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)

In this study, we analyzed the expression and function of the lymphocyte surface lectin NKRP1A on peripheral blood monocytes (Mo) or Mo and dendritic cells (DC) derived from thymic and bone marrow precursors. De novo expression of NKRP1A and CD14 molecules was detected upon culture of CD2- CD3- CD14- CD16- CD1a- NKRP1A- immature thymic precursors for 7 days in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF). Under these culture conditions, by day 21, a fraction of cells had lost CD14 and acquired both CD80 (B7.1) and CD86 (B7.2) molecules. These cells displayed a DC-like morphology and were surface NKRP1A positive. CD34+ NKRP1A- CD14- precursors, isolated from bone marrow and cultured in the presence of GM-CSF, also expressed both NKRP1A and CD14: these antigens were newly expressed on about one third of cells which had lost the CD34 precursor marker. In addition, NKRP1A was constitutively present on resting CD14+ peripheral blood Mo. When these cells were cultured in the presence of GM-CSF, the resulting DC population retained the expression of NKRP1A and acquired CD80, while they lost the CD14 antigen. Functional analysis revealed that the engagement of NKRP1A molecule leads to a strong intracellular calcium ([Ca2+]i) increase both in resting peripheral blood Mo and in vitro-derived DC. [Ca2+]i increase was mainly due to extracellular calcium influx, as it was completely abrogated by the addition of EGTA. More importantly, the engagement of the NKRP1A molecule induced interleukin (IL)-1 beta and IL-12 production by resting Mo and DC, respectively. Altogether these data indicate that NKRP1A lectin is present at the surface of Mo and DC and may play a relevant role in the activation and function of both cell types.
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PMID:Expression and function of NKRP1A molecule on human monocytes and dendritic cells. 939 25

In an attempt to explore novel treatment modalities in acute myeloid leukemia (AML), we studied the role of costimulatory and cytokine gene immunotherapy in murine AML. We have previously shown that leukemic mice can be cured with CD80 transfected leukemic cells (B7. 1-AML vaccine) administered early in the course of the disease and that the failure B7.1-AML vaccines administered late cannot be attributed to immunosuppression induced by tumor growth. CD8+ T cells, which are necessary for tumor rejection, are activated rather than suppressed during the first half of the leukemic course in nonvaccinated mice. In this report, we question whether CD86 (B7.2) or the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-4 (IL-4), or tumor necrosis factor-alpha (TNF-alpha) can improve the vaccination potential of AML cells. The choice of cytokines was based on their combined and alone as well ability to direct the differentiation of CD34+ cells into potent antigen-presenting dendritic cells in vitro. Our studies show that (1) mice vaccinated with a leukemogenic number of AML cells engineered to express B7.2 (B7.2-AML) or to secrete GM-CSF, IL-4, or TNF-alpha (GM-, IL-4-, TNF-alpha-AML) do not develop leukemia; (2) GM-AML cells are tumorigenic in sublethally irradiated SJL/J mice but not in Swiss nu/nu mice, indicating that killing of tumor cells is not T-cell-dependent; (3) vaccines with irradiated GM-AML, but not B7.2-, IL-4-, or TNF-alpha-AML cells, can elicit leukemia-specific protective and therapeutic immunity; and (4) in head-to-head comparison experiments, vaccination with irradiated GM-AML is more potent than B7.1-AML, curing 80% and providing 20% prolonged survival of the leukemic mice at week 2, as opposed to cures only up to 1 week with B7.1-AML vaccines. These preclinical data emphasize that GM-CSF gene immunotherapy deserves clinical evaluation in AML.
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PMID:Gene immunotherapy in murine acute myeloid leukemia: granulocyte-macrophage colony-stimulating factor tumor cell vaccines elicit more potent antitumor immunity compared with B7 family and other cytokine vaccines. 941 88

