UMLS:C0019158 - FACTA Search

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

Toxoplasma gondii may cause severe infections in immunocompromised patients including fetuses and those with AIDS. Among the factors mediating protection against T. gondii, IFN-gamma has gained special attention. To analyze the role of IFN-gamma in the early phase of toxoplasmosis, IFN-gamma receptor-deficient (IFN-gamma R0/0) mice were orally infected with low-virulent toxoplasms. IFN-gamma R0/0 mice died of the disease up to day 10 postinfection, whereas immunocompetent wild-type (WT) mice developed a chronic toxoplasmosis. Histopathology revealed that in IFN-gamma R0/0 mice, the parasite multiplied unrestrictedly in the small intestine, the intestinal lymphatic tissue, the liver, and the spleen. Ultimately, animals died of a necrotizing hepatitis. In WT mice, the same organs were effected, but multiplication of the parasite was effectively limited. Compared with WT mice, immunohistochemistry and flow cytometry demonstrated that in IFN-gamma R0/0 mice, macrophages were only marginally activated in response to the infection, as evidenced by a reduced expression of major histocompatability complex class II antigens. In addition, immunohistochemistry and RT-PCR showed a reduced production of the macrophage-derived cytokines tumor necrosis factor-alpha, inducible nitric oxide synthase, and IL-1 beta in the liver of IFN-gamma R0/0 mice. In contrast, activation of T cells, recruitment of immune cells to inflammatory foci, and anti-T. gondii IgM antibody production were unaffected by the mutation of the IFN-gamma R. Moreover, induction of IL-2, IL-4, and IL-10 mRNA transcripts in the liver was normal in IFN-gamma R0/0 mice. Adoptive transfer experiments revealed that the immune T cells of WT animals did not protect IFN-gamma R0/0 mice from lethal infection with highly virulent toxoplasms, whereas WT mice were significantly protected by the adoptive transfer. Based on these studies, we conclude that IFN-gamma is absolutely required for an efficient activation of macrophages. Macrophages are of critical importance in toxoplasmosis, and insufficient macrophage activation cannot be compensated by other immune mechanisms.
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PMID:Interferon-gamma receptor-deficiency renders mice highly susceptible to toxoplasmosis by decreased macrophage activation. 897 78

Experimental T-cell-mediated hepatitis induced by concanavalin A (Con A) involves the production of proinflammatory cytokines. Because interleukin (IL)-10 is a potent anti-inflammatory cytokine derived from macrophages and T cells and is produced within the liver, we investigated the role of IL-10 in modulating the hepatotoxicity and the secretion of cytokines following in vivo injection of Con A. IL-10 is produced early in the serum after Con A challenge. Neutralization of endogenous IL-10 by monoclonal antibodies (mAbs) increases the secretion of tumor necrosis factor alpha (TNF-alpha) (+111%), interferon gamma (IFN-gamma) (+92%), and IL-12 (+730%) 8 hours after Con A injection, and increases the hepatotoxicity, assessed by serum alanine transaminase (ALT) (+174%) measurement and by histology, 24 hours after induction of hepatitis. Conversely, preadministration of recombinant IL-10 reduces the production of these proinflammatory cytokines (-47%, -80%, and -47% for TNF-alpha, IL-12, and IFN-gamma, respectively), and decreases neutrophil infiltration and ALT serum concentration (-74%) 8 hours after Con A challenge. We conclude that IL-10, either endogenously produced or exogenously added, has a hepatoprotective role in Con A-induced hepatitis, through its suppressive property on proinflammatory cytokine production, and that it might be of therapeutic relevance in human liver diseases involving activated T cells.
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PMID:Production and role of interleukin-10 in concanavalin A-induced hepatitis in mice. 918 57

The potential role(s) of cytokines in the reduction of infectious virus and persistent viral infection in the central nervous system was examined by determining the kinetics of cytokine mRNA expression following infection with the neurotropic JHM strain of mouse hepatitis virus. Mice were infected with an antibody escape variant which produces a nonlethal encephalomyelitis and compared to a clonal virus population which produces a fulminant fatal encephalomyelitis. Infection with both viruses induced the accumulation of mRNAs associated with Th1- and Th2-type cytokines, including IFN-gamma, IL-4, and IL-10. Peak mRNA accumulations were coincident with the clearance of virus and there was no obvious differences between lethally and nonlethally infected mice. TNF-alpha mRNA was induced more rapidly in lethally infected mice compared to mice undergoing a nonfatal encephalomyelitis. Rapid transient increases in the mRNAs encoding IL-12, iNOS, IL-1alpha, IL-1beta, and IL-6 occurred following infection. Nonlethal infections were associated with increased IL-12, IL-1beta, and earlier expression of IL-6, while lethal infections were associated with increased iNOS and IL-1alpha mRNA. These data suggest a rapid but differential response within the central nervous system cells to infection by different JHMV variants. However, neither the accumulation nor kinetics of induction provide evidence to distinguish lethal infections from nonlethal infections leading to a persistent infection. Accumulation of both Th1 and Th2 cytokines in the central nervous system of JHMV-infected mice is consistent with the participation of both cytokines and cell immune effectors during resolution of acute viral-induced encephalomyelitis.
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PMID:Kinetics of cytokine mRNA expression in the central nervous system following lethal and nonlethal coronavirus-induced acute encephalomyelitis. 921 50

