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)

Aminoguanidine is an inhibitor of the inducible form of nitric oxide synthase (iNOS). In the present study, the effect of aminoguanidine on concanavalin A-induced hepatitis was examined. Treatment of mice with concanavalin A (10 mg/kg, i.v.) induced interferon-gamma and iNOS mRNA expression in the liver before the elevation of plasma alanine aminotransferase activity. Immunohistochemical study showed the induction of iNOS protein expression in the area of necrosis. Aminoguanidine (1, 3 and 10 mg/kg, i.p.) inhibited the concanavalin A-induced elevation of alanine aminotransferase activity. Aminoguanidine (10 mg/kg, i.p.) did not inhibit concanavalin A-induced interleukin-2, interferon-gamma, tumor necrosis factor-alpha or iNOS mRNA expression in the liver. The plasma nitrite/nitrate level was elevated at 6 and 24 h after concanavalin A treatment. The elevation of nitrite/nitrate was inhibited by aminoguanidine (10 mg/kg, i.p.). From these results, we conclude that nitric oxide formed by iNOS may be involved in the development of concanavalin A-induced hepatitis.
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PMID:Aminoguanidine prevents concanavalin A-induced hepatitis in mice. 1082 65

Hepatitis delta virus (HDV) superinfection is one of the major causes of fulminant hepatitis in endemic areas of hepatitis B virus (HBV) infection. Currently, there is no effective treatment or vaccine against HDV superinfection. DNA-based immunization is a promising antiviral strategy to prevent or treat persistent viral infections. In this study, we investigated the immunological effects of DNA vaccines against HDV in BALB/c mice. Plasmid (pD) encoding large hepatitis D antigen (L-HDAg), or plasmid (pS/pD) coexpressing hepatitis B surface antigen (HBsAg) and L-HDAg, were injected into mice intramuscularly. The seroconversion rate, anti-HBs levels, anti-HDV titers, T-cell proliferation responses, and T-helper (Th)-release cytokine profiles were analyzed. Mice immunized with plasmids, pS/pD or pD, produced low, but significant, titers of anti-HDV antibodies. In contrast, pS/pD induced much stronger anti-HBs titers in the immunized animals. Interestingly, splenic lymphocytes derived from pS/pD-inoculated mice demonstrated significant proliferation responses to recombinant HBsAg and HDAg, and resulted in a Th1-like immune response as suggested by the production of interferon gamma (INF-gamma) and interleukin-2 (IL-2), but not IL-4. The splenic lymphocyte derived from the pD-inoculated mice showed a similar Th1 response to the stimulation of HDAg, but not to HBsAg. In conclusion, our results suggest that DNA vaccines against HDV can induce significant cellular immune responses with a Th1 preference. HBV and HDV coimmunization can be performed by DNA vaccines. These results are promising for the future development of prophylactic and therapeutic HDV vaccines.
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PMID:DNA-Based immunization produces Th1 immune responses to hepatitis delta virus in a mouse model. 1086 96

Immunotherapy with interferon-alpha (IFNalpha) may induce depressive symptoms, anxiety and major depression when administered for at least 1-3 months at a dose of 3-10 MUI daily, twice or three times a week. Previously, it has been shown that immunotherapy with interleukin-2 (IL-2) significantly induces the cytokine network, as measured by increases in serum IL-6, IL-10 and the IL-2 receptor (IL-2R), and that the immunotherapy-induced changes in the cytokine network are significantly correlated with the increases in depression ratings. The main aim of this study was to examine the effects of immunotherapy with IFNalpha on the cytokine network in relation to changes in depression and anxiety ratings. Fourteen patients, affected by chronic active C-hepatitis, were treated with IFNalpha (3-6 MUI s.c. three/six times a week for 6 months) and had measurements of serum IFN-gamma (IFNgamma), IL-2, IL-6, IL-6R, IL-8 and IL-10 before starting therapy and 2, 4, 16 and 24 weeks after immunotherapy with IFNalpha. Severity of depression and anxiety were measured with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A), respectively. Repeated measure (RM) design ANOVAs showed significantly higher MADRS and HAM-A scores 2-4 weeks and 4-6 months after starting IFNalpha-based immunotherapy than at baseline. RM design ANOVAs showed significantly higher serum IL-6 and IL-8 levels 2-4 weeks after starting IFNalpha-based immunotherapy and higher serum IL-10 levels 2-4 weeks and 4-6 months after starting therapy than at baseline. There were significant relationships between the IFNalpha-induced changes in serum IL-6 or IL-8 and the depression and anxiety scores. The findings show that IFNalpha-based immunotherapy induces the cytokine network and that IFNalpha-induced increases in IL-6 predicts the development of depressive symptoms. Depressive symptoms following IFNalpha treatment may be secondary to cytokine induction, including that of IL-6.
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PMID:Immunotherapy with interferon-alpha in patients affected by chronic hepatitis C induces an intercorrelated stimulation of the cytokine network and an increase in depressive and anxiety symptoms. 1174 Sep 74

