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)

Human adenoviruses have been developed as an attractive vehicle for in vivo liver-directed gene therapy. Problems with the application of first generation recombinant adenoviruses to liver-directed gene therapy have been transient expression of the recombinant gene and development of hepatitis. Previous studies in mouse models of gene transfer to liver and lung suggested that MHC class I-restricted cytotoxic T lymphocytes (CTLs) to viral antigens may be effectors in the elimination of transgene expression. The goal of this study was to evaluate the importance of viral antigens versus transgene product in inducing CTL mediated hepatocyte destruction in vivo. Immunization of C57BL/6 mice with a lacZ-expressing adenovirus elicited CTL responses to both viral antigens and the transgene product, beta-galactosidase (beta-gal). Adoptive transfer experiments, as well as studies involving lacZ-transgenic mice (ROSA-26) revealed that CTLs to viral antigens are sufficient to destroy virus-infected hepatocytes, indicating that CTLs to beta-gal can not solely account for the observed hepatocyte destruction that has characterized the use of first generation viruses. In addition, we confirmed that B cell-mediated events do not participate in destruction of hepatocytes in vivo, despite the production of virus- and beta-gal-specific antibodies. These data confirm the hypothesis that viral gene expression elicits host responses that contribute to the problem of transgene instability. Recombinant adenoviruses must be redesigned to diminish viral gene expression if they are to be used in the treatment of chronic diseases.
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PMID:Immune responses to viral antigens versus transgene product in the elimination of recombinant adenovirus-infected hepatocytes in vivo. 886 61

Con A-induced hepatic injury of mice accompanied by elevated transaminase was inhibited after in vivo depletion of liver NK cells and NK1+ T cells with intermediate TCR by anti-NK1 Ab or anti-IL-2Rbeta Ab. However, depletion of liver NK cells alone by anti-asialo-GM1 Ab did not inhibit hepatic injury. Although depletion of NK1+ T cells inhibited Con A-induced IL-2R expression of CD4+ high TCR (TCRhigh) cells and IL-4 mRNA expression of hepatic mononuclear cells, exogenous IL-4 engendered Con A-induced hepatic injury and endowed the expression of IL-2R of CD4+ TCRhigh cells. It was also found that in vivo treatment with anti-IL-4 Ab before Con A administration inhibited Con A-induced hepatic injury. In addition, although Con A did not induce hepatic injury in MHC class I-deficient mice, exogenous IL-4 again engendered severe hepatic injury in these mice. Further, while serum TNF-alpha levels induced by Con A were greatly decreased in NK1+ T cell-depleted mice and class I-deficient mice, TNF-alpha levels were recovered by exogenous IL-4. These findings reveal that although CD4+ TCRhigh cells in the liver and their production of TNF-alpha are the direct effectors of Con A-induced hepatic injury, liver NK1+ T cells also play an important role in this hepatitis model. Con A hepatitis may serve as an experimental model for human autoimmune hepatitis.
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PMID:Requirement of IL-4 and liver NK1+ T cells for concanavalin A-induced hepatic injury in mice. 923 53

We have studied the relationship between T-cell receptor (TCR) density, genetic factors and the specific immune response in 153 end stage renal disease (ESRD) patients on haemodialysis immunised with HBsAg vaccine. One-hundred and nineteen patients raised a protective (> 10 U/ml) antibody response to hepatitis-B vaccination (responder, R), while 34 patients were found to be non-responders (NR). The density of the T-cell receptors was determined by flow cytometry. Proliferation of the T-cells induced by autologous monocytes presenting HBsAg was also measured and expressed as a stimulation index (SI). MHC class I, II and III alleles of the patients were also determined. The densities of TCR/CD3 receptors in NR patients were found to be significantly decreased as compared to the R patients (189 +/- 22 vs. 282 +/- 58 arbitrary units, P = 1.3 x 10(-7). TCR/CD3 receptor densities were found to be strongly associated (Spearman correlation coefficient: 0.84, P < 0.000001) with the SI values. Both parameters were found to be under dual genetic control: (a) very low density of the TCR/CD3 receptors and very low SI were found mainly in NR patients carrying HLA-A1, HLA-B8 and HLA-DR3 alleles; and (b) TCR/CD3 densities and function in R group were found to be significantly lower in carriers than in non-carriers of two MHC class III complement protein alleles: C4A*6, and Bf*F. Non-responsiveness to hepatitis-B vaccination was found to be associated with extremely increased neopterin levels. These findings indicate that both genetic and acquired factors contribute to the hepatitis-B vaccination failure in ESRD patients.
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PMID:Genetic regulation of the impaired immune response to hepatitis-B vaccine associated with low TCR density in end stage renal disease patients: contribution of complement C4 and factor B alleles. 933 52

Adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) have been implicated in the pathogenesis of various inflammatory liver disease states, including viral and autoimmune hepatitis as well as liver allograft rejection. Tumor necrosis factor alpha (TNF-alpha) is an inflammatory cytokine known to up-regulate adhesion molecules as well as major histocompatibility complex (MHC) class I expression, and has been demonstrated to be important in the rejection of vascularized organ allografts. The current studies address the effect of TNF-alpha and the role of ICAM-1 expression on liver cell immunogenicity in vitro in mixed lymphocyte hepatocyte culture (MLHC), in vitro in mixed lymphocyte liver nonparenchymal cell culture (MLNPC), in vivo in hepatocyte sponge matrix allografts (HC-SMA), and in vivo in liver nonparenchymal cell sponge matrix allografts (NPC-SMA). Purified allogeneic hepatocytes (HC) and liver nonparenchymal cells (NPC) under naive, unstimulated conditions demonstrated different profiles of MHC antigen and adhesion molecule expression, but both liver cell populations stimulated the proliferation and development of allospecific cytotoxic effectors in vitro and in vivo. Despite significant up-regulation of MHC class I and ICAM-1 on both HC and liver NPCs by in vivo treatment with TNF-alpha, the immunogenicity of TNF-alpha-stimulated liver cells was not appreciably different from naive, unstimulated liver cells. In contrast, ICAM-1-negative HC and NPCs were significantly less immunogenic both in terms of lymphocyte proliferative responses and the generation of allospecific cytolytic effectors. These results suggest that constitutive expression of ICAM-1 enhances the immunogenicity of "donor" liver cells but is not absolutely required to elicit immune responses to allogeneic liver cells. Further studies to determine the role of adhesion molecule expression on trafficking of host immune cells to the liver and the role of adhesion molecule expression by host cells are required to clarify their role in immune responses to liver cells.
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PMID:Effect of tumor necrosis factor alpha and intercellular adhesion molecule-1 expression on immunogenicity of murine liver cells in mice. 969 13

Adenovirus vectors transduce liver hepatocytes with extreme efficiency; however, transgene expression is eliminated within 2 weeks. Extinction of transgene expression has been attributed to infiltrating cytotoxic T lymphocytes (CTLs) in the liver in a process that resembles a number of human diseases, including viral and autoimmune hepatitis. In this study we investigated the role of Fas-Fas ligand interactions in killing of vector-transduced hepatocytes in vitro and in vivo. Intrahepatic lymphocytes (IHLs) isolated from livers of mice administered adenovirus vector demonstrated cytolytic activity against vector-infected primary hepatocytes. The in vitro CTL activity of the IHLs involving both CD4+ and CD8+ T cells was MHC class I restricted and could be blocked by soluble Fas-IgG. Adoptive transfer of IHLs from immune-competent mice immunized with Ad-lacZ into Ragl-deficient mice previously infused with Ad-lacZ resulted in rapid elimination of beta-galactosidase-transduced hepatocytes. Transfer of these cells into Fas-deficient mice (B6-lpr) failed to eliminate lacZ expression; likewise IHLs from immunized FasL-deficient mice (B6-gld) failed to eliminate lacZ expression in Rag1-deficient mice. Finally, in vivo administration of soluble Fas-IgG abrogated the ability of Ad-lacZ-primed IHLs to eliminate transgene expression. These studies establish an essential role for Fas-Fas ligand interactions in the mechanism of elimination of adenoviral vector-mediated transgene expression in the liver.
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PMID:Fas-Fas ligand interactions play a major role in effector functions of cytotoxic T lymphocytes after adenovirus vector-mediated gene transfer. 1002 50

