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:3.2.1.23 (beta-galactosidase)
14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dendritic cells (DCs) are bone marrow-derived leukocytes that function as potent antigen presenting cells capable of initiating T cell-dependent responses from quiescent lymphocytes. DC pulsed with tumor-associated antigen (TAA) peptide or protein have recently been demonstrated to elicit antigen-specific protective antitumor immunity in a number of murine models. Transduction of DCs with TAA genes may allow stable, prolonged antigen expression as well as the potential for presentation of multiple, or unidentified, epitopes in association with major histocompatibility complex class I and/or class II molecules. To evaluate the potential efficacy of retrovirally transduced DCs, bone marrow cells harvested from BALB/c mice were transduced with either a model antigen gene encoding beta-galactosidase (beta-gal) or a control gene encoding rat HER-2/neu (Neu) by coculture with irradiated ecotropic retroviral producer lines. Bone marrow cells were differentiated into DC in vitro using granulocyte/macrophage colony-stimulating factor and interleukin-4. After 7 d in culture, cells were 45-78% double positive for DC phenotypic cell surface markers by FACS(R) analysis, and DC transduced with beta-gal were 41-72% positive for beta-gal expression by X-gal staining. In addition, coculture of beta-gal transduced DC with a beta-gal-specific T cell line (CTLx) resulted in the production of large amounts of interferon-gamma, demonstrating that transduced DCs could process and present endogenously expressed beta-gal. DC transduced with beta-gal and control rat HER-2/neu were then used to treat 3-d lung metastases in mice bearing an experimental murine tumor CT26.CL25, expressing the model antigen, beta-gal. Treatment with beta-gal-transduced DC significantly reduced the number of pulmonary metastatic nodules compared with treatment with Hank's balanced salt solution or DCs transduced with rat HER-2/neu. In addition, immunization with beta-gal-transduced DCs resulted in the generation of antigen-specific cytotoxic T lymphocytes (CTLs), which were significantly more reactive against relevant tumor targets than CTLs generated from mice immunized with DCs pulsed with the Ld-restricted beta-gal peptide. The results observed in this rapidly lethal tumor model suggest that DCs transduced with TAA may be a useful treatment modality in tumor immunotherapy.
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PMID:Dendritic cells retrovirally transduced with a model antigen gene are therapeutically effective against established pulmonary metastases. 933 60

In a search for means to deliver exogenous gene(s) into human dendritic cells (DCs) from the perspective of tumor-specific vaccination, we have evaluated two recombinant viruses, both of which carry a reporter gene which is namely a modified vaccinia virus Ankara (MVA) and an adenovirus, as possible expression vectors. The recombinant MVA-P11 LZ vector carries the Escherichia coli lacZ gene coding for the enzyme beta-galactosidase, and the recombinant Ad-MFG-AP vector carries a modified membrane-exposed alkaline phosphatase (AP) gene. DCs were generated ex vivo in the presence of tumor necrosis factor-alpha, granulocyte macrophage colony-stimulating factor, stem cell factor, and flk-2/flt-3 ligand taken from CD34+ hematopoietic progenitors that were mobilized into the peripheral blood of cancer patients treated with high-dose cyclophosphamide and filgrastim. The target cells used for gene delivery were either CD34+ cells that had been subsequently induced to differentiate into mature DCs or DCs transduced after ex vivo generation from CD34+ cells. The results showed that: (a) infection of CD34+ cell derived-DCs (mature DCs) with either viral vector resulted in the efficient synthesis of recombinant protein, and (b) CD34+ cells were permissive for the expression of the recombinant reporter gene after infection with Ad-MFG-AP but not after infection with MVA-P11 LZ. In conclusion, these results suggest that vaccinia and adenovirus vectors are candidate to act as vehicles in genetically engineering human DCs.
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PMID:Gene transfer into human dendritic antigen-presenting cells by vaccinia virus and adenovirus vectors. 991 89