Recurrent chronic hepatitis, cholestatic hepatitis, and acute rejection in conjunction with hepatitis C virus (HCV) recurrence are well-recognized clinical sequelae of reinfection of the hepatic allograft with HCV. The aim of this study is to characterize intrahepatic cytokine responses associated with reinfection of the allograft with HCV in these settings. Intrahepatic messenger RNA expression of T helper cell subtype 1 (TH1) cytokines interleukin-2 (IL-2), interferon-gamma, and tumor necrosis factor-alpha and TH2 cytokines IL-4 and IL-10 was measured by real-time polymerase chain reaction system using TaqMan probes in 53 liver specimens from six groups of patients. These were: (1) recurrent chronic hepatitis C (CH-I; n = 15), (2) cholestatic hepatitis (n = 6), (3) acute rejection associated with HCV recurrence (AR-HCV; n = 12), (4) acute rejection in non-HCV-infected allografts (AR non-HCV; n = 5), (5) patients with chronic hepatitis C who did not undergo transplantation (CH-C; n = 10), and (6) non-diseased liver tissue (n = 6). Intrahepatic viral loads were measured using an Amplicor monitor assay (Roche Diagnostic Systems, Branchburg, NJ). The CH-I and CH-C groups had similar TH1 intrahepatic cytokine profiles. Compared with the CH-I group, the cholestatic group expressed increased levels of the TH2 cytokines IL-10 (P =.024) and IL-4 (P =.0024). The AR-HCV group also expressed more TH2 cytokines IL-10 (P =.014) and IL-4 (P =.034) compared with the CH-I group. Both the AR-HCV and AR non-HCV groups showed similar intrahepatic cytokine profiles. Intrahepatic viral loads were highest in the cholestatic group compared with the AR-HCV, CH-I, and CH-C groups (P =.0007). In conclusion, a novel observation is that the cholestatic group showed upregulation of the TH2 cytokines IL-10 and IL-4, in addition to high viral loads. In this setting, the TH2 immune response may favor viral replication and graft damage.
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PMID:Intrahepatic cytokine profiles associated with posttransplantation hepatitis C virus-related liver injury. 1191 May 76

