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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primitive human hematopoietic cells have recently been identified within a rare subfraction of CD34(-) lineage-depleted (Lin(-)) cells and further characterized by their restriction to a rarer subset expressing AC133. Here we show that CD34(-)AC133(+)Lin(-) cells can be transduced by retrovirus at a comparatively higher efficiency than either CD34(-)AC133(-)Lin(-) or CD34(+)CD38(-)Lin(-) cells. Subpopulations were transduced by enhanced green fluorescent protein (eGFP)-containing retrovirus in serum-free conditions. During the culture period, both CD34(-)AC133(+)Lin(-) and CD34(+)CD38(-)Lin(-) subfractions expanded, whereas CD34(-)AC133(-)Lin(-) cells could not be sustained. Fluorescent microscopic examination of progenitors assayed by colony-forming units (CFU) derived from CD34(-)AC133(+)Lin(-) cells revealed expression of eGFP, with the presence of provirus confirmed by clonal PCR analysis. Flow cytometry detecting eGFP revealed that cultures seeded with CD34(-)AC133(+)Lin(-) cells had a greater than threefold higher frequency of eGFP(+) cells compared with transduced cultures of CD34(+)CD38(-)Lin(-) cells. Our results demonstrate that retroviral transduction efficiency and level of transgene expression into CD34(-)AC133(+)Lin(-) cells is distinct to either CD34(-)AC133(-)Lin(-) or CD34(+)CD38(-)Lin(-) cells. This study represents the first evaluation of retroviral transduction into this population of primitive CD34(-) cells, and therefore provides the basis for optimization of gene transfer protocols to examine the role of gene-marked CD34(-) stem cells in a clinical setting.
Mol Ther 2002 May
PMID:Characterization of retroviral gene transfer into highly purified human CD34(-) cells with primitive hematopoietic capacity. 1199 55

To define a dynamic sequence of phenotypic changes related to early and late phases of NK-cell activation, we have analyzed by four-color flow cytometry the immunophenotype of normal blood NK-cells from 12 healthy individuals and compared it with those from 15 patients with acute viral infections and 15 patients with either chronic infections or tumors. Although a great interindividual variability was found, nonstimulated CD56(+) NK-cells, present in normal blood samples, usually were CD2(-/+lo), CD7(+hi), HLA-DR(-), CD11b(+), CD38(+), CD11a(+hi), CD45RA(+hi), and CD45RO(-), the expression of CD11c and CD57 being heterogeneous and variable. Recently activated NK-cells, herein corresponding to NK-cells from patients with acute viral infections, displayed a pattern of expression of CD2/CD7 similar to that referred to above, but they typically showed higher levels of CD11a, CD38, and HLA-DR, as well as downregulation of CD11b and CD45RA, accompanied in some cases by coexpression of CD45RO; in addition, these NK-cells were CD11c(+) and CD57(-/+lo). Late-activated NK-cells, represented by NK-cells present in patients with chronic infections and tumors, converted into a CD2(+hi)/CD7(-/+lo) immunophenotype and expressed heterogeneously low levels of CD38 and CD11b; moreover, they were CD57(+) and CD11c(-/+). At this stage, most NK-cells had already reverted into their original CD45RA(+)/CD45RO(-)/HLA-DR(-) phenotype. In summary, we show that the patterns of expression of CD2/CD7, CD57/CD11c, CD38/CD11b, CD45RA/CD45RO, and CD11a/HLA-DR may help us to define the immunophenotypic profiles associated with early and late NK-cell activation phases in 'in vivo' models.
Blood Cells Mol Dis
PMID:The "ex vivo" patterns of CD2/CD7, CD57/CD11c, CD38/CD11b, CD45RA/CD45RO, and CD11a/HLA-DR expression identify acute/early and chronic/late NK-cell activation states. 1206 14

