12 in CLD and, more conspicuously, in fulminant hepatitis B. In contrast, expression of IFN-gamma and IL-10 was restricted to lymphocytes and Kupffer cells, respectively. In fulminant hepatitis B, numbers of IL-12- and IFN-gamma-positive cells markedly exceeded those found in CLD and NCs. A close correlation existed between IL-12 and IFN-gamma expression (r = 0.68; P <.001). In contrast, IL-10 expression was not significantly different in CLD and fulminant hepatitis. The quantitative differences in immunohistologic cytokine expression closely corresponded to the mRNA levels. In conclusion, our data indicate massive induction of the proinflammatory cytokines IL-12 and IFN-gamma in fulminant hepatitis B, which is apparently not counterbalanced by the anti-inflammatory cytokine IL-10. This cytokine imbalance may play an important role in promoting inflammatory reactions leading to massive liver damage in fulminant hepatitis B.
 ...
PMID:Imbalanced intrahepatic expression of interleukin 12, interferon gamma, and interleukin 10 in fulminant hepatitis B. 1229 50

Interleukin-18 (IL-18) produced by activated antigen-presenting cells stimulates natural killer (NK) cells, natural killer T (NKT) cells, and T cells to secrete gamma interferon (IFN-gamma). In this study, injection of a single 10- micro g dose of recombinant murine IL-18 rapidly, reversibly, and noncytopathically inhibited hepatitis B virus (HBV) replication in the livers of HBV transgenic mice. Furthermore, HBV replication was inhibited by as little as 1 micro g of IL-18 injected repetitively, and also by a single 0.1- micro g dose of IL-18 injected together with 1 ng of IL-12, neither of which inhibited HBV replication individually, demonstrating synergy between these cytokines in this system. The antiviral effect of IL-18 was mediated by its ability to activate resident intrahepatic NK cells and NKT cells to produce IFN-gamma and by its ability to induce IFN-alpha/beta production in the liver. These results suggest that IL-18 has the potential to contribute to the control of HBV replication during self-limited infection and that it may have therapeutic value for the treatment of patients with chronic hepatitis.
 ...
PMID:Interleukin-18 inhibits hepatitis B virus replication in the livers of transgenic mice. 1236 12

In this study we evaluated the ability of activated intrahepatic APCs to inhibit hepatitis B virus (HBV) replication in transgenic mice. Intrahepatic APCs were activated by administration of an anti-CD40 agonistic mAb (alphaCD40). We showed that a single i.v. injection of alphaCD40 was sufficient to inhibit HBV replication noncytopathically by a process associated with the recruitment of dendritic cells, macrophages, T cells, and NK cells into the liver and the induction of inflammatory cytokines. The antiviral effect depended on the production of IL-12 and TNF-alpha by activated APCs; however, it was mediated primarily by IFN-gamma produced by NK cells, and possibly T cells, that were activated by IL-12. Collectively, these results suggest that activated APCs can directly produce antiviral cytokines (IL-12, TNF-alpha) and trigger the production of other cytokines (i.e., IFN-gamma) by other cells (e.g., NK cells and T cells) that do not express CD40. These results provide insight into a hitherto unsuspected antiviral function of intrahepatic APCs, and they suggest that therapeutic activation of APCs may represent a new strategy for the treatment of chronic HBV infection.
 ...
PMID:Activated intrahepatic antigen-presenting cells inhibit hepatitis B virus replication in the liver of transgenic mice. 1239 Dec 36


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>