Adoptive immunotherapy in form of donor leukocyte infusions is effective in a significant number of patients with chronic myeloid leukemia (CML) that have relapsed after allogeneic bone marrow transplantation (BMT). However, the therapy is associated with clinically significant side effects such as graft-versus-host disease (GVHD) and bone marrow (BM) hypoplasia that may be avoided through the administration of T cells with specific antileukemic activity. Dendritic cells (DC) functioning as potent antigen presenting cells (APC) may play an important role in the generation of T cells with specificity against CML. We examined a subpopulation of CD1a+/CD14- DC generated in vitro from BM of normal subjects and patients with CML using granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-alpha) and interleukin-4 (IL-4). These DC derived from both the BM of normal subjects and of patients with CML, differentiated and matured in culture in a similar way. However, DC derived from patients with CML, displayed decreased activity when tested with allogeneic T cells in a mixed lymphocyte reaction (MLR). Addition of interferon-alpha (IFN-alpha) to DC cultures significantly upregulated the expression of major histocompatibility complex (MHC) molecules (class I and class II) and costimulatory molecules (B7.1 and B7.2) on DC from normal donors and CML patients. However, DC grown from CML patients required a higher concentration of IFN-alpha. IFN-alpha also significantly improved the capacity of CML DC to stimulate T-lymphocyte responses. Fluorescence in situ hybridization (FISH) showed that only some CD1a+/CD14- DC derived from BM of patients with CML expressed the bcr/abl fusion gene. Incubation with INF-alpha decreased the proportion of bcr/abl positive DC.
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PMID:Clonal heterogeneity of dendritic cells derived from patients with chronic myeloid leukemia and enhancement of their T-cells stimulatory activity by IFN-alpha. 1039 Jan 93

T-cell apoptosis is a mechanism regulating T-cell homeostasis. Activation renders T cells susceptible to activation-induced cell death, a process mediated through CD95 ligand/CD95 (Apo-1/Fas) ligation. The aim of this study was to test whether antigen-presenting cells can inhibit CD95/Fas-triggered activation-induced cell death. Dendritic cells (DC), which are highly effective antigen-presenting cells, were generated in vitro from human peripheral blood monocytes by culture in granulocyte-macrophage colony-stimulating factor and interleukin 4. Subsequently, DC were cocultured with activated T cells and the effect of DC on CD95/Fas-mediated apoptosis was determined. Coculture with increasing amounts of DC prevented CD95/Fas-triggered apoptosis in a dose-dependent fashion by inhibiting activation of caspase 8 and caspase 3. This protective effect of the DC on T-cell death could be blocked by 50% by adding an anti-CD58 antibody, whereas further addition of anti-CD80 (B7.1) and anti-CD86 (B7.2) led to an even more pronounced effect. Our findings suggest that DC can protect T cells from activation-induced cell death, with CD58 ligation playing a key role.
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PMID:CD95/Fas-triggered apoptosis of activated T lymphocytes is prevented by dendritic cells through a CD58-dependent mechanism. 1048 Apr 31

Microglial cells are non-professional antigen-presenting cells (APC) the function of which is still controversial. Here, we studied the function of microglia derived from H-2(u) mice. We show that these microglia express a low level of B7.2 and CD40 and, interestingly, lack surface expression of B7.1. Resting and IFN-gamma-activated microglia were unable to activate naive and primed myelin basic protein (MBP)-specific CD4(+) T cells in the presence of MBP and encephalomyelitic MBP Ac1-11 peptide. Furthermore, in the presence of Ac1-11 peptide, CD4(+) TCR-transgenic T cells became anergized. Microglia became professional APC only after a multistep activation process involving both stimulation through cytokines [granulocyte-macrophage colony-stimulating factor (GM-CSF) and IFN-gamma] and cognate signaling (B7-CD28 and CD40-CD40 ligand interactions). As such they were able to present MBP to both unprimed and primed T cells. Co-culture of microglia with GM-CSF up-regulated co-stimulatory molecules, in particular B7.1. Additional activation with IFN-gamma induced MHC class II and CD40 up-regulation. CD40-CD40 ligand interaction significantly enhanced microglial ability to prime TCR-transgenic T cells and was essential for presentation of MBP to in vivo primed non-transgenic T cells. We propose that microglia may serve different functions under different inflammatory conditions, depending on the cytokine milieu and the type of cognate interaction they are involved in.
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PMID:Microglia induce myelin basic protein-specific T cell anergy or T cell activation, according to their state of activation. 1054 Mar 17