There is evidence for a role of cyclic ADP-ribose (cADPR) in intracellular Ca2+ regulation in smooth muscle. cADPR is synthesized and degraded by ADP-ribosyl cyclase and cADPR hydrolase, respectively, by a bifunctional protein, CD38. Nitric oxide (NO) inhibits intracellular Ca2+ mobilization in airway smooth muscle. The present study was designed to determine whether this inhibition is due to regulation of ADP-ribosyl cyclase and/or cADPR hydrolase activity. Sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine, NO donors, produced a concentration-dependent decrease in ADP-ribosyl cyclase, but not cADPR hydrolase, activity. The NO scavenger carboxy-PTIO prevented and reversed, and reduced glutathione prevented, the inhibition of ADP-ribosyl cyclase by SNP, suggesting S-nitrosylation by NO as a mechanism. N-ethylmaleimide, which covalently modifies protein sulfhydryl groups, making them incapable of nitrosylation, produced a marked inhibition of ADP-ribosyl cyclase, but not cADPR hydrolase, activity. SNP and N-ethylmaleimide significantly inhibited the ADP-ribosyl cyclase activity in recombinant human CD38 without affecting the cADPR hydrolase activity. These results provide a novel mechanism for differential regulation of CD38 by NO through a cGMP-independent pathway involving S-nitrosylation of thiols.
Am J Physiol Lung Cell Mol Physiol 2002 Nov
PMID:Nitric oxide inhibits ADP-ribosyl cyclase through a cGMP-independent pathway in airway smooth muscle. 1237 59

Photopheresis (ECP) is a novel immunomodulatory therapy effectively used to treat several T-cell-mediated diseases and to reverse allograft rejection after organ transplantation. It consists of infusion of UVA-irradiated autologous leukocytes collected by apheresis and extracorporeally incubated with 8-methoxypsoralen (8-MOP). In this study we explored the potential immunological events for therapeutic efficacy of photopheresis in preventing allograft rejection by evaluating in vitro the combined effects of 8-MOP and UVA (PUVA) on multiple immunological parameters, such as induction of apoptosis, production of soluble mediators, and expression of cell antigens. Peripheral blood mononuclear cells (PBMCs) obtained from healthy subjects were treated with 8-MOP and UVA at the same doses as those clinically used in ECP. We demonstrate that PUVA treatment induced leukocyte hyporesponsiveness and a decrease in expression of co-stimulatory and adhesion molecules as well as of cytokine levels. Additionally, PUVA treatment induced apoptosis in both mononuclear cells (possibly through the Fas/FasL system and/or the CD38 pathway) and purified monocytes. In conclusion, our work focuses attention on the initial phase of immune response and identifies some new targets of therapy (e.g., costimulatory molecules) able to trigger final effects underlying therapeutic efficacy of photopheresis.
Blood Cells Mol Dis
PMID:Psoralen and UVA light: an in vitro investigation of multiple immunological mechanisms underlying the immunosuppression induction in allograft rejection. 1248

Although paroxysmal nocturnal hemoglobinuria (PNH) is often associated with aplastic anemia (AA), the nature of the pathogenetic link between PNH and AA remains unclear. Moreover, the PIG-A mutation appears to be necessary but not sufficient for the development of PNH, suggesting other factors are involved. The ability of PNH marrow cells to form in vitro hematopoietic colonies and the ability of PNH marrow to generate stroma that could support hematopoiesis of normal or PNH marrow in cross culture were investigated. PNH marrow from both post-Ficoll and post-lineage depleted hematopoietic progenitor cells grew similarly significantly fewer colonies than normal marrow. Sorting of CD59(+) and CD59(-) CD34(+) CD38(-) cells from patients with PNH showed similarly impaired clonogenic efficiency, indicating that the hematopoietic defect in PNH does not directly relate to GPI-anchored protein expression. PNH marrow readily grew stroma similar to marrow from normal donors. Cross culture experiments revealed that PNH stroma appears to function normally in vitro; it can support growth of normal marrow cells as well as normal stroma does, but neither PNH nor normal stroma could support the growth of PNH marrow cells. The hematopoietic defect in PNH is not due to defective stroma, but is due to defective progenitor cell growth related to additional unknown factors.
Blood Cells Mol Dis
PMID:The hematopoietic defect in PNH is not due to defective stroma, but is due to defective progenitor cells. 1249 Feb 82

