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)

Accumulated data indicate that current generation lentiviral vectors, which generally utilize an internal human cytomegalovirus (CMV) immediate early region enhancer-promoter to transcribe the gene of interest, are not yet optimized for efficient expression in human hematopoietic stem/progenitor cells (HSPCs). As a first step toward this goal, we constructed self-inactivating derivatives of the HIV-1-based transfer vector pHR' containing the enhanced green fluorescent protein (GFP) gene as reporter and the Woodchuck hepatitis virus posttranscriptional regulatory element (WPRE). GFP expression was driven by a variety of strong viral and cellular promoters, including the murine stem cell virus (MSCV) long terminal repeat (LTR), a Gibbon ape leukemia virus (GALV) LTR, the human elongation factor 1alpha (EF1alpha) promoter, the composite CAG promoter (consisting of the CMV immediate early enhancer and the chicken beta-actin promoter), and the human phosphoglycerate kinase 1 (PGK) promoter. In contrast to results obtained in human embryonic kidney 293T cells and fibrosarcoma HT1080 cells, in which the CMV promoter expressed GFP at the highest levels, significantly higher levels of GFP expression (3- to 5-fold) were achieved with the MSCV LTR, the EF1alpha promoter, and the CAG promoter in the human HSPC line KG1a. Removal of the WPRE indicated that it stimulated GFP expression from all of the vectors in KG1a cells (up to 3-fold), although it only marginally improved the performance of the intron-containing EF1alpha and CAG promoters (<1.5-fold stimulation). The vectors using the MSCV LTR, the GALV LTR, and the PGK promoter were the most efficient at transducing primary human CD34+ cord blood progenitors under the conditions employed. High-level GFP expression in the NOD/SCID xenograft model was demonstrated with the pHR' derivative bearing the MSCV LTR. These new lentiviral vector backbones provide a basis for the rational design of improved delivery vehicles for human HSPC gene transfer applications.
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PMID:Lentiviral vectors for enhanced gene expression in human hematopoietic cells. 1108 19

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

Gene therapy of many genetic diseases requires permanent gene transfer into self-renewing stem cells and restriction of transgene expression to specific progenies. Human immunodeficiency virus (HIV)-derived lentiviral vectors are very effective in transducing rare, nondividing stem cell populations (e.g., hematopoietic stem cells) without altering their long-term repopulation and differentiation capacities. We developed a strategy for transcriptional targeting of lentiviral vectors based on replacing the viral long terminal repeat (LTR) enhancer with cell lineage-specific, genomic control elements. An upstream enhancer (HS2) of the erythroid-specific GATA-1 gene was used to replace most of the U3 region of the LTR, immediately upstream of the HIV type 1 (HIV-1) promoter. The modified LTR was used to drive the expression of a reporter gene (the green fluorescent protein [GFP] gene), while a second gene (a truncated form of the p75 nerve growth factor receptor [DeltaLNGFR]) was placed under the control of an internal constitutive promoter to monitor cell transduction, or to immunoselect transduced cells, independently from the expression of the targeted promoter. The transcriptionally targeted vectors were used to transduce cell lines, human CD34+ hematopoietic stem-progenitor cells, and murine bone marrow (BM)-repopulating stem cells. Gene expression was analyzed in the stem cell progeny in vitro and in vivo after xenotransplantation into nonobese diabetic-SCID mice or BM transplantation in coisogenic mice. The modified LTR directed high levels of transgene expression specifically in mature erythroblasts, in a TAT-independent fashion and with no alteration in titer, infectivity, and genomic stability of the lentiviral vector. Expression from the modified LTR was higher, better restricted, and showed less position-effect variegation than that obtained by the same combination of enhancer-promoter elements placed in a conventional, internal position. Cloning of the woodchuck hepatitis virus posttranscriptional regulatory element at a defined position in the targeted vector allowed selective accumulation of the genomic transcripts with respect to the internal RNA transcript, with no loss of cell-type restriction. A critical advantage of this targeting strategy is the use of a spliced, major viral transcript to express a therapeutic gene and that of an internal, independently regulated promoter to express an additional gene for either cell marking or in vivo selection purposes.
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PMID:Transcriptional targeting of lentiviral vectors by long terminal repeat enhancer replacement. 1190 39

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

Infection of the central nervous system (CNS) with the neurotropic JHM strain of mouse hepatitis virus produces acute and chronic demyelination. The contributions of perforin-mediated cytolysis and gamma interferon (IFN-gamma) secretion by CD8(+) T cells to the control of infection and the induction of demyelination were examined by adoptive transfer into infected SCID recipients. Untreated SCID mice exhibited uncontrolled virus replication in all CNS cell types but had little or no demyelination. Memory CD8(+) T cells from syngeneic wild-type (wt), perforin-deficient, or IFN-gamma-deficient (GKO) donors all trafficked into the infected CNS in the absence of CD4(+) T cells and localized to similar areas. Although CD8(+) T cells from all three donors suppressed virus replication in the CNS, GKO CD8(+) T cells expressed the least antiviral activity. A distinct viral antigen distribution in specific CNS cell types revealed different mechanisms of viral control. While wt CD8(+) T cells inhibited virus replication in all CNS cell types, cytolytic activity in the absence of IFN-gamma suppressed the infection of astrocytes, but not oligodendroglia. In contrast, cells that secreted IFN-gamma but lacked cytolytic activity inhibited replication in oligodendroglia, but not astrocytes. Demyelination was most severe following viral control by wt CD8(+) T cells but was independent of macrophage infiltration. These data demonstrate the effective control of virus replication by CD8(+) T cells in the absence of CD4(+) T cells and support the necessity for the expression of distinct effector mechanisms in the control of viral replication in distinct CNS glial cell types.
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PMID:Perforin and gamma interferon-mediated control of coronavirus central nervous system infection by CD8 T cells in the absence of CD4 T cells. 1474 39