Immunologic reagents and methodology are essential to develop further the woodchuck and woodchuck hepatitis virus (WHV) as a model of immune response, inflammation, and immunotherapy in hepatitis B virus (HBV) infection. Partial cDNA clones for the woodchuck CD3epsilon marker of T cells (536 bp) and for selected woodchuck cytokines were developed, including IL-1beta (332 bp), IL-2 (249 bp), IL-4 (205 bp), IL-10 (476 bp), IFN-gamma (476 bp), and TNF-alpha (381 bp). This panel of markers includes sets to measure RNAs for T cells (CD3epsilon), immune response induction (IL-1beta, IL-2), TH subsets (TH1, IL-2/IFN-gamma vs. TH2, IL-4/IL-10), and effector molecules that regulate hepadnavirus replication and liver injury (IFN-gamma, TNF-alpha). Primers representing highly conserved segments of genes from other species were used to derive the partial cDNA clones. Target RNA was obtained from woodchuck peripheral blood mononuclear cells (PBMC) that were stimulated in vitro with ConA, LPS, and human rIL-2. The cDNA clones were validated by 1) comparison with other species for homologies in the nucleotide and predicted amino acid sequences and 2) a first generation assay demonstrating induction of the respective RT-PCR products in stimulated woodchuck PBMC. The corresponding RNAs were also detectable in most cases in the total RNA from the livers of uninfected and WHV-infected woodchucks and differential expression of IFN-gamma and TNF-alpha RNAs was suggested. Second generation, semi-quantitative assays for the RNAs were validated using RT-PCR and dot-blot hybridization with 32P-oligomers derived from the internal sequences of the respective clones. Continued study of the woodchuck immune response to WHV infection using these assays will provide insight into the kinetics and immune mechanisms that initiate and maintain chronic hepadnavirus infection and, hence, enable development of improved immunotherapies for established chronic HBV infection.
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PMID:Cloning and characterization of partial cDNAs for woodchuck cytokines and CD3epsilon with applications for the detection of RNA expression in tissues by RT-PCR assay. 929 38

Several immune responses are either limited to or concentrated in a given organ. Cytokines produced during ongoing immune responses have organ-localized effects that can be only partially mimicked upon their systemic delivery. Recombinant adenoviruses are efficient vectors to induce transient organ-localized cytokine expression. This allows in vivo analysis of the effects of cytokines produced spatially and temporally in a manner comparable to that observed during immune responses. The authors generated recombinant adenovirus for rat IL-4 (AdIL-4) and IL-10 (AdIL-10) to analyse the in vivo effects of these two important immunoregulatory molecules after gene transfer in the liver. It was first established that AdIL-4 and AdIL-10 were able to direct the production of biologically active cytokines by different rat cell types in vitro. Intraportal injection of doses of up to 10(10) pfu of AdIL-10 or control non-coding recombinant adenovirus were well tolerated, and hepatic histology showed only mild alterations. Conversely, animals receiving more than 2.5 x 10(9) pfu of AdIL-4 showed dose-dependent mortality, with clinical signs of hepatic dysfunction. Liver histology in animals receiving 2.5 x 10(9) pfu of AdIL-4 showed severe acute hepatitis with maximal lesions between day 7 and 14 and almost complete normalization by day 28 after gene transfer. The leukocyte infiltrate was composed primarily of mononuclear cells, but eosinophils and mast cells were significantly increased as compared to control animals. Hepatic function was also altered in animals that received AdIL-4, with kinetics similar to that of histological lesions. Our study describes a model for investigating cytokine function in vivo through liver-localized transgene expression mediated by adenoviral vectors and demonstrates that liver production of IL-4 but not IL-10 results in acute severe hepatitis.
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PMID:Adenovirus-mediated gene transfer in rat liver of interleukin 4 but not interleukin 10 produces severe acute hepatitis. 936 42

We characterized liver-infiltrating leucocytes (LIL) from BALB/c and C57BL/6 mice 0-56 days after murine cytomegalovirus (MCMV) infection. Inflammation clears from C57BL/6 mice 4-5 weeks post infection (pi), but persists for several months in BALB/c mice. The LIL obtained were 60-80% Thy 1.2+ by flow cytometry. The percentage of CD8+ cells rose sharply in all mice 7 days pi, with little decrease in BALB/c mice by day 56. CD4-CD8-Thy 1.2+/TCR alpha beta + cells were more prevalent in LIL than lymph node cells (LNC) irrespective of MCMV infection, whilst infection increased the proportion of CD8+ L-selectin- LIL (but not LNC). LIL from both mouse strains demonstrated cytotoxic activity against YAC-1 cells, but only LIL from BALB/c mice proliferated spontaneously ex vivo 21 days pi, as measured by tritiated thymidine incorporation. BALB/c LIL produced IFN gamma and IgG2a 7-21 days pi, whilst IL-10 secretion was similar in both strains. Thus, persistent hepatitis in BALB/c mice is associated with activation and proliferation of intrahepatic leucocytes with some bias towards a Th1 response.
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PMID:Contrasting phenotypes of liver-infiltrating leucocytes isolated from MCMV-infected BALB/c and C57BL/6 mice. 961 48

