Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

An in vivo murine model for immunodeficiency of both B and T cells is produced by continuous intraperitoneal infusion of 2'-deoxycoformycin (DCF), a specific tightly binding inhibitor of adenosine deaminase (ADase; adenosine aminohydrolase, EC 3.5.4.4). After DCF infusion, ADase of thymus, spleen, and lymph nodes was inhibited to varying degrees ranging from 57% to 100%. Immunodeficiency under these conditions was indicated by: (i) a striking decrease in lymphocyte response to the T-cell mitogens concanavalin A and phytohemagglutinin; (ii) an impairment of delayed hypersensitivity measured by the footpad reaction; (iii) a decrease in antibody production measured in both in vivo and in vitro plaque-forming cell assay; (iv) a significant prolongation of mouse skin allograft survival after transplantation into the C57BL/6J (H-2b) strain of skin from BALB/c (H-2d) mice; and (v) a marked lymphopenia. Histological examination indicated lymphoid degeneration in the thymus, lymph nodes, and spleen with no alterations in other tissues including bone marrow, kidney, lung, gastrointestinal tract, and liver except for the occurrence of hepatitis. A decrease in the number of Thy-1-positive cells in both spleen and lymph nodes further supported the fact of cytotoxicity of DCF to T cells. Anorexia and weight loss were observed within 5 days of continuous DCF infusion at 0.4 mg/kg body weight per day. These data indicate that this method provides an experimental model for future studies on the biochemical mechanisms responsible for the genetically determined severe combined immunodeficiency disease in man.
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PMID:Animal model for immune dysfunction associated with adenosine deaminase deficiency. 696 8

Review of liver biopsy or autopsy material from 33 patients with severe combined immunodeficiency or combined immunodeficiency and four patients with DiGeorge syndrome revealed a wide range of hepatic pathology. The most common abnormality was graft-versus-host disease (16 patients), followed by viral infection (4 patients had adenovirus hepatitis, 3 had cytomegalovirus hepatitis). Centrilobular fibrosis with or without veno-occlusive disease was seen in five patients. Three patients had nonspecific hepatitis, four had changes attributed to total parenteral nutrition, and two had lymphoproliferative disorders involving the liver. Both patients with lymphoproliferative disorders had received transplants. Two patients had resolving necrosis probably secondary to non-A, non-B hepatitis. One had atypical mycobacterial infection. Hemosiderosis was a common nonspecific abnormality, seen in nine patients. All patients with hepatic graft-versus-host disease had received transplants or nonirradiated blood products. Hepatic graft-versus-host disease varied in severity from hepatic necrosis with destruction of both large and small bile ducts in a transfusion-associated case to subtle damage to interlobular bile ducts. Even minimal bile duct changes correlated with the clinical impression of graft-versus-host disease in these patients. Late chronic graft-versus-host disease was not seen in any patient, although acute graft-versus-host disease sometimes occurred late after transplant.
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PMID:Pathology of the liver in severe combined immunodeficiency and DiGeorge syndrome. 837 33

Human hepatitis delta virus (HDV), obtained from the serum of an experimentally infected woodchuck, was injected into either the peritoneal cavity or the tail vein of both adult CB17 mice and mice with a severe combined immunodeficiency (CB17-scid mice). Three lines of evidence indicated that the virus was able to reach the liver and infect hepatocytes: (i) the amount of HDV genomic RNA detected in the liver by Northern (RNA) analysis increased during the first 5 to 10 days postinoculation, reaching a peak that was about threefold the amount in the original inoculum; (ii) also detected in the liver was the viral antigenomic RNA, which is complementary to the genomic RNA found in virions, and is diagnostic for virus replication; and (iii) by immunoperoxidase staining of liver sections, the delta antigen was detected in the nuclei of scattered cells identifiable as hepatocytes. In all of the mice, clearance of the infection occurred between 10 and 20 days after inoculation. The half-life for clearance was about 3 days in CB17-scid mice, indicating that clearance of infection did not involve a T- and B-cell-dependent immune response. Cell-to-cell spread of the initial infection was not detected. One possible interpretation of our results is that HDV infection of hepatocytes is directly cytopathic. Also, the results imply that chronic infection of the liver in humans may require continuous spread of virus within the liver. Alternatively, HDV in the absence of helper virus may be unable to cause a chronic infection of hepatocytes in vivo.
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PMID:Experimental transmission of human hepatitis delta virus to the laboratory mouse. 849 56