Toxoplasmosis has gained particular attention in the AIDS era as the most common opportunistic encephalitis in HIV-infected patients. Since there are important parallels between the human and rodent infection, experimental murine toxoplasmosis is widely used to study the immune reactions to this protozoal parasite. Oral application of low-virulent Toxoplasma (T.) gondii cysts leads to a biphasic disease characterized by an acute, generalized phase followed by a chronic stage confined to the brain, where an encephalitis with persistence of the parasite develops. Immunity to T. gondii is T cell mediated, and there is increasing evidence for a critical role of cytokines for an effective immune response. In order to address the functional role of interferon (IFN)-gamma in toxoplasmosis, we took advantage of mice lacking the IFN-gamma-receptor. Inactivation of the IFN-gamma-receptor rendered mice highly susceptible to T. gondii, and they died of a fulminant acute toxoplasmosis. Among the various organs affected, hepatitis was severe enough to cause death. In contrast to wild type animals, IFN-gamma-receptor-deficient mice were unable to activate their macrophages as evidenced by a lack of major histocompatibility complex (MHC) class II antigen induction and the absence of an upregulation of tumor necrosis factor (TNF)-alpha and inducible nitric oxide synthase (iNOS) mRNA transcripts, two macrophage effector molecules. These observations prompted the investigation of TNF- and TNF-receptor-mediated effects in toxoplasmosis by use of mice deficient in either the TNF-receptor type 1 (TNFR1) and/or the TNF-receptor type 2 (TNFR2). The lethal outcome of T. gondii-infected TNFR1/2- and TNFR1-deficient mice, but not of TNFR2-deficient and wild type animals, illustrated the important role of TNF-alpha and TNFR1-mediated signalling, respectively, in this infection. Histopathology attributed death of TNFR1- and TNFR1/2-deficient mice to a severe, necrotizing encephalitis. Unrestricted intracerebral parasite replication in these strains was associated with reduced numbers of iNOS+ leukocytes and a lack of iNOS mRNA induction in their brains as compared to resistant wild type and TNFR2-deficient mice. To precisely identify the cellular sources of cytokines in the brain, flow cytometry of leukocytes isolated from the brain, in situ hybridization, immunohistochemistry and RT-PCR analysis of cytokine mRNA transcripts of magnetically purified leukocyte populations were performed. These studies disclosed that both CD4+, CD8+ T lymphocytes and macrophages recruited to the brain as well as resident cell populations of the CNS including neurons, astrocytes and microglia contributed to the intracerebral cytokine synthesis. Each population was characterized by a specific cytokine pattern. Interestingly, activation of brain cells is a hallmark of Toxoplasma encephalitis. The marked induction of a variety of immunologically important cell surface molecules as MHC class I and II antigens, cell adhesion molecules and their ligands on microglia points to a particular important role of this cell type for the immune response to T. gondii, since the expression of these molecules is a prerequisite for cellular interactions with T cells. The observation of a prominent interleukin (IL)-10 production in the T. gondii-infected brain initiated studies addressing the function of this powerful immunosuppressive mediator in chronic Toxoplasma encephalitis. Neutralization experiments revealed that IL-10 facilitates persistence of the parasite in the brain by downregulating the intracerebral immune response. On the other hand, IL-10 may exert a regulatory role and may be necessary to prevent immunopathological effects of an uncontrolled immune response. In conclusion, these studies demonstrate the important role of the cytokines IFN-gamma and TNF-alpha and their receptors, respectively, for an effective control of T. gondii. In the CNS, the target organ of the parasite, a
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PMID:[Rudolf-Virchow Prize 1998. Award lecture. Toxoplasmosis: a model infection for studying systemic and intracerebral immune reactions]. 1009 13

The immunopathogenesis of AIDS-associated hepatitis was explored in the SIV/rhesus monkey model. The livers of SIV-infected monkeys showed a mild hepatitis, with a predominantly CD8+ T lymphocyte infiltration in the periportal fields and sinusoids. These liver-associated CD8+ T cells were comprised of a high percentage of SIV-specific CTL as defined by MHC class I/Gag peptide tetramer binding and Gag peptide epitope-specific lytic activity. There was insufficient viral replication in these livers to account for attracting this large number of functional virus-specific CTL to the liver. There was also no evidence that the predominant population of CTL were functionally end-stage cells trapped in the liver and destined to undergo apoptotic cell death in that organ. Interestingly, we noted that liver tetramer-binding cells showed an increased expression of CD62L, an adhesion molecule usually only rarely expressed on tetramer-binding cells. This observation suggests that the expression of specific adhesion molecules by CTL might facilitate the capture of these cells in the liver. These results demonstrate that functional SIV-specific CD8+ T cells are present in large numbers in the liver of chronically SIV-infected monkeys. Thus, the liver may be a trap for virus-specific cytotoxic T cells.
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PMID:Simian immunodeficiency virus (SIV)-specific CTL are present in large numbers in livers of SIV-infected rhesus monkeys. 1082 Feb 85

