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)

The effects of genetic adjuvants on humoral and cell-mediated immunity to two human immunodeficiency virus antigens, Env and Nef, have been examined in mice. Despite similar levels of gene expression and the same gene delivery vector, the immune responses to these two gene products differed following DNA immunization. Intramuscular immunization with a Nef expression vector plasmid generated a humoral response and antigen-specific gamma interferon (IFN-gamma) production but little cytotoxic-T-lymphocyte (CTL) immunity. In contrast, immunization with an Env vector stimulated CTL activity but did not induce a high-titer antibody response. The ability to modify these antigen-specific immune responses was investigated by coinjection of DNA plasmids encoding cytokine and/or hematopoietic growth factors, interleukin-2 (IL-2), IL-12, IL-15, Flt3 ligand (FL), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Coadministration of these genes largely altered the immune responses quantitatively but not qualitatively. IL-12 induced the greatest increase in IFN-gamma and immunoglobulin G responses to Nef, and GM-CSF induced the strongest IFN-gamma and CTL responses to Env. A dual approach of expanding innate immunity by administering the FL gene, together with a cytokine that enhances adaptive immune responses, IL-2, IL-12, or IL-15, generated the most potent immune response at the lowest doses of Nef antigen. These findings suggest that intrinsic properties of the antigen determine the character of immune reactivity for this method of immunization and that specific combination of innate and adaptive immune cytokine genes can increase the magnitude of the response to DNA vaccines.
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PMID:Effects of antigen and genetic adjuvants on immune responses to human immunodeficiency virus DNA vaccines in mice. 1173 89

We attempted to determine whether various cytokine levels in the serum and synovial fluid (SF) of rheumatoid arthritis (RA) patients are influenced by the performance of filtration leukocytapheresis (LCP). The filtration LCP procedure that used a Cellsorba column (LCP group: n=22; responder subgroup: n=17, non-responder subgroup: n=5) or sham apheresis (control group; n=7) was repeated three times at 1-week intervals. Serum (LCP group, n=22; control group, n=7) and SF (LCP group, n=6; control group, n=3) samples were collected before and after LCP. Levels of tumor necrosis factor alpha (TNFalpha), interleukins (IL-1 beta, IL-2, IL-6, IL-8, IL-10, and IL-15), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1), RANTES were measured by an enzyme-linked immunosorbent assay. Serum TNF alpha, IL-15, and RANTES were significantly reduced only in the LCP group. Serum IL-10 significantly increased only in the LCP group. In the LCP subgroup, serum IL-15, GM-CSF, and RANTES levels were reduced significantly, while serum IL-10 levels increased significantly only in the responder group after treatment. Serum TNF alpha levels were reduced significantly in both subgroups. Changes in serum IL-10 correlated positively with the improvement of patient's assessment of pain and global severity, and physician's assessment of global severity. These results indicate that the removal of leukocytes from the peripheral blood of RA patients provokes dynamic changes in some cytokine levels in the serum and/or synovial fluid. These changes may explain some of the mechanisms by which the articular symptoms are improved by filtration LCP.
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PMID:Dynamic changes in cytokine levels in serum and synovial fluid following filtration leukocytapheresis therapy in patients with rheumatoid arthritis. 1174 32

Chronic lymphocytic leukaemia (CLL) remains an incurable disease. Although modern available treatments are able to induce disease regression, relapse almost inexorably occurs. Therefore, novel therapeutic strategies aimed at reducing the disease relapse rate are very much needed. Among these, the induction of tumour-associated antigen-specific cytotoxic T lymphocytes (CTL), through either DNA vaccines or injection of idiotype pulsed dendritic cells (DCs), has been actively investigated with encouraging preliminary results in B-cell malignancies. As the CLL B lymphocyte characteristically expresses low amounts of surface immunoglobulin (Ig) and T cells from these patients have been reported to display impaired functional activity, there are concerns related to the possibility of generating specific cytotoxic antitumoral T cells in this disease. In addition, no information is presently available regarding the functional ability of CLL-derived DCs. In the present work, freshly purified monocytes from CLL patients and normal donors were induced to differentiate in granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 serum-free medium and compared for their morphological, phenotypic and functional characteristics. Our results demonstrate that: (1) functional DCs can be generated from CLL patients with similar phenotype and function to those observed from normal donors; (2) in contrast to normal control subjects, monocyte-derived DCs from CLL patients spontaneously secrete endogenous IL-10; and (3) interferon (IFN)-gamma in combination with CD40L plays a major role in priming DCs from CLL patients for IL-12 and IL-15 production. Overall, these results indicate that it is possible to derive functionally competent DCs from circulating monocytes in CLL patients.
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PMID:Functional monocyte-derived dendritic cells can be generated in chronic lymphocytic leukaemia. 1184 17

