Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fumaric acid esters have proved to be effective for the systemic treatment of severe psoriasis vulgaris. These compounds have been shown to induce a Th2-like cytokine secretion pattern in T cells and to reduce keratinocyte proliferation in vitro. Dendritic cells seem to be of major importance as regulatory cells driving the psoriatic tissue reaction. Monocytes or CD34-positive myeloid progenitor cells are precursors of dendritic cells that can be generated in vitro by culture with granulocyte-macrophage colony-stimulating factor and interleukin-4. Using this model the effect of fumaric acid esters on granulocyte-macrophage colony-stimulating factor/interleukin-4-induced differentiation of monocyte-derived dendritic cells was investigated. The results of this study show that dimethylfumarate as well as methylhydrogenfumarate-calcium-salt (0.01-100 microg per ml) concentration-dependently inhibit monocyte-derived dendritic cell differentiation. This was reflected by an inhibition of CD1a, CD40, CD80, CD86, and HLA-DR expression as well as by a reduced capacity of dimethylfumarate-treated monocyte-derived dendritic cells to stimulate lymphocytes in the allogeneic mixed lymphocyte reaction. Other fumaric acid esters showed no effect on monocyte-derived dendritic cell-differentiation. At higher concentrations (30-100 microg per ml) dimethylfumarate, but not methylhydrogenfumarate calcium-salt induced apoptosis in monocyte-derived dendritic cells as measured by expression of Apo 2.7 and DNA fragmentation (TUNEL assay). These data point to a high susceptibility of the monocyte/dendritic cell system to dimethylfumarate and its main metabolite methylhydrogenfumarate. Other fumaric acid esters investigated were without effect. As the effects of fumarates on monocyte-derived dendritic cells observed occur at concentrations 20-fold lower compared with lymphocytes, our data seem to be of relevance in explaining the possible mode of action of these compounds in psoriasis.
 ...
PMID:Inhibition of dendritic cell differentiation by fumaric acid esters. 1117 94

Dendritic cells (DC) play a key role in the initiation of primary immune response, and pilot clinical studies have demonstrated their ability to induce efficient antitumor immunity. However, the DC used in these clinical trials were generated with various serum sources and were poorly characterized. Obtaining fully characterized DC in controlled and reproducible culture conditions is thus of major interest. We demonstrate that X-VIVO 15 medium supplemented with 2% human albumin can be used to obtain DC. The phenotypic and functional characteristics of these clinical-grade DC were analyzed according to their differentiation stages. CD83 immature DC, obtained in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4, were able to endocyte soluble antigens and internalize apoptotic tumor cells, and also expressed receptors for inflammatory chemokines. Tumor necrosis factor-alpha (TNF-alpha) induced irreversible DC maturation in association with a decreased ability to uptake antigens and an increased allostimulatory capacity. CD83+ mature DC became responsive to EBI1 ligand chemokine (ELC), a chemokine specifically expressed in secondary lymphoid organs. In addition, mature DC obtained with TNF-alpha produced IL-12 and some IL-10 in response to CD40 stimulation. In conclusion, we present well-defined culture conditions allowing the control of DC maturation for clinical or fundamental studies.
 ...
PMID:Extensive characterization of dendritic cells generated in serum-free conditions: regulation of soluble antigen uptake, apoptotic tumor cell phagocytosis, chemotaxis and T cell activation during maturation in vitro. 1118 9