Although a number of studies on the phenotypic changes that occur after T-cell activation have already been published, the specific immunophenotypic features of T-lymphocytes and the frequency at which TCR-variable region (TCR-V) restricted T-cell expansions occur "in vivo" during acute viral infection still remains to be established. We report on the immunophenotype and TCR-V repertoire of peripheral blood T-cells from 28 patients with acute infectious mononucleosis. Immunophenotypic studies were performed by flow cytometry using direct immunofluorescence techniques and stain-and-then-lyse sample preparation protocols with three- and four-colour combinations of monoclonal antibodies directed against a large panel of T- and NK-cell associated markers, activation- and adhesion-related molecules and TCR-Vbeta, -Vgamma and -Vdelta families. Nearly all patients (27/28) showed a massive expansion of CD8(+)/TCRalphabeta(+) T cells, the majority (>90%) of which displayed an immunophenotype compatible with T-cell activation: CD2(+high), CD7(+low), CD11a(+high), CD38(+high), HLA-DR(+high), CD28(+/-low), CD45RO(+high), CD45RA(-/+low), CD11b(-/+low), CD11c(+/-low), CD16(-), CD56(-), CD57(-), CD62L(-), CD94(-), CD158a(-), CD161(-), NKB1(-). Additionally, the levels of both CD3 and CD5 were slightly decreased compared to those found in normal individuals. Late-activation antigens, such as CD57, were found in small proportions of CD8(+)/TCRalphabeta(+) T-cells. Increased numbers of CD4(+)/TCRalphabeta(+) T-cells, TCRgammadelta(+) T-cells and NK-cells were also noticed in 17, 16 and 13 of the 28 cases studied, respectively. Evidence for activation of CD4(+)/TCRalphabeta(+) and TCRgammadelta(+) T-cells relied on changes similar to those described for CD8(+)/TCRalphabeta(+) although less pronounced, except for higher levels of both CD5 and CD28 in the absence of reactivity for CD11c on CD4(+)/TCRalphabeta(+) T-cells and higher levels of CD161 and CD94 on TCRgammadelta(+) T-cells. Small expansions of one or more TCR-Vbeta families accounting for 12 +/- 7% of either the CD8(+)/TCRalphabeta(+) or the CD4(+)/TCRalphabeta(+) T-cell compartment were found in 12 of 14 patients studied, whereas the distribution of the TCR-Vgamma and -Vdelta repertoires tested in 2 of the individuals with expanded TCRgammadelta(+) T-cells was similar to that observed in control individuals. The results presented here provide evidence for an extensive T-cell activation during acute viral infection and establish the immunophenotype patterns associated with this condition.
Blood Cells Mol Dis
PMID:Immunophenotype and TCR-Vbeta repertoire of peripheral blood T-cells in acute infectious mononucleosis. 1266 82

Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by a specific deficiency in erythroid progenitors. Since some patients with DBA develop a reduction in thrombocytes and granulocytes with age, we asked whether multipotent hematopoietic progenitors from DBA patients had normal proliferative capacity in liquid expansion cultures. CD34(+) cells derived from DBA patients showed deficient proliferation in liquid culture containing IL-3, IL-6, and SCF. Single CD34(+) CD38(-) cells from DBA patients exhibited deficient proliferation recruitment in a limiting dilution assay containing IL-3, IL-6, SCF, Tpo, FL, and G-CSF or containing IL-3, IL-6, and SCF. Our findings suggest that the underlying hematopoietic defect in DBA may not be limited to the erythroid lineage. Since a fraction of DBA patients have a deficiency in ribosomal protein S19 (RPS19), we constructed lentiviral vectors containing the RPS19 gene for overexpression in hematopoietic progenitors from RPS19-deficient DBA patients. Enforced expression of the RPS19 transgene improved the proliferation of CD34(+) cells from DBA patients with RPS19 mutation. Similarly, enforced expression of RPS19 improved erythroid development of RPS19-deficient hematopoietic progenitors as determined by colony assays and erythroid differentiation cultures. These findings suggest that gene therapy for RPS19-deficient DBA is feasible.
Mol Ther 2003 May
PMID:Proliferation deficiency of multipotent hematopoietic progenitors in ribosomal protein S19 (RPS19)-deficient diamond-Blackfan anemia improves following RPS19 gene transfer. 1271 4

