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:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Low recovery and poor retroviral vector infection efficiency of hematopoietic stem cells has hindered application of gene therapy for disease affecting blood-forming tissues. Developmental restriction (or death) of stem cells during ex vivo infection has contributed to these difficulties. In these studies we report that the cytokine leukemia inhibitory factor (LIF) directly or indirectly supported the survival of hematopoietic stem cells during culture of bone marrow with vector-producing fibroblasts, resulting in efficient recovery of stem cells able to compete for engraftment in irradiated recipient animals. The infection efficiency of hematopoietic stem cells recovered from these cultures was approximately 80%; and all recipients (20/20) of the LIF-treated marrow were stably engrafted with the progeny of provirus-bearing stem cells. Expression of vector-encoded human adenosine deaminase (hADA) was detected in all recipients at levels averaging 15-50% of endogenous murine ADA in all their hematolymphoid tissues. Survival of stem cells in untreated cultures was approximately 10% of that observed from LIF-treated cultures, resulting in poor engraftment of recipient animals with transplanted cells. The infection efficiency of the few stem cells recovered from untreated cultures, however, was high (approximately 80%), suggesting that LIF did not have an effect on infection efficiency per se, but acted at the level of stem cell survival. Consistent with the poor engraftment observed in the control animals, expression of vector-encoded ADA was only approximately 4-20% of the endogenous levels. These results support the postulated role of LIF as a regulator of hematopoiesis and suggest that cytokine stimulation can positively affect inefficient retroviral vector transduction in hematopoietic stem cells.
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PMID:Leukemia inhibitory factor improves survival of retroviral vector-infected hematopoietic stem cells in vitro, allowing efficient long-term expression of vector-encoded human adenosine deaminase in vivo. 165 47

We have investigated the effects of the cytokine leukemia inhibitory factor (LIF) on recovery and retroviral infection of murine hematopoietic stem cells maintained in short-term culture. Up to a two-fold increase in CFU-S13 recovery was observed, from 9.7 x 10(-5) cells in untreated controls to 17.6 x 10(-5) cells when 10U/ml LIF is added to the culture medium. Intermediate concentrations of LIF (.1U/ml and 1U/ml) were not significantly different from the control. Histological analysis of spleen colonies harvested thirteen days posttransplant demonstrated that LIF does not cause a detectable alteration in the differentiative potential of CFU-S13. The efficiency of retroviral-vector infection in CFU-S13 is also improved, from 15% (24/158) in untreated controls to 91% (116/127) at a LIF concentration of 10U/ml. LIF concentrations of .1U/ml and 1U/ml increased infection efficiency to 35% (14/40) and 71% (37/51), respectively. Analysis of proviral insertion sites in spleen colonies indicated that some CFU-S13 precursors were infected in the LIF-treated marrows, but no identical pairs were detected in the controls. Finally, long-term expression of provirally-encoded human adenosine deaminase (hADA) was measured in hematopoietic tissues of bone marrow transplant recipients six months posttransplant. In all tissues analyzed (spleen, thymus, bone marrow, splenic B cells, peritoneal macrophages, and blood) differentiated progeny of LIF-treated marrows had higher levels of hADA than untreated controls. Tenfold increases in levels of hADA are detected in some tissues, but levels were variable. These experiments demonstrate that LIF directly or indirectly enhances retroviral infection efficiency of hematopoietic stem cells, and might be used to improved existing gene transfer protocols.
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PMID:Effects of leukemia inhibitory factor (LIF) on gene transfer efficiency into murine hematolymphoid progenitors. 195 Jul 65

Severe combined immunodeficiency (SCID) was originally thought to be one disease. Accumulating evidence indicates that SCID is a heterogeneous group of diseases that are clinically similar but are caused by quite different biochemical abnormalities. The best-studied form of SCID is that associated with an autosomal recessive inheritance pattern of adenosine deaminase (ADA) deficiency. Several biochemical mechanisms have been postulated to explain how a deficiency of ADA causes immune dysfunction. In forms of SCID not associated with ADA deficiency, other biochemical abnormalities have been detected. These abnormalities include deficiency in biotin-dependent carboxylases, alteration in lymphocyte surface membranes and irregularities in cytokine production. Two animal models for SCID now exist. Neither of these models is associated with ADA deficiency. Evidence for a possible defect in purine metabolism in one model has been demonstrated.
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PMID:Metabolic defects in severe combined immunodeficiency in man and animals. 351 64