MHC class I-restricted cytotoxic T lymphocyte (CTL) response to hepatitis B virus (HBV) surface antigens (HBsAg) has been suggested to play essential roles in viral clearance and pathogenesis of HBV-induced hepatitis. In the present study, we analyzed CTL responses to endogenously synthesized or exogenously introduced HBsAg in C57BL/6 mice (H-2(b)). We show that the endogenously synthesized surface antigens of adr-type HBV encoded by recombinant vaccinia virus efficiently elicit CTL responses in C57BL/6 mice previously defined as non-responders to vaccinia-HBV immunization. We also show that two peptides, S(179-186) (FVQWFVGL) and S(208-216) (ILSPFLPLL), serve as effective motifs for CTL response in H-2(b) system after in vitro restimulation of the primed T cells with either of the two synthetic peptides. S(208-215) has recently been identified as a CTL epitope which could be produced by exogenous pathway only, in contrast to the current result, while S(179-186) appeared a novel epitope for CTL response. In addition, we show that soluble HBsAg also elicits CTL responses in H-2(b) mice upon in vitro restimulation with the two peptides, although less efficiently compared with the recombinant vaccinia viruses. These findings may provide an efficient experimental system for studying H-2(b)-restricted immune responses against endogenously synthesized and exogenously introduced HBsAg.
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PMID:Induction of CTL responses and identification of a novel epitope of hepatitis B virus surface antigens in C57BL/6 mice immunized with recombinant vaccinia viruses. 1116 41

Demyelination in multiple sclerosis and in animal models is associated with infiltrating CD8+ and CD4+ T cells. Although oligodendrocytes and axons are damaged in these diseases, the roles T cells play in the demyelination process are not completely understood. Antigen-specific CD8+ T cell lysis of target cells is dependent on interactions between the T cell receptor and major histocompatibility complex (MHC) class I-peptide complexes on the target cell. In the normal central nervous system, expression of MHC molecules is very low but often increases during inflammation. We set out to precisely define which central nervous system cells express MHC molecules in vivo during infection with a strain of murine hepatitis virus that causes a chronic, inflammatory demyelinating disease. Using double immunofluorescence labeling, we show that during acute infection with murine hepatitis virus, MHC class I is expressed in vivo by oligodendrocytes, neurons, microglia, and endothelia, and MHC class II is expressed only by microglia. These data indicate that oligodendrocytes and neurons have the potential to present antigen to T cells and thus be damaged by direct antigen-specific interactions with CD8+ T lymphocytes.
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PMID:In vivo expression of major histocompatibility complex molecules on oligodendrocytes and neurons during viral infection. 1158 48

Natural T (NT) lymphocytes recognize infected cells or microbial compounds without the classical genetic restriction of polymorphic major histocompatibility complex (MHC) molecules. This innate recognition pathway results in a broad and rapid antimicrobial response that may be critical for controlling the spread of intracellular pathogens, requiring the elimination of the infecting agent from both extracellular spaces and host cells. NT cells are mainly composed of alphabeta and gammadelta T lymphocytes that express natural killer (NK) receptors and recognize preferentially various nonpeptidic antigens. Similar to NK cells, NT lymphocytes can 'see' and kill target cells deficient in the expression of one or more MHC class I molecules. NT cells expressing the alphabeta TCR can recognize lipid and lipoglycan antigens presented in the context of nonpolymorphic CD1 molecules, whereas phosphocarbohydrates and akilamines induce constitutive responses in most Vgamma9Vdelta2 NT lymphocytes. The remaining fraction of gammadelta NT cells express the Vdelta1 chain associated with different Vgamma-chains and may directly recognize self-antigens such as MICA, MICB or CD1 molecules. It is possible that NT lymphocytes may play two opposite roles during intracellular infections. First, in the acute phase, they may be critical for the initiation of pathogen elimination. Second, in the chronic phase, NT cells may be dangerous, if their potential autoreactivity is not well controlled. It is conceivable that novel strategies of immune intervention against emerging and re-emerging intracellular pathogens, such as human immundeficiency virus (HIV), hepatitis-C virus (HCV) and Mycobacterium tuberculosis (MTB) may involve the control of NT cell activation/anergy by (nonpeptidic) immunoregulatory drugs.
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PMID:Natural T cell immunity to intracellular pathogens and nonpeptidic immunoregulatory drugs. 1189 39


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