Orthotopic liver transplantation (OLT) is effective therapy for end-stage liver disease but immunosuppression with calcineurin inhibitors (CNI) leads to significant nephrotoxicity, resulting in either a reduction of dosage to below the therapeutic level or omission of the drug altogether. Basiliximab (Bx) is a human/mouse chimeric monoclonal antibody that inhibits binding of interleukin-2 (IL-2) to IL-2 receptors and thus prevents proliferation of T cells, which is the main step in the development of acute cellular rejection. The aim of this study was to identify the role of Bx in the prevention of acute cellular rejection and in the reduction of nephrotoxicity in children post-liver transplantation. We evaluated three children (19 months, 22 months, and 11 yr of age; one male, two female) who were treated with Bx post-OLT on compassionate grounds. The indications were: nephrotoxicity in two children, requiring re-transplantation for hepatic artery thrombosis and recurrent giant cell hepatitis, respectively; and nephrotoxicity secondary to chemotherapy for hepatoblastoma in the third child. All patients received 10 mg of Bx, at OLT and on Day 4. Tacrolimus (0.15 mg/kg/day) was started at 48 h (n = 2) and cyclosporin (5 mg/kg/day) at 2 weeks (n = 1). Trough levels of tacrolimus were maintained at 5-8 ng/mL and trough levels of cyclosporin at 100-150 mg/L for the first 3 months. All patients received methylprednisolone (2 mg/kg) with azathioprine (1.5 mg/kg) (n = 2) and/or mycophenolate mofetil (20 mg/kg) (n = 1). The glomerular filtration rate (cGFR) was calculated using the Schwartz formula before and 10 weeks after transplant. Bx was found to be easy to administer and no major side-effects were reported. One child had two episodes of mild acute rejection at 5 and 9 weeks post-OLT and one developed chronic rejection requiring re-transplantation at 9 weeks post-OLT. One child did not develop rejection. The mean pretransplant cGFR was 58.1 (54.6-64.1) mL/min/m2. Within 10 weeks of transplantation, the cGFR had improved by 69% to a mean of 116 (88-157.6) mL/min/m2. To conclude, Bx was well tolerated in all children and had a renal sparing effect. It was effective in preventing early acute rejection, but the combination of Bx and low-dose CNI drugs did not prevent late acute or chronic rejection. Further studies to evaluate the appropriate levels of CNI immunosuppression with Bx are required.
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PMID:Concomitant basiliximab with low-dose calcineurin inhibitors in children post-liver transplantation. 1210 May 5

Refinements in the understanding of the mechanisms of immunocyte activation and the emergence of new immunosuppressive agents with highly selective actions has created opportunities for improving the treatment of autoimmune hepatitis. Drugs, such as budesonide and deflazacort, may inhibit immunocyte activation and limit corticosteroid-related side effects. Agents, such as cyclosporine and tacrolimus, can impair calcineurin activity and restrict the generation of transcription factors necessary for T cell responses. Intravenous immunoglobulin can bind anti-idiotype antibodies and reduce interleukin-2 secretion, and monoclonal antibodies directed against critical components of the T cell activation cascade can dampen the immune reaction. Drugs, such as mycophenolate mofetil, cyclophosphamide, methotrexate, and KF20444, can inhibit T cell proliferation, and other interventions promise to deplete activated T cells, impair effector mechanisms, and induce self-tolerance.
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PMID:Evolving new therapies of autoimmune hepatitis. 1236 83

The successful induction of a T-cell-mediated tumor-protective immunity against poorly immunogenic malignancies remains a major challenge for cancer immunotherapy. We achieved this by immunization with a tyrosine hydroxylase (mTH)-based DNA vaccine, enhanced with the posttranscriptional regulatory acting RNA element (WPRE), derived from woodchuck hepatitis virus in combination with an antibody-cytokine fusion protein (ch14.18-IL-2) that targets interleukin-2 (IL-2) to the tumor microenvironment. This DNA vaccine mTH-WPRE was carried by attenuated Salmonella typhimurium and applied by oral gavage in a mouse model of neuroblastoma. Mice immunized with the mTH-WPRE vaccine, and which additionally received a boost with suboptimal doses of ch14.18-IL-2, were completely protected against hepatic neuroblastoma metastases. In contrast, all controls presented with disseminated metastases. Both T-cell and natural killer (NK) cell-dependent mechanisms were involved in the induction of a systemic tumor-protective immunity. Thus, up-regulation of interferon-gamma (IFN-gamma) expression in CD8(+) T cells occurred only in those animals that received the mTH-WPRE vaccine plus the ch14.18-IL-2 boost. Up-regulation of this proinflammatory cytokine was not observed in mice immunized with mTH-WPRE vaccine alone. A role for NK cells was indicated by the complete abrogation of systemic tumor-protective immunity in all animals that were depleted of NK cells in vivo. Taken together, these data demonstrate that immunization with a posttranscriptionally enhanced DNA vaccine encoding the WPRE sequence, combined with a boost of the ch14.18-IL-2 fusion protein, completely protects against hepatic metastases in a murine model of neuroblastoma and therefore may lead to a new strategy for immunotherapy and prevention of metastatic neuroblastoma.
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PMID:Immunotherapy with a posttranscriptionally modified DNA vaccine induces complete protection against metastatic neuroblastoma. 1239 80