Endothelial progenitor cells (EPCs) have been isolated from circulating mononuclear cells in human peripheral blood and shown to be incorporated into foci of neovascularization, consistent with postnatal vasculogenesis. We determined whether endogenous stimuli (tissue ischemia) and exogenous cytokine therapy (granulocyte macrophage-colony stimulating factor, GM-CSF) mobilize EPCs and thereby contribute to neovascularization of ischemic tissues. The development of regional ischemia in both mice and rabbits increased the frequency of circulating EPCs. In mice, the effect of ischemia-induced EPC mobilization was demonstrated by enhanced ocular neovascularization after cornea micropocket surgery in mice with hindlimb ischemia compared with that in non-ischemic control mice. In rabbits with hindlimb ischemia, circulating EPCs were further augmented after pretreatment with GM-CSF, with a corresponding improvement in hindlimb neovascularization. There was direct evidence that EPCs that contributed to enhanced corneal neovascularization were specifically mobilized from the bone marrow in response to ischemia and GM-CSF in mice transplanted with bone marrow from transgenic donors expressing beta-galactosidase transcriptionally regulated by the endothelial cell-specific Tie-2 promoter. These findings indicate that circulating EPCs are mobilized endogenously in response to tissue ischemia or exogenously by cytokine therapy and thereby augment neovascularization of ischemic tissues.
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PMID:Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. 1020 35

Antigen presenting cells (APC) play an essential role in the generation of tumor-specific immune responses. Dendritic cells are the most potent of APC, capable of activating both antigen-specific CD4+ and CD8+ T cells. Previously, we have described how vaccination of mice with irradiated tumor cells producing granulocyte/macrophage-colony-stimulating factor (GM-CSF) induces tumor-specific immunity capable of protecting mice from a subsequent tumor challenge. The present study extends these findings to examine the types of APC infiltrating vaccination sites and the chemokines responsible for their recruitment. GM-CSF released from genetically engineered tumor cells led to the local accumulation of dendritic cells in and around the vaccination site. Quantification revealed a significant ten-fold increase in the number of dendritic cells infiltrating GM-CSF-producing as opposed to beta-galactosidase-producing (control) vaccination sites. Reverse transcription/polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemical analysis of vaccination sites revealed that MIP-1alpha may be responsible for dendritic cell infiltration into GM-CSF-producing tissues. These findings suggest that GM-CSF may indirectly recruit dendritic cells into vaccination sites through the local production of MIP-1alpha.
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PMID:Granulocyte/macrophage-colony-stimulating factor released by adenovirally transduced CT26 cells leads to the local expression of macrophage inflammatory protein 1alpha and accumulation of dendritic cells at vaccination sites in vivo. 1041 66

To identify developmentally regulated genes during myeloid differentiation, a self-inactivating retroviral gene-trap vector carrying a beta-galactosidase-neomycin (SA/lacZ/neo) fusion gene was constructed and used to infect myeloid progenitor cells (FDCP-Mix A4). G418-resistant and beta-galactosidase positive cell lines (gene-trap integration [GTI] clones) were established and induced to differentiate in vitro into either macrophages or granulocytes. Expression of the trapped loci was monitored at a single-cell level by analysing the mature cell types for beta-galactosidase activity. All 37 GTI clones tested showed down-regulation either during granulocyte or both granulocytic and macrophage differentiation. The endogenous coding regions fused to the SA/lacZ/neo reporter gene were isolated from eight clones. Molecular analysis revealed that half of them represented novel mouse genes (def-2, -3, -6 and -8) which we confirmed to be differentially expressed in primary haemopoietic tissues. Database searches revealed no significant similarities for def-2 (associated with haemopoietic progenitors) and def-8 (expressed most strongly in peripheral leucocytes). Def-6, which is down-regulated upon the differentiation into myeloid as well as erythroid lineages, was found to be closely related but not identical with the recently described B-cell-specific switch recombinase SWAP-70. Def-3, which is down-regulated upon differentiation into granulocytes but expressed in progenitor cells and macrophages, defines a novel family of RNA binding proteins.
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PMID:Def-2, -3, -6 and -8, novel mouse genes differentially expressed in the haemopoietic system. 1046 May 89