CTLL-2 cells are a clone of CTL that are dependent on IL-2 for proliferation. In addition to various cytokine receptors, we observed that these cells express three subtypes of adenosine receptors (ARs). In an initial attempt to delineate the functions of these receptors in CTLL-2 cells, we tested their role in proliferation. Elimination of endogenous adenosine with adenosine deaminase (ADA) markedly suppressed IL-2-dependent proliferation of these cells. This proliferative response was restored by addition of R-phenylisopropyladenosine (R-PIA), a non-hydrolyzable adenosine analogue. The stimulatory response to R-PIA was attenuated following blockade of ARs by 0.5 mM theophylline and 10 microM BW-A1433, but not by blockade of the A1AR with 100 nM xanthine amine congener. The rank order of potency of adenosine analogues in proliferation assays was R-PIA > or = N-ethylcarboxamide adenosine > S-PIA > PAPA-APEC (a substituted ethylamino-5'-N-ethylcarboxamidoadenosine). These data suggest a potential role of the A3AR in the proliferative response. R-PIA stimulates production of 1,4,5-inositol trisphosphate in CTLL-2 cells, suggesting a role of the phospholipase C signaling pathway in the proliferative response. A23187 (100 nM) and phorbol 12,13 dibutyrate (10 nM), but not 4 alpha-phorbol (10 nM), were able to restore IL-2-dependent CTLL-2 proliferation in the presence of ADA. Furthermore, inhibition of protein kinase C by staurosporine (10 nM) and of phospholipase C by tricyclodecan-9-yl-xanthogenate (D609) blocked R-PIA-mediated cell proliferation. These data demonstrate an obligatory role of adenosine in IL-2-dependent proliferation of CTLL-2 cells and support the involvement of an AR-stimulated phospholipase C signaling pathway in this process.
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PMID:Adenosine acts as an endogenous modulator of IL-2-dependent proliferation of cytotoxic T lymphocytes. 767 97

Recombinant adenoviral vectors have been shown to be potential new tools for a variety of human gene therapy protocols. We examined the effectiveness of an adenovirus vector for gene transfer into human bone marrow (BM). Mononuclear cells from one adenosine deaminase (ADA)-deficient and two normal human BM samples were transduced by an E1-defective adenoviral vector encoding human ADA and kept in myeloid long-term culture. Retroviral gene transfer was also performed with the ADA-deficient bone marrow as a control. The transduced cells were harvested at different times and the expression of the vector-encoded ADa in crude cell extracts of nonadherent cells was analyzed. The expression from Ad-ADA was higher than that from a retroviral vector at 1 week post-transduction. In half of the experiments, the ADA activity decreased with passage. Unexpectedly, sustained expression from Ad-ADA was observed in the other half. At the end of the experiments (2 months), free virus from BM cultures which showed sustained expression of ADA was detected on 293 cells. Several independent virus clones were isolated and analyzed and found to be Ad-ADA. Our results suggest potential use of adenoviral vectors for gene therapy that does not require sustained expression, as with cytokine gene transfer for cancer gene therapy. However, our finding that infectious virus can sometimes persist might raise issues regarding the leakiness of human adenovirus vectors in cells of some human tissues.
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PMID:Transduction of human bone marrow by adenoviral vector. 794 43