Immature dendritic cells (DC) take up, process and present protein antigens; mature DC are specialized for stimulating primary T cell responses with increased expression of MHC class II and co-stimulatory molecules, but are incapable of processing and presenting soluble protein. The current study examined whether maturation of DC is triggered by T cell recognition of antigens presented by immature DC. Human DC derived from CD34+ progenitor cells by culture with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-6 (IL-6) in serum-free medium could prime naive CD4+ T cells to keyhole limpet hemocyanin (KLH) and ovalbumin (OVA). The cultured DC retained the ability to prime T cells to native protein for at least 15 days. To test for changes in DC function after participation in an immune response, DC were co-cultured with either allogeneic or autologous CD4+ T cells. DC co-cultured with autologous T cells retained the ability to prime T cells to intact protein antigens. By contrast, DC which had previously stimulated an allogeneic T cell response lost ability to prime T cells to soluble proteins. However, such <<T cell-activated DC>> induced a MLR and stimulated peptide-specific primary CD4+ T cell responses. This indicated that <<T cell-activated DC>> did not die or lose the ability to prime, but lost the ability to process and present subsequent antigens. Following participation in T cell activation, DC increased surface expression of MHC class II, co-stimulatory molecules CD40 and B7.2, and the intercellular adhesion molecule-1 (ICAM-1). In addition, our data suggest that interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) are involved in this T cell-mediated DC maturation.
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PMID:Dendritic cells lose ability to present protein antigen after stimulating antigen-specific T cell responses, despite upregulation of MHC class II expression. 1083 14

A specific cellular immune response directed against a panel of three defined tumor-associated antigen (TAA) epitopes was induced in metastatic melanoma patients by a prime-boost strategy taking advantage of an innovative recombinant vaccinia virus as evaluated by quantitative assessment of cytotoxic T lymphocytes (CTLs) with corresponding specificity. The immunization protocol consisted of the administration of psoralen-UV-treated and replication-incompetent recombinant vaccinia virus encoding the three immunodominant HLA-A*0201-restricted epitopes Melan-A(27-35), gp100(280-288), and tyrosinase(1-9) together with two costimulatory molecules, B7.1 and B7.2, in the context of systemic granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment. Boosts were subsequently applied with corresponding synthetic nonapeptides and GM-CSF. Specific CTL induction was assessed by tetramer staining and CTL precursor (CTLp) frequency evaluation. Within 12 days of injection of the recombinant vector, cytotoxic T cell responses specific for engineered epitopes were detectable in three of three patients. During the vaccination treatment, antigen-specific CTLp frequencies exceeding 1:10,000 peripheral CD8(+) T cells could be observed. Tetramer staining also revealed significant increases in specific CD8(+) T cell numbers. We conclude that active specific antitumor vaccination can raise a concurrent and specific cellular immune response against a panel of molecularly defined antigens, thereby increasing the chance of an immune hit against neoplastic cells with heterogeneous antigen expression. Data from this study emphasize the potency of a recombinant vaccinia virus vector encoding multiple minigenes and costimulatory molecules in the context of exogenously administered GM-CSF. Clinical effectiveness of this immunologically active protocol should therefore be explored in appropriately selected groups of patients.
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PMID:Rapid induction of specific cytotoxic T lymphocytes against melanoma-associated antigens by a recombinant vaccinia virus vector expressing multiple immunodominant epitopes and costimulatory molecules in vivo. 1187 34

Distinct subsets of dendritic cells (DCs) based on the origin, phenotypes, and the nature of the signals that promote DC maturation can determine polarized immune responses of T cells. In this study, DCs were cultured from mouse bone marrow (BM) progenitors in granulocyte-macrophage colony-stimulating factor (GM-CSF). To generate mature DCs (mDCs), lipopolysaccharide (LPS) was used in the culture for 24 h. LPS-stimulated DCs were phenotypically mature, which exhibited strongly upregulated CD40, B7.1, and B7.2 compared to non-LPS-stimulated immature DCs (imDCs). Both mDCs and imDCs expressed high levels of MHC class II but low level of CD54. mDCs produced higher levels of IL-10 and lower IL-12 compared to imDCs. No IFN-gamma or IL-4 was found in both groups. When mDCs were injected intraperitoneally (i.p.) to the mice with experimental autoimmune encephalomyelitis (EAE), the severity of clinical signs and inflammation in the CNS was significantly suppressed compared to imDC-injected mice (p<0.01) and PBS-injected mice (p<0.02). Moreover, lymphocytes from mDC-injected mice produced lower level of IL-12, IFN-gamma, but higher level of IL-10, compared to imDC-injected and non-DC-injected mice. We conclude that BM-mDCs, but not BM-imDCs, promote Th2 differentiation and have the potential for suppression of inflammatory demyelination.
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PMID:Mature bone marrow-derived dendritic cells polarize Th2 response and suppress experimental autoimmune encephalomyelitis. 1247 84