Adenosine deaminase (ADA) deficiency typically causes severe combined immunodeficiency (SCID) in infants. We report metabolic, immunologic, and genetic findings in two ADA-deficient adults with distinct phenotypes. Patient no. 1 (39 years of age) had combined immunodeficiency. She had frequent infections, lymphopenia, and recurrent hepatitis as a child but did relatively well in her second and third decades. Then she developed chronic sinopulmonary infections, including tuberculosis, and hepatobiliary disease; she died of viral leukoencephalopathy at 40 years of age. Patient no. 2, a healthy 28-year-old man with normal immune function, was identified after his niece died of SCID. Both patients lacked erythrocyte ADA activity but had only modestly elevated deoxyadenosine nucleotides. Both were heteroallelic for missense mutations: patient no. 1, G216R and P126Q (novel); patient no. 2, R101Q and A215T. Three of these mutations eliminated ADA activity, but A215T reduced activity by only 85%. Owing to a single nucleotide change in the middle of exon 7, A215T also appeared to induce exon 7 skipping. ADA deficiency is treatable and should be considered in older patients with unexplained lymphopenia and immune deficiency, who may also manifest autoimmunity or unexplained hepatobiliary disease. Metabolic status and genotype may help in assessing prognosis of more mildly affected patients.
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PMID:Adenosine deaminase deficiency in adults. 910 4

Under certain conditions, C57BL/6 mice persistently infected with mouse hepatitis virus strain JHM (MHV-JHM) develop clinical disease and histological evidence of demyelination several weeks after inoculation with virus. In a previous report, we showed that mutations in the RNA encoding an immunodominant CD8 T-cell epitope within the surface glycoprotein (epitope S-510-518) were present in all persistently infected animals and that these mutations abrogated recognition by virus-specific cytotoxic T cells (CTLs) in direct ex vivo cytotoxicity assays. To obtain further evidence that these mutations were necessary for the development of clinical disease, the temporal course of their appearance was determined. Mutations in the epitope were identified by 10 to 12 days after inoculation, and in some mice, virus containing mutated epitope was the dominant species detected by 15 days. In addition, most mice that remain asymptomatic at 80 days after inoculation, a time after which clinical disease almost never develops, were infected with only wild-type virus. Finally, analysis of virus isolated from mice with severe combined immunodeficiency (SCID) revealed the presence only of wild-type epitope S-510-518. These results, by showing that mutations are not selected in SCID mice and occur at early times after inoculation in C57BL/6 mice, support the view that they result from immune pressure and contribute to virus persistence and demyelination in mice infected persistently with MHV-JHM.
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PMID:Cytotoxic T-cell-resistant variants arise at early times after infection in C57BL/6 but not in SCID mice infected with a neurotropic coronavirus. 931 46