The efficacy of a recombinant vaccinia virus (rvv-GM-CSF) expressing the granulocyte macrophage colony stimulating factor (GM-CSF) as tumor vaccine was evaluated in the murine B16-F10 melanoma model. The vaccine was prepared by infection of irradiated tumor cells with rvv-GM-CSF. Control vaccine was B-16 cells infected with a recombinant vaccinia virus expressing Escherichia coli beta-galactosidase (rvv-lacZ). Pre-vaccination of naive C57BL/6 mice later inoculated with tumor cells and treatment of mice bearing tumors with GM-CSF vaccine inhibited tumor development and prolonged survival. Lung metastasis of B-16 was also inhibited by treatment with GM-CSF vaccine. The vaccine effects appeared to be tumor cell specific. The efficacy of the vaccine was comparable to a retroviral vaccine (MFG-muGM-CSF) in this system. The vaccine was also effective when rvv-GM-CSF was directly injected into the tumor. These data suggest that this vaccine approach has potential for use in cancer treatment, especially for patients with easily accessible tumors.
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PMID:Recombinant vaccinia virus expressing cytokine GM-CSF as tumor vaccine. 1065 66

Adenovirus infection of hematopoietic cells frequently requires high virus concentrations and long incubation times to obtain moderate infection levels because these cells have low levels of Coxsackie and adenovirus receptor (CAR) and alpha(v) integrin. The effect of treatment with FR901228 (depsipeptide), a histone deacetylase inhibitor in phase 2 clinical trials, was studied in K562 cells, granulocyte-colony-stimulating factor-mobilized peripheral blood mononuclear cells (PBMCs), and CD34+ peripheral blood stem cells (PBSCs). FR901228 increased CAR and alpha(v) integrin RNA levels and histone H3 acetylation. FR901228 treatment before adenovirus infection was associated with at least a 10-fold increase in transgene expression from a beta-galactosidase-expressing adenoviral vector. More than 80% of the PBMCs or CD34+ PBSCs from 7 different donors were beta-galactosidase-positive after adenovirus infection with a multiplicity of infection of 10 for 60 minutes. Increased CAR, alpha(v) integrin, and acetylated histone H3 levels were observed in PBMCs from a patient treated with FR901228. These studies suggest that FR901228 can increase the efficiency of adenoviral infection in hematopoietic cells.
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PMID:Histone deacetylase inhibitor FR901228 enhances adenovirus infection of hematopoietic cells. 1187 6

Dendritic cells (DCs) are the most potent antigen-presenting cells and a prerequisite for the initiation of primary immune response. This study was performed to investigate the contribution of DCs to the initiation of Graves' hyperthyroidism, an organ-specific autoimmune disease in which the thyrotrophin receptor (TSHR) is the major autoantigen. DCs were prepared from bone marrow precursor cells of BALB/c mice by culturing with granulocyte macrophage-colony stimulating factor and interleukin-4. Subcutaneous injections of DCs infected with recombinant adenovirus expressing the TSHR (but not beta-galactosidase) in syngeneic female mice induced Graves'-like hyperthyroidism (8 and 35% of mice after two and three injections, respectively) characterized by stimulating TSHR antibodies, elevated serum thyroxine levels and diffuse hyperplasitc goiter. TSHR antibodies determined by ELISA were of both IgG1 (Th2-type) and IgG2a (Th1-type) subclasses, and splenocytes from immunized mice secreted interferon-gamma (a Th1 cytokine), not interleukin-4 (a Th2 cytokine), in response to TSHR antigen. Surprisingly, IFN-gamma secretion, and induction of antibodies and disease were almost completely suppressed by co-administration of alum/pertussis toxin, a Th2-dominant adjuvant, whereas polyriboinosinic polyribocytidylic acid, a Th1-inducer, enhanced splenocyte secretion of IFN-gamma without changing disease incidence. These observations demonstrate that DCs efficiently present the TSHR to naive T cells to induce TSHR antibodies and Graves'-like hyperthyroidism in mice. In addition, our results challenge the previous concept of Th2 dominance in Graves' hyperthyroidism and provide support for the role of Th1 immune response in disease pathogenesis.
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PMID:Dendritic cells infected with adenovirus expressing the thyrotrophin receptor induce Graves' hyperthyroidism in BALB/c mice. 1256 82