The effects of the carbocyclic nucleoside MDL 201,112 and the purine nucleoside adenosine on the interferon-gamma (IFN-gamma)-induced priming of macrophages (m phi s) for the respiratory burst and major histocompatibility class II (MHC class II) Ia+ antigen expression were compared. Priming of purified, peritoneal m phi s from Lewis (LEW/N) rats for 18 h with recombinant rat IFN-gamma (rRaIFN-gamma) in the presence of either adenosine (100 microM) or MDL 201,112 (10 microM) resulted in a fourfold decrease in superoxide anion (O2-) production after stimulation with opsonized zymosan. Both agents were effective even when added 2 or 4 h after rRaIFN-gamma treatment. Peritoneal m phi s from LEW/N rats stimulated with LPS/rRaIFN-gamma were observed to secrete immunoreactive and bioactive TNF-alpha over 18 h in vitro and this cytokine could be dose-dependently inhibited by MDL 201,112. MDL 201,112 did not bind to classical A1 or A2 receptors on rat brain homogenates. Physiological levels of adenosine deaminase, or treatment with the nucleoside transport inhibitor dipyridamole, reversed the effects of adenosine; however, these agents at physiological concentrations had little or no effect on the inhibition of O2- release mediated by MDL 201,112. Furthermore, incubation of LEW/N m phi s for 18 h in vitro with rRaIFN-gamma resulted in significant enhancement of MHC class II Ia+ antigen expression, and these levels could be blocked by nearly 50% by either MDL 201,112 (10 microM) or adenosine (100 microM). MDL 201,112 and adenosine were also effective in decreasing m phi opsonized zymosan-stimulated O2- levels and MHC class II Ia+ antigen expression in vivo. The effects of MDL 201,112 on the down-regulation of heat-killed M. tuberculosis-activated LEW/N m phi MHC class II Ia+ antigen expression in vitro appear to be mediated by a novel pathway, because there was no rank order of potency of ADO A1 or A2 agonist/antagonists (CCPA, NECA, XAC, or CPT) in our in vitro system. In summary, our data provide compelling evidence that immunoregulatory carbocyclic nucleoside analogues such as MDL 201,112 or adenosine appear to regulate LEW/N rat m phi activation through novel molecular mechanisms and may have important therapeutic implications for acute and chronic inflammatory diseases.
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PMID:Effect of the carbocyclic nucleoside analogue MDL 201,112 on inhibition of interferon-gamma-induced priming of Lewis (LEW/N) rat macrophages for enhanced respiratory burst and MHC class II Ia+ antigen expression. 807 90

Ischemia induces excessive ATP catabolism with subsequent local release of its metabolite adenosine, an autacoid with anti-inflammatory properties. Because activation of the vascular endothelium is critical to the inflammatory host response during ischemia and reperfusion, the effects of adenosine on two major determinants of endothelial cell activation (i.e., the release of proinflammatory cytokines and the expression of adhesion molecules) were studied. Adenosine dose dependently inhibited the release of interleukin (IL)-6 and IL-8 by stimulated human umbilical vein endothelial cells (HUVEC). Expression of E-selectin and vascular cell adhesion molecule 1 (VCAM-1), but not intercellular adhesion molecule 1 (ICAM-1), by activated HUVEC was also reduced by adenosine. Inhibition of endogenous adenosine deaminase activity by erythro-9-(2-hydroxy-3-nonyl)adenine or 2'-deoxycoformycin strongly enhanced the inhibitory effects of exogenous adenosine on cytokine release and expression of E-selectin and VCAM-1. However, a clear role for specific adenosine receptors in the described inhibitory events could not be established. Together, these data imply that the vascular endothelium constitutes an important target for the anti-inflammatory actions of adenosine.
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PMID:Adenosine inhibits cytokine release and expression of adhesion molecules by activated human endothelial cells. 877 15

Pleural fluids obtained from 26 patients with tuberculous pleurisy (T-group), 11 with parapneumonic pleurisy (B-group) and 21 with malignant pleurisy (M-group) were tested for their biologic parameters and cytokine concentrations. 1) The average age of T-group was over 10 years lower than that of M-group with a statistically significant difference. 2) The average CRP value of B-group and the positivity on PPD skin test of T-group were higher than those of the other groups, respectively. 3) Yellowish pleural fluids were mainly observed in T- and B-group, while bloody pleural fluids were mostly seen in M-group with a statistically significant difference. The average total protein amount and adenosine deaminase value in pleural fluid significantly increased in T-group. The percentage of polymorphonuclear leukocytes showed a significant increase in B-group, while lymphocytes significantly increased in T-group with a statistically significant difference. 4) Although no significant difference in concentrations of IL-1 beta, IL-2, IFN-gamma and TNF-alpha in serum was noticed among the three groups, the average concentrations of IFN-gamma and TNF-alpha in pleural fluid in T-group were significantly higher than those in the other groups. 5) TNF-alpha-mRNA of mononuclear cells in pleural fluid was strongly expressed in 3 out of 11 patients of T-group, while no expression was observed in 6 patients of M-group. In conclusion, the measurement of concentrations of two kinds of cytokines in pleural fluid, IFN-gamma and TNF-alpha, may be clinically useful for the differential diagnosis of tuberculous pleurisy from parapneumonic pleurisy and malignant pleurisy.
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PMID:[Differential diagnosis of tuberculous pleurisy by the measurement of cytokine concentration in pleural effusion]. 901 Nov 34

