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: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T cells recognizing self or microbial antigens may trigger or reactivate immune-mediated diseases. Monitoring the frequency of specific T cell clonotypes to assess a possible link with the course of disease has been a difficult task with currently available technology. Our goal was to track individual candidate pathogenic T cell clones, selected on the basis of previous extensive studies from patients with immune-mediated disorders of the CNS, including multiple sclerosis, HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) and chronic Lyme neuroborreliosis. We developed and applied a highly specific and sensitive technique to track single CD4(+) and CD8(+) T cell clones through the detection and quantification of T cell receptor (TCR) alpha or beta chain complementarity-determining region 3 transcripts by real-time reverse transcriptase (RT)-PCR. We examined the frequency of the candidate pathogenic T cell clones in the peripheral blood and CSF during the course of neurological disease. Using this approach, we detected variations of clonal frequencies that appeared to be related to clinical course, significant enrichment in the CSF, or both. By integrating clonotype tracking with direct visualization of antigen-specific staining, we showed that a single T cell clone contributed substantially to the overall recognition of the viral peptide/MHC complex in a patient with HAM/TSP. T cell clonotype tracking is a powerful new technology enabling further elucidation of the dynamics of expansion of autoreactive or pathogen-specific T cells that mediate pathological or protective immune responses in neurological disorders.
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PMID:Molecular tracking of antigen-specific T cell clones in neurological immune-mediated disorders. 1247 92

Hematopoietic reconstitution could be associated with premature ageing of the transplanted cells and a high frequency of myelodysplastic syndrome and secondary leukaemia. Telomere length decreases with cell divisions and age, and at a crucial length it is associated with chromosomal instability and cell senescence. Telomerase is a reverse transcriptase enzyme that adds nucleotides to chromosomal ends. Most somatic cells lack telomerase activity yet haematopoietic stem cells retain low levels of telomerase. Some studies have found that chemotherapy and stem cell transplantation lead to the accelerated shortening of telomere length. As granulocyte colony-stimulating factor (G-CSF) is routinely used in the mobilization of stem cells for transplantation, we evaluated its effects on telomerase activity and regulation, and on telomere dynamics, in normal donors and selected lymphoma patients. Administration of G-CSF increased telomerase activity in CD34+ haematopoietic cells compared with controls. In marrow-derived CD34+ cells, telomerase activity increased sevenfold, compared with a 14-fold increase in peripheral-blood-mobilized CD34+ cells. A parallel increase in the expression of human telomerase enzyme reverse transcriptase RNA and protein kinase C alpha occurred. In addition, G-CSF administration to five lymphoma patients after consecutive courses of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy, resulted in telomere length preservation or elongation, as opposed to marked attrition in patients who did not receive growth factors. We conclude that the in vivo administration of G-CSF prevents or attenuates telomere attrition associated with chemotherapy administration. This attenuation may contribute to the preservation of telomere integrity inG-CSF-primed transplanted stem cells.
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PMID:Granulocyte colony-stimulating factor administration upregulates telomerase activity in CD34+ haematopoietic cells and may prevent telomere attrition after chemotherapy. 1254 95

The influence of transport mechanisms at the blood-brain barrier (BBB) and blood-CSF barrier (choroid plexus) on the CNS distribution of anti-human immunodeficiency virus (HIV) drugs was examined using guinea-pig brain perfusion and incubated choroid plexus models. 2',3'-dideoxyinosine (ddI) passage across the BBB was demonstrated to be via non-saturable (Kd = 0.22 +/- 0.3 microL/min/g) and saturable (Km = 20.1 +/- 15.0 microm, Vmax = 6.5 +/- 2.1 pmol/min/g) processes. Cross competition studies implicated an equilibrative nucleoside transporter in this influx. The brain distribution of ddI was unchanged in the presence of additional nucleoside reverse transcriptase inhibitors (NRTIs). ddI transport from blood into choroid plexus was demonstrated to involve an organic anion transporting polypeptide 2-like transporter. The NRTIs, abacavir, 3'-azido 3'-deoxythymidine and (-)-beta-L-2',3'-dideoxy-3'-thiacytidine, competed with ddI for transporter binding sites at the choroid plexus, altering the tissue concentration of ddI. This has clinical implications as the choroid plexus is a site of HIV replication, and suboptimal CNS concentrations of anti-HIV drugs could result in neurological complications. Furthermore, this may promote the selection of drug resistant variants of HIV within the CNS, which could re-infect the periphery and lead to HIV therapy failure. This study indicates that understanding drug interactions at the transporter level could prove valuable when selecting drug combinations to treat HIV within the CNS.
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PMID:Mechanisms by which 2',3'-dideoxyinosine (ddI) crosses the guinea-pig CNS barriers; relevance to HIV therapy. 1256 17