Patients with acquired immune deficiency syndrome (AIDS) and boys with mutations of the CD154 gene (causing congenital X-linked immunodeficiency with hyper-IgM [XHIM]) are susceptible to chronic infections of the biliary tract with Cryptosporidium parvum (CP) that may lead to biliary sclerosis and ultimately to cholangiocarcinoma. To determine whether the CP infection and the consequent immune response contribute independently to this morbidity, we infected mice with severe combined immunodeficiency (SCID) or with disrupted genes for CD154, CD40, or interferon gamma (IFN-gamma) with CP. Even when CP infection persisted for 16 weeks, the SCID mice developed only mild triaditis, without apoptosis of biliary epithelial cells (BEC). Fifty percent of the CD154 knockout mice developed lobular hepatitis with acute and chronic triaditis. The CD40 knockout mice developed marked triaditis, and the IFN-gamma knockouts either succumbed to enteritis or survived to develop marked triaditis, portal fibrosis, biliary sclerosis, necrosis with dilation of duct-like structures within the porta hepatis, and dysplastic changes. CP-infected SCID mice reconstituted with T cells from IFN-gamma knockout donors either developed severe enteritis or survived to develop triaditis, cholangitis, lobular hepatitis with periductular sclerosis, and scarring. Mice with disruptions of both the CD40 and IFN-gamma genes remained infected by CP and developed bile duct and liver disease, but not enteritis. Our results suggest that T-cell cytokines are required for the inflammatory and sclerosing responses to CP infection in immunodeficient animals. The response of immunodeficient mice to CP infection may model at least the initial steps toward the development of sclerosing cholangitis or bile duct cancers in XHIM patients.
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PMID:Liver and bile duct pathology following Cryptosporidium parvum infection of immunodeficient mice. 1038 35

The evolution of transfusion or infusion therapies for diseases requiring specific protein replacements (e.g., hemophilia A and B and severe combined immunodeficiency syndrome) was dramatic over the second half of the 20th century. Unfortunately, it was accompanied by extreme manifestations of transfusion-transmitted diseases, such as human immunodeficiency virus (HIV), hepatitis B, and hepatitis C. The milestones of both the replacement therapies and the associated diseases are discussed in this presentation, which focuses on the technologic advances that resulted in even more "pure" replacement therapies for plasma-protein diseases. From donor screening to the development of viral attenuation techniques, every facet of production for these products was impacted by the exigent push for viral safety created by HIV and hepatitis. Almost invariably, this negatively affects total product yield. At the beginning of the 21st century, success in making plasma products safe from recognized and potential pathogens has dramatically increased societal pressures to produce a zero-risk, plasma-derived protein therapy. However, past improvements and low theoretic risks for future pathogen contamination have increased product cost. This is associated with a possible decrease in the overall supply of these plasma proteins because of the reduced numbers of acceptable donors and the loss of protein from expanded attenuation technology. These impacts and the role of dynamic societal and scientific pressures on these decision processes are discussed.
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PMID:History of plasma-product safety. 1144 15

High-titer self-inactivating human immunodeficiency virus type-1 (HIV-1)-based vectors expressing the green fluorescent protein reporter gene that contained the central polypurine and termination tract and the woodchuck hepatitis virus posttranscriptional regulatory element were constructed. Transduction efficiency and biodistribution were determined, following systemic administration of these improved lentiviral vectors. In adult severe combined immunodeficiency (SCID) mice, efficient stable gene transfer was achieved in the liver (8.0% +/- 6.0%) and spleen (24% +/- 3%). Most transduced hepatocytes and nonhepatocytes were nondividing, thereby obviating the need to induce liver cell proliferation. In vivo gene transfer with this improved lentiviral vector was relatively safe since liver enzyme concentration in the plasma was only moderately and transiently elevated. In addition, nondividing major histocompatibility complex class II-positive splenic antigen-presenting cells (APCs) were efficiently transduced in SCID and normal mice. Furthermore, B cells were efficiently transduced, whereas T cells were refractory to lentiviral transduction in vivo. However, in neonatal recipients, lentiviral transduction was more widespread and included not only hepatocytes and splenic APCs but also cardiomyocytes. The present study suggests potential uses of improved lentiviral vectors for gene therapy of genetic blood disorders resulting from serum protein deficiencies, such as hemophilia, and hepatic disease. However, the use of liver-specific promoters may be warranted to circumvent inadvertent transgene expression in APCs. In addition, these improved lentiviral vectors could potentially be useful for genetic vaccination and treatment of perinatal cardiac disorders.
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PMID:Lentiviral vectors containing the human immunodeficiency virus type-1 central polypurine tract can efficiently transduce nondividing hepatocytes and antigen-presenting cells in vivo. 1213 Apr 91