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 aim of this study was to examine the immunomodulating effects of rhIL-12 on the immune response induced by hepatitis B virus (HBV) antigens in clinical subgroups of patients with HBV infection. Peripheral blood mononuclear cells (PBMC) of 80 patients were stimulated with HBsAg, HBcAg, pre-S1Ag and tetanus toxoid in the absence or presence of IL-12 (0.01, 0.1 and 1 ng/ml). Stimulation by anti-CD3+ anti-CD28 and lipopolysaccharide (LPS) were used as controls. Proliferation and cytokine production were determined by 3H-thymidine uptake and ELISA after 72 h. After stimulation with HBV antigens only, production of tumour necrosis factor-alpha (TNF-alpha) or IL-10 was observed in all patients, while interferon-gamma (IFN-gamma) was detectable in only 27 patients. After costimulation with IL-12 and HBV antigens, however, large amounts of IFN-gamma were found in all patients, while HBV-induced IL-10 production remained mostly unchanged. When clinical subgroups including patients with compensated liver cirrhosis were compared, PBMC from patients with HBeAg+ hepatitis showed the lowest capacity to produce IFN-gamma after HBV antigen-positive IL-12. These data suggest that the ability of IL-12 to enhance IFN-gamma production against HBV antigens is correlated with the presence of HBeAg and is not impaired in patients with advanced liver disease. In addition, IL-12 and IL-10 production by antigen-presenting cells may be a critical factor that determines the efficacy of the immune response against the hepatitis B virus.
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PMID:HBV-specific immune defect in chronic hepatitis B (CHB) is correlated with a dysregulation of pro- and anti-inflammatory cytokines. 1019 26

The CD3+/TCRalphabeta+ T-cell-mediated hepatic inflammation induced by Propionibacterium acnes could be divided into an acute and a chronic phase. The acute phase occurred within 72 h after injection and displayed hepatic apoptosis. Anti-TNFalpha antibody inhibited both the P. acnes-induced hepatic apoptosis and lymphocyte infiltration seen in this phase, indicating the involvement of this cytokine. Thereafter, a chronic phase was manifested from days 7 to 14 after injection. It was characterized as granulomatous inflammation admixed with apoptosis of infiltrating lymphocytes and some hepatocytes. Immunohistochemical staining showed that the infiltrating lymphocytes displayed TNFalpha, TNF type I receptor and a variety of cytokines including IL-1beta, IL-4, IL-6, IL-10, IFNgamma or IL-12. Interestingly, in naive mice, the arteries in the liver constitutively expressed IFNgamma. Its expression appeared to be substantially increased at 48 h, decreased at 72 h, and increased again on day 14 after P. acnes injection. Furthermore, Fas or FasL was only detected on the lymphocytes within the granuloma. We conclude that P. acnes can induce a TNFalpha-mediated acute hepatic apoptosis which subsequently progress to a T-cell-mediated granulomatous hepatitis with increased expression of multiple cytokines and Fas/FasL.
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PMID:Propionibacterium acnes induces acute TNFalpha-mediated apoptosis of hepatocytes followed by inflammatory T-cell-mediated granulomatous hepatitis in mice. 1049 42

One single intra-venous (i.v.) injection of Concanavalin A (Con A) into mice provokes a cell-mediated immunoinflammatory hepatitis. We have presently evaluated the immunopharmacological effects of exogenous interleukin (IL)-10 and the role of endogenous IL-10 in this model by using exogenous IL-10, anti-IL-10 monoclonal antibody (mAb) and mice with disrupted IL-10 gene (IL-10 KO mice). Whilst exogenous IL-10 administered in a prophylactic (1 h prior to Con A) and even "early" therapeutic fashion (30 min after Con A) reduced the elevation of transaminase activities in plasma in a dose-dependent manner, observed in control mice, these biochemical markers of liver injury were significantly increased both in IL-10 KO mice as well as in those receiving anti-IL-10 mAb. Interestingly, doses of Con A lower than 20 mg/kg that were only capable of inducing slight serological signs of hepatitis in mice, exerted marked hepatitic effects when administered to either anti-IL-10 mAb-treated mice or to IL-10 KO mice. The disease modulating effects of exogenous IL-10 and either genetical or pharmacologically-induced IL-10 deficiency were associated with profound and opposite modifications of the Con A-induced increase in the circulating levels of IFN-gamma and TNF-alpha. Relative to control animals, the blood levels of these cytokines were diminished in IL-10-treated mice and augmented in both IL-10 KO mice and anti-IL-10 mAb-treated mice. These results prove the physiological antiinflammatory role of endogenous IL-10 in Con A induced hepatitis and the beneficial effects of IL-10 treatment to prevent this condition.
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PMID:Concanavalin A-induced hepatitis in mice is prevented by interleukin (IL)-10 and exacerbated by endogenous IL-10 deficiency. 1068 Jul 45

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