Chronic lymphocytic leukemia (CLL) is a common hematopoietic malignant disease with variable outcome. CLL has been divided into distinct groups based on whether somatic hypermutation has occurred in the variable region of the immunoglobulin heavy-chain locus or alternatively if the cells express higher levels of the CD38 protein. We have analyzed the proteome of 12 cases of CLL (six mutated (M-CLL) and six unmutated (UM-CLL) immunoglobulin heavy-chain loci; seven CD38-negative and five CD38-positive) using two-dimensional electrophoresis and mass spectrometry. Statistical evaluation using principal component analysis indicated significant differences in patterns of protein expression between the cases with and without somatic mutation. Specific proteins indicated by principal component analysis as varying between the prognostic groups were characterized using mass spectrometry. The levels of F-actin-capping protein beta subunit, 14-3-3 beta protein, and laminin-binding protein precursor were significantly increased in M-CLL relative to UM-CLL. In addition, primary sequence data from tandem mass spectrometry showed that nucleophosmin was present as several protein spots in M-CLL but was not detected in UM-CLL samples, suggesting that several post-translationally modified forms of nucleophosmin vary between these two sample groups. No specific differences were found between CD38-positive and -negative patient samples using the same approach. The results presented show that proteomic analysis can complement other approaches in identifying proteins that may have potential value in the biological and diagnostic distinction between important clinical subtypes of CLL.
Mol Cell Proteomics 2003 Dec
PMID:Proteomic analysis of chronic lymphocytic leukemia subtypes with mutated or unmutated Ig V(H) genes. 1455 98

Several lines of embryonic stem cells (ESC) have been established from rhesus monkey blastocysts. We have examined two of these cell lines for their potential for generating hematopoietic progenitors in cell culture, and we identified culture conditions, including supplementation with bone morphogenetic proteins (BMP), that result in hematopoietic differentiation of rhesus ESC with high efficiency. We have also characterized the resulting hematopoietic progenitor cells for their patterns of gene expression, as compared to those of hematopoietic progenitor cells harvested from rhesus monkey bone marrow. Of more than 60 genes examined in this manner, CD34+/CD38- cells derived from embryonic stem cells and those obtained from bone marrow demonstrated very similar patterns of gene expression. However, with integrin alphaL, IL-6 receptor, and flt-3 gene expression was greatly diminished or absent in CD34+/CD38- cells derived from the ESC, whereas the bone marrow-derived progenitors showed substantial expression of all of these genes. When the same type of comparison was done with mouse (D3 and CCE) as well as human (H1) embryonic stem cells, in each case comparing ESC-derived hematopoietic progenitors with those harvested from bone marrow, the only consistent deficiency of gene expression was that of flt-3. In hematopoietic precursors derived from mouse ESC, globin-gene expression has previously been shown to be a useful index of the embryological maturity of the cells, and we also examined globin-gene expression in rhesus monkey ESC-derived hematopoietic precursor cells, using a semiquantitative technique. CD34+/CD38- cells demonstrated expression of the epsilon- and gamma-globin genes, but negligible levels of beta globin, suggesting that these cells were at the developmental stage in which the yolk sac and fetal liver are the primary sites of hematopoiesis.
Blood Cells Mol Dis
PMID:Hematopoietic differentiation of rhesus monkey embryonic stem cells. 1475 5

CD38/cyclic adenosine diphosphate ribose (cADPR) signaling plays an important role in the regulation of intracellular calcium responses to agonists in a variety of cells, including airway smooth muscle (ASM) cells. The present study was aimed at determining the effect of interleukin (IL)-13, a cytokine implicated in the pathogenesis of asthma, on CD38/cADPR signaling and to ascertain the contribution of CD38/cADPR signaling to IL-13-induced airway hyperresponsiveness. Human ASM cells maintained in culture were exposed to 50 ng/ml IL-13 for 22 h and levels of CD38 expression and intracellular calcium responses to agonists were measured. Treatment of human ASM cells with IL-13 resulted in increased CD38 expression as determined by real-time polymerase chain reaction, Western blot analysis, and indirect immunofluorescence. Increased CD38 expression was reflected as increased ADP-ribosyl cyclase activity in the ASM cell membranes. The net intracellular calcium responses to bradykinin, thrombin, and histamine were significantly (P < or = 0.05) higher in cells treated with IL-13 compared with controls. Furthermore, 8-bromo-cADPR, a cADPR antagonist, attenuated IL-13-induced augmented intracellular calcium responses to agonists in human ASM cells. These findings indicate that the CD38/cADPR-dependent pathway has a major role in IL-13-induced modulation of calcium signaling in human ASM.
Am J Respir Cell Mol Biol 2004 Jul
PMID:Modulation of calcium signaling by interleukin-13 in human airway smooth muscle: role of CD38/cyclic adenosine diphosphate ribose pathway. 1476 28


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