We previously reported successful peripheral T cell-directed gene therapy in a boy with adenosine deaminase (ADA)-SCID. In the present study, to better understand the reconstitutive effect of this gene therapy on his immunological system, we investigated the in vivo kinetics and functional subsets of T cells in PBL. Apparent immunological improvements were obtained after infusion of transduced cells at more than 4 x 108 cells/kg/therapy/3 mo. Frequency of ADAcDNA-integrated cells in PBL, ADA activity in PBL and clinical improvement showed good correlation, even though CD8+ cells gradually became predominant in PBL. On the basis that polyethylene glycol (PEG)-ADA was maintained at the same dosage as before gene therapy, we consider that his immunological improvement resulted from the gene therapy itself. Most CD3+ cells in PBL after gene therapy expressed TCRalphabeta. Analysis of TCR repertoire based on TCR V region usage revealed no expansion of limited clones in his PBL. The T cell subset cells CD8+CDw60+ and CD8+CD27+CD45RA-, which are reported to provide substantial help to B cells, were maintained throughout the gene therapy. Furthermore, his reconstituted peripheral T cells helped normal B cells to produce substantial IgG in vitro. Expression of both Th1- and Th2-type cytokine genes was induced in his reconstituted T cells at the same comparably high level as in normal subjects. Collectively, these results provide evidence of persistent and distinct functions of transduced cells in this patient's PBL after gene therapy.
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PMID:In vivo kinetics of transduced cells in peripheral T cell-directed gene therapy: role of CD8+ cells in improved immunological function in an adenosine deaminase (ADA)-SCID patient. 1043 69

Immune cell activation releases ATP into the extracellular space. ATP-sensitive P2 purinergic receptors are expressed on immune cells and activation of these receptors alters immune cell function. Furthermore, ATP is metabolized by ectonucleotidases to adenosine, which has also been shown to alter cytokine production. In the present study, we investigated how extracellular ATP affects interleukin (IL)-12 and tumour necrosis factor (TNF)-alpha production in bacterial lipopolysaccharide (LPS)-treated murine peritoneal macrophages and we also examined whether extracellular ATP alters the production of the T helper 1 cytokine interferon (IFN)-gamma. Pretreatment of the peritoneal macrophages with ATP or various ATP analogues decreased both IL-12 and TNF-alpha production induced by LPS (10 microgram ml(-1)). The effect of ATP was partially reversed by cotreatment with adenosine deaminase (0.1 - 1 u ml(-1)), suggesting that the suppressive effect of ATP on cytokine production is, in part, due to its degradation products. Immunoneutralization with an anti-IL-10 antibody demonstrated that although ATP increases IL-10 production, the inhibition of IL-12 and TNF-alpha production is independent of the increased IL-10. The effect of ATP was pretranslational, as it suppressed steady state levels of mRNAs for IL-12 (both p35 and p40). In spleen cells stimulated with either LPS (10 microgram ml(-1)) or anti-CD3 (2 microgram ml(-1)) antibody, ATP suppressed, in a concentration-dependent manner, the production of IFN-gamma. These results suggest that extracellular ATP has multiple anti-inflammatory effects and that release of ATP into the extracellular space may play a role in blunting the overactive immune response in autoimmune diseases.
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PMID:ATP suppression of interleukin-12 and tumour necrosis factor-alpha release from macrophages. 1069 89


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