The principal interferon-alpha/beta (IFN-I)-producing cells are plasmacytoid dendritic cell (PDC) precursors belonging to the lymphoid lineage. Monocytes that can differentiate into dendritic cells (DC) also produce IFN-I, although much less than PDC, after interaction with infectious agents. We show that whereas viruses trigger these cells to produce IFN-I, the amount of IFN is tightly controlled by cytokines. Monocytes produced IFN-I in response to Sendai virus (SV) infection, and PDC responded to both SV and herpes simplex virus (HSV). All cytokines tested failed to induce production of IFN-I in the absence of infection. However, among 18 relevant cytokines, incubation of PDC with interleukin-4 (IL-4), IL-15, and IL-7 alone or in combination with IL-3 before infection, enhanced IFN-I secretion. At variance, IL-12 alone or in synergy with granulocyte-macrophage colony-stimulating factor (GM-CSF) was active on SV-infected but not on HSV-infected monocytes. Tumor necrosis factor-alpha (TNF-alpha) and IL-4 inhibited IFN-I production by PDC and monocytes, respectively, and IL-10 strongly inhibited IFN-I production in both cell lineages. The response of PDC to IL-7 and IL-15, which also activate natural killer (NK) cell maturation, further emphasizes the cooperation between these two cell subsets in the control of innate immunity.
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PMID:Type I interferon production by plasmacytoid dendritic cells and monocytes is triggered by viruses, but the level of production is controlled by distinct cytokines. 1216 75

Natural killer (NK) cell differentiation from pluripotent CD34(+) human hematopoietic stem cells or oligopotent lymphoid progenitors has already been reported. In the present study, long-term cultures of the CD56(-)/CD34(-) myeloid-like adherent cell fraction (ACF) from umbilical cord blood (UCB), characterized by the expression of CD14(+) as well as other myeloid markers, were set up with flt3 ligand (FL) and interleukin-15 (IL-15). The UCB/ACF gradually expressed the CD56 marker, which reached fairly high levels (approximately 90% of the cells were CD56(+)) by day 15. FL plus IL-15-driven ACF/CD56(+) cells progressively expressed a mature NK functional program lysing both NK- and lymphokine-activate killer (LAK)-sensitive tumor targets and producing high levels of interferon-gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor, tumor necrosis factor alpha, and IL-10 upon stimulation with IL-12 and IL-18. Similar results were obtained when highly purified CD14(+) cells from UCB were cultured with FL and IL-15. In contrast, UCB/CD34(+) cells cultured under the same conditions showed a delayed expression of CD56 and behaved functionally differently in that they exhibited NK but not LAK cytotoxicity and produced significantly fewer cytokines. Kinetic studies on the phenotype of UCB/ACF or UCB/CD14(+) cells cultured in the presence of FL and IL-15 showed a rapid decrease in CD14 expression after day 5, which reached levels of zero by day 20. Approximately 60% of the CD56(+) derived from the UCB/ACF or the UCB/CD14(+) cells coexpressed CD14 by day 5. Taken together, our data support the role of CD14(+) myeloid-like cells within UCB as a novel progenitor for lymphoid NK cells.
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PMID:A novel myeloid-like NK cell progenitor in human umbilical cord blood. 1250 32