Human hepatocarcinoma-intestine-pancreas/pancreatic-associated protein HIP/PAP is a secreted C-type lectin belonging to group VII, according to Drickamer's classification. HIP/PAP is overexpressed in liver carcinoma; however, its functional role remains unclear. In this study, we demonstrate that HIP/PAP is a paracrine hepatic growth factor promoting both proliferation and viability of liver cells in vivo. First, a low number of implanted hepatocytes deriving from HIP/PAP-transgenic mice (<1:1,000) was sufficient to stimulate overall recipient severe combined immunodeficiency liver regeneration after partial hepatectomy. After a single injection of HIP/PAP protein, the percentages of bromodeoxyuridine-positive nuclei and mitosis were statistically higher than after saline injection, indicating that HIP/PAP acts as a paracrine mitogenic growth factor for the liver. Comparison of the early events posthepatectomy in control and transgenic mice indicated that HIP/PAP accelerates the accumulation/degradation of nuclear phospho-signal transducer activator transcription factor 3 and tumor necrosis factor alpha level, thus reflecting that HIP/PAP accelerates liver regeneration. Second, we showed that 80% of the HIP/PAP-transgenic mice versus 25% of the control mice were protected against lethal acetaminophen-induced fulminate hepatitis. A single injection of recombinant HIP/PAP induced a similar cytoprotective effect, demonstrating the antiapoptotic effect of HIP/PAP. Comparison of Cu/Zn superoxide dismutase activity and glutathione reductase-like effects in control and transgenic liver mice indicated that HIP/PAP exerts an antioxidant activity and prevents reactive oxygen species-induced mitochondrial damage by acetaminophen overdose. In conclusion, the present data offer new insights into the biological functions of C-type lectins. In addition, HIP/PAP is a promising candidate for the prevention and treatment of liver failure.
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PMID:HIP/PAP accelerates liver regeneration and protects against acetaminophen injury in mice. 1611 31

Unlike T cells, the role of natural killer (NK) cells is not well documented in the concanavalin (ConA)- induced hepatitis model. This study aimed to investigate the regulatory effect of high levels of interferon-gamma (IFN-gamma) on NK cells in ConA-induced hepatitis. The cytotoxicities of NK cells from ConA-injected mice or NK cell lines (NK92 and NKL) were detected by the 4-h 51Cr release assay. Depletion of NK cells with AsGM1 antibody was used to assess the NK cell role in ConA-induced hepatitis. Expression of NK cell receptors and cytotoxic molecules was measured by reverse transcription-polymerase chain reaction. Twelve hours after ConA injection, serum IFN-gamma was significantly increased in wild mice, but not in severe combined immunodeficiency mice, and hepatic NK cells exerted impaired cytotoxicity against YAC-l cells in wild mice. Eight hours after NK cells were incubated in serum from ConA-treated mice, NK cell cytotoxicity was down-modulated and the effect was abolished by pretreatment with neutralizing serum IFN-gamma with specific antibody in vitro. A high concentration of IFN-gamma (> 1000 U/mL) inhibited the cytotoxicities of 2 NK cell lines in vitro, accompanied with down-regulation of NKG2D transcripts and up-regulation of NKG2A/B and KIR2DL transcripts. The inhibitive role of IFN-gamma was not seen in NKG2D ligand negative cells. These results suggest that NK cell cytotoxicity was inhibited by high levels of IFN-gamma in ConA-induced hepatitis, which may relate to the dispensable role of NK cells.
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PMID:Impaired NK cell cytotoxicity by high level of interferon-gamma in concanavalin A-induced hepatitis. 1639 13


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