The immunoregulatory roles of interleukin-2 (IL-2), IL-4, IL-10, gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), the soluble form of the IL-2 receptor (sIL-2R), and the soluble form of CD30 (sCD30) were evaluated in patients with hepatitis B virus (HBV) infection. Two groups of subjects were studied: 15 healthy individuals without hepatitis antecedents and 15 patients with HBV infection. Blood samples were taken during the acute and convalescent phases. The analysis of the samples was done by the enzyme-linked immunosorbent assay technique. IFN-gamma and TNF-alpha levels decreased in the convalescent phase. IL-10, IL-2, and sIL-2R levels increased in the acute and convalescent phases, while sCD30 levels increased during the acute phase. The IL-4 concentrations decreased in both phases. During the acute phase, IFN-gamma and TNF-alpha induced increases in IL-2, sIL-2R, IL-10, and sCD30 levels in serum, which allowed the development of immunity characterized by the nonreactivity of the HBV surface antigen, the onset of antibodies to the HBV surface antigen (anti-HBs), and normal alanine aminotransferase levels during the convalescent phase. Increased IL-2 levels during the acute phase would stimulate the activities of NK cells and CD8(+) lymphocytes, which are responsible for viral clearing. The raised sIL-2R levels reveal activation of T lymphocytes and control of the IL-2-dependent immune response. The sCD30 increment during the acute phase reflects the greater activation of the Th2 cellular phenotype. Its decrease in the convalescent phase points out the decrease in the level of HBV replication. The increase in IL-10 levels could result in a decrease in IL-4 levels and modulate IFN-gamma and TNF-alpha levels during both phases of disease, allowing the maintenance of anti-HBs concentrations.
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PMID:Concentrations of cytokines, soluble interleukin-2 receptor, and soluble CD30 in sera of patients with hepatitis B virus infection during acute and convalescent phases. 1241 77

Non-human primates could prove to be suitable models for the study of infectious diseases such as malaria, tuberculosis, and hepatitis; the molecules of their immune systems are in the process of being fully characterized. Due to the relevance of cytokines in the modulation of the immune response, a molecular analysis of these proteins in non-human primates from the Aotus genus was carried out. Peripheral blood mononuclear cells from four species of Aotusmonkey were obtained and their mRNAs for interleukin-2 (IL-2), IL-4, IL-6, IL-10, interferon-gamma (IFN), and tumor necrosis factor (TNF)-alpha were characterized. This study shows a high degree of conservation between nucleotide and amino acid sequences of cytokines from different Aotus species and those from humans. The TNF-alpha molecules were identical in amino acid sequences for both.
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PMID:Identification, cloning, and sequencing of different cytokine genes in four species of owl monkey. 1246 97

The JHM strain of mouse hepatitis virus (JHMV) is rapidly cleared from the central nervous system (CNS) by CD8(+) T cells. In the absence of CD4(+) T cells, fewer CD8(+) T cells are found within the CNS in association with a coordinate increase in apoptotic lymphocytes. Previous data suggested that CD4(+) T cells may support CD8(+) T cells through secretion of interleukin-2 (IL-2). To determine the in vivo role of IL-2 during CNS infection, IL-2 signaling was inhibited via administration of a neutralizing IL-2-specific monoclonal antibody (mAb). In contrast to depletion of CD4(+) T cells, inhibition of IL-2 signaling did not influence CD8(+) T cell infiltration, effector cell function or survival within the CNS. These data suggest that the cellular immune response to acute neurotropic JHMV infection requires a distinct CD4(+) T cell component, but is independent of a requirement for IL-2 for induction, activation, recruitment, and/or maintenance of CD8(+) T cells within the CNS during acute infection.
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PMID:Maintenance of CD8+ T cells during acute viral infection of the central nervous system requires CD4+ T cells but not interleukin-2. 1580 60


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