We examined whether plasmids encoding granulocyte-macrophage colony-stimulating factor (pGM-CSF) or CD40-ligand (pCD40L) could modify the immune response to antigen encoded by co-injected plasmid DNA. For this we used as antigen Escherichia coli beta galactosidase (beta-gal), encoded by the plasmid pLacZ. We found that intradermal co-injection of pLacZ with both pGM-CSF and pCD40L enhanced the anti-beta-gal IgG response by approximately two orders of magnitude compared to injections of pLacZ alone. Co-injection of both pGM-CSF and pCD40L with pLacZ significantly enhanced antigen-specific IgG, and in particular IgG(2a), over that of animals co-injected with pLacZ and either pGM-CSF or pCD40L. We found that co-injection of pGM-CSF and pCD40L with pLacZ enhanced the generation of beta-gal-specific cytotoxic T cells, and allowed for a significant expansion of CD8(+) T cells from splenocytes co-cultured with beta-gal expressing stimulator cells. The immunostimulatory effects induced by pGM-CSF or pCD40L required injection of these plasmids to the same site that received pLacZ. 'Priming' experiments, where the site of injection was pre-injected with either plasmid adjuvant, showed that pGM-CSF, but not pCD40L, could enhance the anti-beta-gal immune response induced by subsequently administered plasmid antigen. We conclude that plasmids encoding GM-CSF and CD154 are particularly effective genetic adjuvants when used together to enhance the humoral and cellular immune response to a plasmid-encoded antigen.
 ...
PMID:Plasmids encoding granulocyte-macrophage colony-stimulating factor and CD154 enhance the immune response to genetic vaccines. 1122 91

Cytomegalovirus (CMV) reactivation in immunocompromised recipients of allogeneic stem cell transplantation is a cause of morbidity and mortality from viral pneumonitis. Antiviral drugs given to reactivating patients have reduced the mortality from CMV but have toxic side effects and do not always prevent late CMV disease. Cellular immunotherapy to prevent CMV disease is less toxic and could provide prolonged protection. However, a practical approach to generating sufficient quantities of CMV-specific cytotoxic T cells (CTLs) is required. This study describes a system for generating sufficient CMV-specific CTLs for adoptive immunotherapy of HLA-A*0201 bone marrow transplant recipients from 200 mL donor blood. Donor monocytes are used to generate dendritic cells (DCs) in medium with autologous plasma, interleukin 4, granulocyte-macrophage colony-stimulating factor, and CD40 ligand. The DCs are pulsed with the immunodominant HLA-A*0201-restricted CMV peptide pp65(495-503), and incubated with donor T cells. These cultures are restimulated twice with peptide-pulsed lymphoblastoid cell lines (LCLs) or CD40-ligated B cells and purified with phycoerythrin (PE)-labeled pp65(495-503)/HLA-A*0201 tetramers by flow sorting, or with anti-PE paramagnetic beads. The pure tetramer-positive population is then rapidly expanded to obtain sufficient cells for clinical immunotherapy. The expanded CTLs are more than 80% pure, of memory phenotype, with a Tc1 cytokine profile. They efficiently kill CMV-infected fibroblasts and express the integrin VLA-4, suggesting that the CTLs could cross endothelial barriers. This technique is reproducible and could be used for generating CMV-specific CTLs to prevent CMV disease after allogeneic blood and marrow transplantation. (Blood. 2001;98:505-512)
 ...
PMID:Isolation and expansion of cytomegalovirus-specific cytotoxic T lymphocytes to clinical scale from a single blood draw using dendritic cells and HLA-tetramers. 1146 43

Dendritic cells (DCs) that acquired antigen from apoptotic tumor cells are able to induce major histocompatibility complex (MHC) class I-restricted cytotoxic T lymphocytes and antitumor immunity. In the present study, we investigated the efficiency of antitumor immunity derived from DCs that had phagocytosed apoptotic/necrotic BL6-10 melanoma cells compared with that of DCs pulsed with the tumor mTRP2 peptide. Our data showed that phagocytosis of apoptotic/necrotic tumor cells resulted in maturation of DCs with up-regulated expression of proinflammatory cytokines [interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha, interferon-gamma and granulocyte-macrophage colony-stimulating factor], chemokines (MIP-1alpha, MIP-1beta and MIP-2), the CC chemokine receptor CCR7 and the cell surface molecules (MHC class II, CD11b, CD40 and CD86), and down-regulated expression of the CC chemokine receptors CCR2 and CCR5. These mature DCs displayed enhanced migration toward the CC chemokine MIP-3beta in a chemotaxis assay in vitro and to the regional lymph nodes in an animal model in vivo. Our data also showed that vaccination with DCs that had phagocytosed apoptotic/necrotic BL6-10 cells was able to (i) more strongly stimulate allogeneic T-cell proliferation in vitro, (ii) induce an in vivo Th1-type immune response leading to more efficient tumor-specific cytotoxic CD8(+) T-cell-mediated immunity and (iii) eradicate lung metastases in all 6 vaccinated mice compared with mice vaccinated with DCs pulsed with the tumor mTRP2 peptide, in which lung metastases were reduced (mean number of 16 per mouse) but not completely eradicated. Therefore, DCs that had phagocytosed apoptotic/necrotic tumor cells appear to offer new strategies in DC cancer vaccines.
 ...
PMID:Efficient antitumor immunity derived from maturation of dendritic cells that had phagocytosed apoptotic/necrotic tumor cells. 1147 58