Exposure of murine bone marrow (BM) cells to ionizing radiation (IR; 4 Gy) resulted in >95% inhibition of the frequency of various day types of cobblestone area-forming cells in association with the induction of apoptosis in hematopoietic stem cell alike cells (Lin(-) ScaI(+) c-kit(+) cells; IR: 64.8 +/- 0.4% versus control: 20.4 +/- 0.5%; P < 0.001) and progenitors (Lin(-) ScaI(-) c-kit(+) cells; IR: 46.2 +/- 1.4% versus control: 7.8 +/- 0.5%; P < 0.001). Incubation of murine BM cells with busulfan (BU; 30 micro M) for 6 h also inhibited the cobblestone area-forming cell frequency but failed to cause a significant increase in apoptosis in these two types of hematopoietic cells. After 5 weeks of long-term BM cell culture, 33% and 72% of hematopoietic cells survived IR- and BU-induced damage, respectively, as compared with control cells, but they could not form colony forming units-granulocyte macrophages. Moreover, these surviving cells expressed an increased level of senescence-associated beta-galactosidase, p16(Ink4a), and p19(Arf). These findings suggest that IR inhibits the function of hematopoietic stem cell alike cells and progenitors primarily by inducing apoptosis, whereas BU does so mainly by inducing premature senescence. In addition, induction of premature senescence in BM hematopoietic cells also contributes to IR-induced inhibition of their hematopoietic function. Interestingly, the induction of hematopoietic cell senescence by IR, but not by BU, was associated with an elevation in p53 and p21(Cip1/Waf1) expression. This suggests that IR induces hematopoietic cell senescence in a p53-p21(Cip1/Waf1)-dependent manner, whereas the induction of senescence by BU bypasses the p53-p21(Cip1/Waf1) pathway.
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PMID:Ionizing radiation and busulfan induce premature senescence in murine bone marrow hematopoietic cells. 1450 Mar 76

Therapeutic augmentation of collateral vessel growth (arteriogenesis) is of particular clinical interest. Because monocytes localize to areas of collateral growth and create a highly arteriogenic environment through secretion of multiple growth factors, we tested the hypothesis that monocyte "homing" can therapeutically be exploited. We have used a rabbit model of arteriogenesis to investigate the therapeutic potential of transplanted rabbit monocytes that were either ex vivo stimulated or adenovirally transduced to express a transgene encoding an arteriogenic growth factor. The monocytes were intravenously injected 24 hr or 7 days after ligation of the animal's right femoral artery. Seven days after transplantation collateral flow was determined with a doppler flow probe and collateral vessels were quantified angiographically. Whereas transplantation of allogeneic cells (same species) resulted in a strong promotion of arteriogenesis, most likely through induction of local inflammation and recruitment of recipient monocytes, transplantation of autologous cells (same animal) was not able to significantly augment collateralization. However, when autologous monocytes were used as vehicles to deliver granulocyte macrophage-colony stimulating factor as therapeutic transgene, collateralization was strongly augmented. Their localization to the site of collateral development posttransplantation was demonstrated by ex vivo transduction with beta-galactosidase. Because isolation of monocytes is clinically widely available their ex vivo engineering and transplantation represents an intriguing new strategy for therapeutic arteriogenesis.
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PMID:Transplantation of monocytes: a novel strategy for in vivo augmentation of collateral vessel growth. 1496 73


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