Anti-inflammatory therapy in asthma is reliant on corticosteroids, particularly in their inhaled form. However, steroids are rather non-specific in their actions and they also raise concerns regarding compliance and side-effect Issues. Furthermore, a small proportion of patients with asthma fail to respond to oral glucocorticoids even at high doses. This Article will review the role that steroids and membrane receptor ligation play in the induction of eosinophil apoptosis together with the mechanisms by which corticosteroids enhance the disposal of apoptotic eosinophils by both professional and non-professional phagocytes. Eosinophils are thought to be the major pro-inflammatory effector cell in asthma and their persistence in the airways is probably enhanced by the presence of several asthma-relevant cytokines that prolong eosinophil survival by inhibition of apoptosis (interleukin (IL)-3, IL-5, granulocyte-macrophage colony-stimulating factor, IL-9, IL-13, IL-15). In contrast, a number of signals have been described that accelerate apoptosis in human eosinophils including corticosteroids or ligation of membrane receptors (CD95, CD45, CD69). Thus, the load of lung eosinophils in asthmatic disease is likely to be related to a balance in the tIssue microenvironment between pro- and anti-apoptotic signals. Furthermore, removal of apoptotic eosinophils by phagocytosis by alveolar macrophages or bronchial epithelial cells in a specific receptor-mediated way is as important as the process of apoptosis induction. Corticosteroids enhance the recognition and engulfment of apoptotic eosinophils by macrophages or bronchial epithelial cells. Caspases are key intracellular molecules in the control of apoptosis and defects in caspase-induced apoptosis in eosinophils from steroid-resistant individuals may contribute to the molecular mechanisms underlying glucocorticoid insensitivity in these cells. These findings point the way to new and more targeted anti-inflammatory therapy for asthma and may provide important clues for the development of alternative therapies for glucocorticoid resistance.
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PMID:Corticosteroids, eosinophils and bronchial epithelial cells: new insights into the resolution of inflammation in asthma. 1284 34

Interleukin 21 (IL-21) is a newly described cytokine with homology to IL-4 and IL-15. They belong to a cytokine family that uses the common gamma chain for signaling but also have their private high-affinity receptors. Since it is well known that IL-4 modulates differentiation and activation of dendritic cells (DCs), we analyzed effects of IL-21 compared with IL-15 on DC differentiation, maturation, and function. Here we show that DCs generated with granulocyte-macrophage colony-stimulating factor (GMCSF) in the presence of IL-21 (IL-21DCs) differentiated into phenotypically and functionally altered DCs characterized by reduced major histocompatibility complex class II (MHCII) expression, high antigen uptake, and low stimulatory capacity for T-cell activation in vitro. Additionally, IL-21DCs completely failed to induce antigen (Ag)-specific T-cell mediated contact hypersensitivity. Furthermore, IL-21 blocked lipopolysaccharide (LPS)-induced activation and maturation of DCs, which was not mediated by release of the anti-inflammatory cytokine IL-10. In contrast, when supplementing GMCSF with IL-15, DCs differentiated into mature antigen-presenting cells (APCs) with low antigen uptake and highly significant increased capacities to stimulate T cells in vitro and in vivo. Taken together, these results identify a dichotomous action of these structurally related cytokines on DCs, establishing IL-21 as inhibitory cytokine on DC activation and IL-15 as potent stimulator of DC function, making both cytokines interesting targets for therapeutic manipulation of DC-induced immune reactions.
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PMID:Interleukin-21 inhibits dendritic cell activation and maturation. 1289 70