Blood monocytes and CD34(+) haemopoietic progenitor cells, as well as certain leukaemic cell lines, acquire characteristics of mature dendritic cells (DC) after stimulation with calcium ionophore (CI). We studied whether the in vitro treatment of primary human acute myelogenous leukaemia (AML) cells with CI leads to differentiation towards DC. Blast cells derived from nine AML patients were cultured in the presence of either CI or an established differentiation cocktail consisting of granulocyte-macrophage colony-stimulating factor plus interleukin 4 and tumour necrosis factor-alpha for 5-7 d. Microscopic examination revealed that under both conditions, AML cells were shifted along the DC pathway. In seven out of nine cases, CI-cultivation led to a higher proportion of cells with dendritic morphology. The percentage of CD40 and CD86 expressing cells was significantly increased upon CI treatment compared with cytokine-cultured cells. DC molecules as CD80 and CD83 were up-regulated upon calcium mobilization of AML cells in four out of nine samples. In four cases, CI-treated stimulator cells induced an enhanced proliferative allogeneic T-cell response compared with cytokine-treated stimulator cells. In conclusion, these data demonstrate that CI treatment is an alternative in vitro strategy to differentiate human AML cells into DC.
 ...
PMID:Calcium ionophore: a single reagent for the differentiation of primary human acute myelogenous leukaemia cells towards dendritic cells. 1152 71

Dendritic cells (DCs) are pivotal antigen-presenting cells for regulating immune responses. A major focus of contemporary vaccine research is the genetic modification of DCs to express antigens or immunomodulatory molecules, utilizing a variety of viral and nonviral vectors, to induce antigen-specific immune responses that ameliorate disease states as diverse as malignancy, infection, autoimmunity, and allergy. The present study has evaluated adeno-associated virus (AAV) type 2 as a vector for ex vivo gene transfer to human peripheral blood monocyte (MO)-derived DCs. AAV is a nonpathogenic parvovirus that infects a wide variety of human cell lineages in vivo and in vitro, for long-term transgene expression without requirements for cell proliferation. The presented data demonstrate that recombinant AAV (rAAV) can efficiently transduce MOs as well as DCs generated by MO culture with granulocyte-macrophage colony-stimulating factor plus interleukin in vitro. rAAV transgene expression in MO-derived DCs could be enhanced by etoposide, previously reported to enhance AAV gene expression. rAAV transduction of freshly purified MO followed by 7 days of culture with cytokines to generate DCs, and subsequent sorting for coexpression of DC markers CD1a and CD40, showed robust transgene expression as well as evidence of nuclear localization of the rAAV genome in the DC population. Phenotypic analyses using multiple markers and functional assays of one-way allogeneic mixed leukocyte reactions indicated that rAAV-transduced MO-derived DCs were as equivalent to nontransduced DCs. These results support the utility of rAAV vectors for future human DC vaccine studies.
 ...
PMID:Adeno-associated virus type 2-mediated transduction of human monocyte-derived dendritic cells: implications for ex vivo immunotherapy. 1153 11