The T-cell cytokine interleukin (IL)-17 selectively accumulates neutrophils in murine airways in vivo and may thus constitute a link between activation of T-lymphocytes and accumulation of neutrophils. In this study, the authors evaluated the role of granulocyte macrophage-colony stimulating factor (GM-CSF) in accumulation of neutrophils in the airways caused by IL-17 and tumour necrosis factor (TNF)-alpha. In vitro, human (h) IL-17 concentration-dependently stimulated the release of GM-CSF protein (enzyme-linked immunosorbent assay) in human bronchial epithelial cells (16HBE). IL-17 also time-dependently stimulated the release of GM-CSF protein in venous endothelial (human umbilical vein endothelial cells) cells in vitro. Co-stimulation with IL-17 plus the pro-inflammatory cytokine TNF-alpha potentiated the release of GM-CSF protein in 16HBE cells. hIL-17 also enhanced the expression of GM-CSF messenger ribonucleic acid in 16HBE cells (reverse transcriptase polymerase chain reaction), with a similar order of magnitude as TNF-alpha. Conditioned cell medium from bronchial epithelial cells co-stimulated with hIL-17 plus TNF-alpha prolonged survival (trypan blue exclusion) of human neutrophils in vitro and this effect was blocked by an anti-GM-CSF antibody. In vivo, local co-stimulation with mouse IL-17 plus TNF-alpha caused an additive potentiation of the accumulation of neutrophils in bronchoalveolar lavage fluid from mouse airways and this effect was blocked by an anti-GM-CSF antibody given systemically. In conclusion, granulocyte macrophage-colony stimulating factor is involved in the accumulation of neutrophils in the airways caused by interleukin-17 and tumour necrosis factor-alpha, probably via effects on both recruitment and survival of neutrophils.
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PMID:A role of GM-CSF in the accumulation of neutrophils in the airways caused by IL-17 and TNF-alpha. 1266 90

We investigated the expression and function of matrix metalloproteinase-12 (MMP-12) in a model of allergic airway inflammation. Mice were sensitized mucosally by exposure to aerosolized ovalbumin (OVA) daily over a period of 10 d in the context of adenovirus-mediated granulocyte macrophage colony-stimulating factor (GM-CSF) expression. The ensuing inflammatory response is characterized by a Th2 cytokine profile, OVA-specific IgE, and airway eosinophilia. Using real-time, quantitative reverse transcriptase-polymerase chain reaction we assessed MMP-12 mRNA expression in whole lung tissue. We observed a 12- and 70-fold increase in expression at Days 7 and 11, respectively, in OVA-exposed mice when compared with naive controls. Immunoblot analysis revealed an increase in MMP-12 protein in the bronchoalveolar lavage fluid of mice exposed to OVA in the context of GM-CSF. No such elevation was observed in mice exposed to saline only in the context of GM-CSF. To assess functional role of MMP-12, MMP-12 knockout (KO) mice were subjected to the aforementioned protocol. We observed an 80% reduction in eosinophils in the bronchoalveolar lavage fluid of KO mice compared with their wild-type littermates. Using interleukin-13 KO mice, we demonstrated that expression of MMP-12 is interleukin-13-dependent. Collectively, our data indicate a novel function for MMP-12 in the process of airway eosinophil accumulation.
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PMID:Interleukin-13-dependent expression of matrix metalloproteinase-12 is required for the development of airway eosinophilia in mice. 1284 50

Neutrophil adhesion to extracellular matrix is necessary for an effective inflammatory response. Adhesion may accelerate neutrophil activation by affecting intracellular signaling pathways. The nuclear transcription factor kappaB (NF-kappaB) controls several cellular functions, including inflammation, proliferation, and cell survival. We explored the role of adhesion in NF-kappaB activation in human neutrophils. Cells were stimulated with tumor necrosis factor-alpha (TNF-alpha), granulocyte macrophage-colony-stimulating factor (GM-CSF), interleukin-8 (IL-8), and formyl-methionyl-leucyl-phenylalanine (fMLP). All four initiated neutrophil adherence to and spreading on fibronectin. GM-CSF and IL-8 did not activate NF-kappaB in suspended neutrophils but rapidly activated NF-kappaB under adherent conditions on matrix, as shown by IkappaB kinase activity assay, IkappaBalpha degradation, electromobility shift assay, and quantitative reverse transcriptase-PCR. In contrast, TNF-alpha activated NF-kappaB both in suspended cells and adherent cells. fMLP did not activate NF-kappaB in either suspended or adherent cells. Specific beta(2) integrin blockade prevented NF-kappaB activation by GM-CSF and IL-8 on fibronectin. Co-stimulating CD18 and CD11b with activating antibodies resulted in NF-kappaB activation by GM-CSF and IL-8 in suspended cells. We inhibited actin polymerization with cytochalasin and blocked the non-receptor kinase Syk with piceatannol. Both maneuvers prevented the co-stimulatory NF-kappaB-activating signal by beta(2) integrins. Thus, in addition to beta(2) integrin ligand binding, NF-kappaB activation depended on the formation of the receptor-associated intracellular focal adhesion complex. We conclude that beta(2) integrins may provide co-stimulatory signals allowing some soluble mediators to activate the NF-kappaB pathway even when they are not capable of doing so in suspension. This effect may become important when human neutrophils leave the circulating blood and migrate through extracellular matrix during inflammation.
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PMID:Integrins and cytokines activate nuclear transcription factor-kappaB in human neutrophils. 1461 35