Cytokines play an important role in controlling the homoeostasis of the immune system. Infection with HIV results in dysregulation of the cytokine profile in vivo and in vitro. During the course of HIV-1 infection secretion of T-helper type 1 (Th1) cytokines, such as interleukin (IL)-2, and antiviral interferon (IFN)-gamma, is generally decreased, whereas production of T helper type 2 (Th2) cytokines, IL-4, IL-10, proinflammatory cytokines (IL-1, IL-6, IL-8) and tumour necrosis factor (TNF)-alpha, is increased. Such abnormal cytokine production contributes to the pathogenesis of the disease by impairing cell-mediated immunity. A number of cytokines have been shown to modulate in vitro HIV-1 infection and replication in both CD4 T lymphocytes and cells of macrophage lineage. HIV-inductive cytokines include: TNF-alpha, TNF-beta, IL-1 and IL-6, which stimulate HIV-1 replication in T cells and monocyte-derived macrophages (MDM), IL-2, IL-7 and IL-15, which upregulate HIV-1 in T cells, and macrophage-colony stimulating factor, which stimulates HIV-1 in MDM. HIV-suppressive cytokines include: IFN-alpha, IFN-beta and IL-16, which inhibit HIV-1 replication in T cells and MDM, and IL-10 and IL-13, which inhibit HIV-1 in MDM. Bifunctional cytokines such as IFN-gamma, IL-4 and granulocyte-macrophage colony-stimulating factor have been shown to have both inhibitory and stimulatory effects on HIV-1. The beta-chemokines, macrophage-inflammatory protein (MIP)-1alpha, MIP-1beta and RANTES are important inhibitors of macrophage-tropic strains of HIV-1, whereas the alpha-chemokine stromal-derived factor-1 suppresses infection of T-tropic strains of HIV-1. This review outlines the interactions between cytokines and HIV-1, and presents clinical applications of cytokine therapy combined with highly active antiretroviral therapy or vaccines.
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PMID:Cytokines and HIV-1: interactions and clinical implications. 1295 22

We investigated the efficacy of Mo17-1A to improve important immunological parameters in vivo and in vitro in colorectal cancer (CRC) patients receiving no second-line treatment. Eighteen CRC patients stage Dukes' C were treated postoperatively with 5 doses of Mo17-1A. Peripheral blood mononuclear cells (PBMC) were analyzed for proliferative responses and cytolytic activity. Serum levels of cytokines were determined during treatment. Enhancement in the proliferative activity of patients' T cells, improvement in their lymphocytes' killing ability of natural killer (NK) and lymphokine-activated killer (LAK) sensitive tumor targets, and an in vivo increase in serum levels of interleukin (IL)-2, IL-12, IL-15, interferon (IFN)-gamma and granulocyte-macrophage colony-stimulating factor (GM-CSF) were noted. We conclude that treatment of CRC patients with Mo17-1A partially restores deficient cellular immune responses and the secretion of cytokines with immuno-enhancing properties. The development of novel immunotherapeutic protocols using combinations of Mo17-1A with stimuli that enhance the lytic capacity of effector cells (e.g. cytokines), may improve clinical responses in these types of patients.
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PMID:Immune changes in patients with colorectal cancer treated by adjuvant therapy with monoclonal antibody 17-1A: a pilot study. 1296 68

Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease arising from the clonal expansion of a stem cell expressing the bcr/abl oncogene. CML patients frequently respond to treatment with interferon-alpha (IFN-alpha), even though the mechanisms of the response remain unclear. In the present study, we evaluated the role of IFN-alpha in differentiation and activity of monocyte-derived dendritic cells (DCs) from CML patients as well as in modulation of the cell response to lipopolysaccharide (LPS). Treatment of CML monocytes with IFN-alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF) resulted in the rapid generation of activated DCs (CML-IFN-DCs) expressing interleukin-15 (IL-15) and the antiapoptotic bcl-2 gene. These cells were fully competent to induce IFN-gamma production by cocultured autologous T lymphocytes and expansion of CD8(+) T cells. LPS treatment of CML-IFN-DCs, but not of immature DCs generated in the presence of IL-4/GM-CSF, induced the generation of CD8(+) T cells reactive against autologous leukemic CD34(+) cells. Altogether, these results suggest that (1) the generation of highly active monocyte-derived DCs could be important for the induction of an antitumor response in IFN-treated CML patients and (2) IFN-alpha can represent a valuable cytokine for the rapid generation of active monocyte-derived DCs to be utilized for vaccination strategies of CML patients.
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PMID:IFN-alpha promotes the rapid differentiation of monocytes from patients with chronic myeloid leukemia into activated dendritic cells tuned to undergo full maturation after LPS treatment. 1452 81


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