Mature dendritic cells (DCs), in addition to providing costimulation, can define the Th1, in contrast to the Th2, nature of a T-cell response through the production of cytokines and chemokines. Because calcium signaling alone causes rapid DC maturation of both normal and transformed myeloid cells, it was evaluated whether calcium-mobilized DCs polarize T cells toward a Th1 or a Th2 phenotype. After human monocytes were cultured for 24 hours in serum-free medium and granulocyte-macrophage colony-stimulating factor to produce immature DCs, additional overnight culture with either calcium ionophore (CI) or interferon gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and soluble CD40L resulted in phenotypically mature DCs that produced interleukin-8 (IL-8) and displayed marked expression of CD80, CD86, CD40, CD54, CD83, DC-LAMP, and RelB. DCs matured by IFN-gamma, TNF-alpha, and soluble CD40L were additionally distinguished by undetectable CD4 expression, marked secretion of IL-12, IL-6, and MIP-1beta, and preferential ability to promote Th1/Tc1 characteristics during T-cell sensitization. In contrast, DCs matured by CI treatment were distinguished by CD4 expression, modest or absent levels of IL-12, IL-6, and MIP-1beta, and preferential ability to promote Th2/Tc2 characteristics. Calcium signaling selectively antagonized IL-12 production by mature DCs activated with IFN-gamma, TNF-alpha, and soluble CD40L. Although the activation of DCs by calcium signals is largely mediated through calcineurin phosphatase, the inhibition of IL-12 production by calcium signaling was independent of this enzyme. Naturally occurring calcium fluxes in immature DCs, therefore, negatively regulate Dc1 differentiation while promoting Dc2 characteristics and Th2/Tc2 polarization. Calcium-mobilized DCs may have clinical usefulness in treating disease states with excessive Th1/Tc1 activity, such as graft-versus-host disease or autoimmunity.
 ...
PMID:Calcium signaling inhibits interleukin-12 production and activates CD83(+) dendritic cells that induce Th2 cell development. 1158 47

Muramyl dipeptide (MDP)-Lys (L18), a synthetic MDP analogue derived from bacterial cell walls, has been reported to be a potent immunoadjuvant that enhances protective immunity against pathogens and tumors by stimulating immune-competent cells, such as monocytes and macrophages. However, it is not known whether MDP-Lys modulates the function of dendritic cells (DCs), which are the most potent antigen-presenting cells and play a crucial role in initiating T cell-mediated immunity. Therefore, we examined the effects of MDP-Lys on the expression of surface molecules, cytokine production, and antigen-presenting function of human DCs generated from peripheral blood cells in the presence of interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor. We found that MDP-Lys markedly up-regulated the expression of CD80, CD83, CD86, and CD40, but not human leukocyte antigen-DR, and stimulated the production of tumor necrosis factor-alpha, IL-6, IL-8, IL-10, and IL-12 (p40) by human DCs in a dose-dependent manner. Furthermore, MDP-Lys-treated DCs showed enhanced antigen-presenting function compared with untreated DCs, as assessed by an allogeneic mixed lymphocyte reaction. These results suggested that the immunoadjuvant activity of MDP-Lys in vivo is mediated, in part, by its stimulation of DC function.
 ...
PMID:Muramyl dipeptide-Lys stimulates the function of human dendritic cells. 1169 91

Dendritic cells (DCs) have been identified as effective antigen-presenting cells (APCs). We demonstrate that extracellular matrix (ECM), hyaluronic acid (HA) and chondroitin sulphate A (CSA), in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF), can rapidly promote the differentiation of monocyte-derived immature DCs, as characterized by the remarkable upregulation of human leucocyte antigen (HLA-DR), CD40, CD54, CD80 and CD86 expression to levels higher than those in the DCs generated by culturing with GM-CSF and interleukin (IL)-4 for 7 days and aggregation of the cells within 48 h. The upregulation of expression of HLA-DR, CD40, CD54, CD80 and CD86 was dose-dependent. Further studies showed that HA and CSA were able to augment nuclear factor (NF)-kappaB activity, as determined by gel mobility shift assay and promote protein phosphorylation. Inhibition of NF-kappaB by pyrolidine dithiocarbamate and sodium salicylate, and serine-threonine and tyrosine kinase by starosporine as well as phosphatidylinositide-3-kinase (PI-3-K) by wortmannin could prevent the effects of HA and CSA on the expression of HLA-DR, CD40, CD80 and CD86 in various degrees. Thus, our data demonstrate that HA or CSA can effectively and rapidly promote the differentiation of immature DC, suggesting that HA and CSA may possess a potential capacity in regulating immune responses.
 ...
PMID:Hyaluronic acid and chondroitin sulphate A rapidly promote differentiation of immature DC with upregulation of costimulatory and antigen-presenting molecules, and enhancement of NF-kappaB and protein kinase activity. 1184 87


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>