The introduction, in 1995, of highly active antiretroviral therapy (HAART) dramatically reduced the morbidity and mortality of HIV-infected patients. However, the brain remains a site of viral replication for HIV and thus is still an important target for antiretroviral agents. Consequently, a clear understanding of how the current anti-HIV drugs reach the CNS, and interact at the level of the blood-brain barrier and blood-CSF barrier, is important if we are to maximise viral suppression and improve clinical outcome. It would also contribute to the development of new anti-HIV drugs and the identification of transport inhibitors that could be used as adjuvant therapies. In this review we focus on the role of the blood-brain and blood-CSF barriers in the delivery of the main classes of approved anti-HIV drugs. Among these groups, the CNS distribution of the nucleoside reverse transcriptase inhibitors is the best characterised. It involves probenecid efflux transport mechanisms, which limit their brain delivery and probably their, neurological efficacy. Nevirapine and efavirenz, the commonly prescribed non-nucleoside reverse transcriptase inhibitors, can readily enter the CSF, however, it remains to be seen if a transport system is involved in their distribution. The protease inhibitors have only a limited ability to reach the CNS, with the majority of this class of drugs not even being detected in human CSF after administration. This is partly the result of their removal from the CNS by the efflux transporters; P-glycoprotein, and possibly multi-drug resistance associated protein (MRP).
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PMID:Anti-HIV drug distribution to the central nervous system. 1513 83

A cDNA encoding feline granulocyte-macrophage colony stimulating factor was cloned from alveolar macrophages using the reverse transcriptase-polymerase chain reaction (RT-PCR). The cDNA is 426 bp in length and encodes a predicted mature protein of 127 amino acids and the majority of the signal peptide. The recombinant protein (rfGM-CSF) was expressed in both Escherichia coli, as a calmodulin fusion protein, and mammalian cells. Biological activity of both recombinant proteins was demonstrated using the human erythroleukaemic cell line, TF-1. In a soft agar clonogenic assay, rfGM-CSF supported the development of granulocyte, macrophage and granulocyte-macrophage colonies. In combination with phytohaemagglutin (PHA) lymphocyte-conditioned medium, the number and size of such colonies were increased. Culture of feline bone marrow cells with rfGM-CSF was an efficient method for producing cells with morphology typical of dendritic cells (DC). The availability of the recombinant cytokine will permit further studies, in particular, the evaluation of the role of dendritic cells in feline immunopathology and its potential as a vaccine adjuvant.
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PMID:Isolation, expression and bioactivity of feline granulocyte-macrophage colony-stimulating factor. 1514 59

The aim of this study was to determine the effects of mouse granulocyte-macrophage colony-stimulating factor (mGM-CSF) on development of porcine parthenotes and nuclear transferred embryos, and on their expression of implantation-related genes. In the presence of bovine serum albumin, mGM-CSF did not increase the percentage of oocytes that developed to the blastocyst stage and at day 7 did not increase cell numbers of embryos. Addition of 2 ng/ml GM-CSF to protein-free culture medium significantly increased the compaction and blastocoel formation of 1- to 2-cell parthenotes developing in vitro. However, total cell numbers were not increased when they were cultured in the presence of GM-CSF. Semi-quantitative reverse transcriptase polymerase chain reaction revealed that mGM-CSF enhances mRNA expression of the leukemia inhibitory factor receptor, but does not influence interleukin-6 or sodium/glucose co-transporter protein gene expression in blastocyst stage parthenotes. These results suggest that mGM-CSF may enhance viability of porcine embryos developing in vitro in a defined culture medium.
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PMID:Mouse granulocyte-macrophage colony-stimulating factor enhances viability of porcine embryos in defined culture conditions. 1530 96

We recently identified a reduction in the neutrophil surface expression of common beta chain (beta c) of the receptor for granulocyte macrophage-colony stimulating factor (GM-CSF) in the patients with myelodysplastic syndromes (MDS). To determine the etiology of the impaired beta c expression, beta c mRNA from neutrophilic granulocytes of MDS patients and healthy controls was analyzed by a combination of direct reverse transcriptase-polymerase chain reaction-based single-strand conformational polymorphism and sequencing. Nine different beta c transcripts were detected, but none was specific for MDS. However, one of the transcripts (beta c79) containing a 79-base intron insertion between exons V and VI was significantly increased in MDS. This 27-kd isoform consisted of the beta c N-terminal 182 amino acids followed by a new 84-amino-acid sequence. beta c79 was overexpressed in all MDS subtypes. No genomic mutations were detected within the intron or at the intron/exon boundaries. The isoform is predominantly located in the cytoplasm by Western blot analysis and was unable to generate high-affinity binding sites or transduce a signal for proliferation when coexpressed with the receptor for human GM-CSF alpha chain. Our study suggests that the accumulation of the abnormal beta c transcripts with intron V retention results in the reduction in cell-surface expression of beta c observed in MDS.
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PMID:Accumulation of an intron-retained mRNA for granulocyte macrophage-colony stimulating factor receptor common beta chain in neutrophils of myelodysplastic syndromes. 1572 48


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