Helicobacter rodentium was first recognized as a potential pathogen when it was isolated, along with Helicobacter bilis, from a colony of scid/Trp53 knockout mice with diarrhea. Clinical disease in these mice was more severe than that previously reported in mice infected with H. bilis alone, thus suggesting that H. rodentium contributed to the pathogenesis of enteritis. The purpose of the study reported here was to address two questions: is H. rodentium pathogenic in mice, and when co-infection with a pathogenic helicobacter occurs, does H. rodentium augment disease? To this end, A/JCr and C.B-17/IcrCrl-scidBr mice were inoculated with H. rodentium and/or H. hepaticus. Twelve weeks after inoculation, mice were euthanized. The cecum and liver were evaluated microscopically for evidence of disease. Cecal interferon-inducible protein 10 (IP-10), macrophage inflammatory protein 1alpha (MIP-1alpha), interleukin 10 (IL-10), and interferon gamma (IFN-gamma) mRNA values were measured as an indicator of mucosal immune response. Hepatic lesions were not identified in mice mono-infected with H. rodentium; likewise, cecal lesion scores were not significantly different from those of uninfected controls. With the exception of an increased IL-10 mRNA value in SCID mice, mean immune-related gene expression in H. rodentium mono-infected and uninfected control mice was not significantly different. In contrast, all mice infected with H. hepaticus developed moderate to severe hepatitis, significant increase in cecal lesion scores, and increased immune-related gene expression. The C.B-17/IcrCrl-scidBr mice co-infected with H. hepaticus and H. rodentium had liquid cecal contents and low terminal body weight. Further, compared with mice infected with H. hepaticus alone, co-infection was associated with significant increases of IL-10, MIP-1alpha, and IP-10 mRNA values in C.B-17/IcrCrl-scidBr and IFN-gamma and MIP-1alpha mRNA values in A/JCr mice. These results suggested that H. rodentium alone does not cause hepatitis or enteritis in A/JCr or C.B-17/IcrCrl-scidBr mice; however, co-infection with H. hepaticus and H. rodentium was associated with augmented cecal gene expression and clinical manifestation of disease in immunodeficient mice.
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PMID:Pathogenicity of Helicobacter rodentium in A/JCr and SCID mice. 1557 69

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

Infection of SCID mice with a recombinant murine coronavirus (mouse hepatitis virus [MHV]) expressing the T-cell chemoattractant CXC chemokine ligand 10 (CXCL10) resulted in increased survival and reduced viral burden within the brain and liver compared to those of mice infected with an isogenic control virus (MHV), supporting an important role for CXCL10 in innate immune responses following viral infection. Enhanced protection in MHV-CXCL10-infected mice correlated with increased gamma interferon (IFN-gamma) production by infiltrating natural killer (NK) cells within the brain and reduced liver pathology. To explore the underlying mechanisms associated with protection from disease in MHV-CXCL10-infected mice, the functional contributions of the NK cell-activating receptor NKG2D in host defense were examined. The administration of an NKG2D-blocking antibody to MHV-CXCL10-infected mice did not reduce survival, dampen IFN-gamma production in the brain, or affect liver pathology. However, NKG2D neutralization increased viral titers within the liver, suggesting a protective role for NKG2D signaling in this organ. These data indicate that (i) CXCL10 enhances innate immune responses, resulting in protection from MHV-induced neurological and liver disease; (ii) elevated NK cell IFN-gamma expression in the brain of MHV-CXCL10-infected mice occurs independently of NKG2D; and (iii) NKG2D signaling promotes antiviral activity within the livers of MHV-infected mice that is not dependent on IFN-gamma and tumor necrosis factor alpha secretion.
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PMID:Evidence for differential roles for NKG2D receptor signaling in innate host defense against coronavirus-induced neurological and liver disease. 1809 57

The antiviral role of CD4(+) T cells in virus-induced pathologies of the central nervous system (CNS) has not been explored extensively. Control of neurotropic mouse hepatitis virus (JHMV) requires the collaboration of CD4(+) and CD8(+) T cells, with CD8(+) T cells providing direct perforin and gamma interferon (IFN-gamma)-mediated antiviral activity. To distinguish bystander from direct antiviral contributions of CD4(+) T cells in virus clearance and pathology, memory CD4(+) T cells purified from wild type (wt), perforin-deficient (PKO), and IFN-gamma-deficient (GKO) immune donors were transferred to immunodeficient SCID mice prior to CNS challenge. All three donor CD4(+) T-cell populations controlled CNS virus replication at 8 days postinfection, indicating IFN-gamma- and perforin-independent antiviral function. Recipients of GKO CD4(+) T cells succumbed more rapidly to fatal disease than untreated control infected mice. In contrast, wt and PKO donor CD4(+) T cells cleared infectious virus to undetectable levels and protected from fatal disease. Recipients of all CD4(+) T-cell populations exhibited demyelination. However, it was more severe in wt CD4(+) T-cell recipients. These data support a role of CD4(+) T cells in virus clearance and demyelination. Despite substantial IFN-gamma-independent antiviral activity, IFN-gamma was crucial in providing protection from death. IFN-gamma reduced neutrophil accumulation and directed macrophages to white matter but did not ameliorate myelin loss.
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PMID:Memory CD4+ T-cell-mediated protection from lethal coronavirus encephalomyelitis. 1884 12


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