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

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a growth-promoting factor for myeloid-derived dendritic cells (DC) but not for lymphoid DC. The data about its effect on thymic DC (TDC), which are both of lymphoid and myeloid origin, are very scarce. Using an in vitro model, we demonstrated in this work that GM-CSF significantly increased the survival of rat TDC in culture by inhibiting their apoptosis and the effect correlated with up-regulation of Bcl-2 expression. GM-CSF also stimulated differentiation and maturation of TDC as judged by higher expression of MHC class I and II molecules, CD54, CD80 and CD86. These changes correlated with stronger stimulatory activity of GM-CSF-pulsed TDC in syngeneic thymocyte proliferation assay and MLR. The stimulatory potential of TDC was further increased when thymocytes were cultivated with an anti-alphabeta TCR (R73) monoclonal antibody (mAb). The influence of unstimulated TDC on proliferation of thymocytes was inhibited by anti-CD86 but not anti-CD80 mAb, whereas in cultures with GM-CSF-treated TDC both mAbs exerted an additive blocking effect. After separation of TDC on CD11b(+) and CD11b(-) we demonstrated that GM-CSF inhibited apoptosis and potentiated accessory activity of both TDC subsets independently of the myeloid marker expression. Cummulatively, our results suggest that GM-CSF is one of the regulatory cytokine involved in survival, maturation, differentiation and accessory function of TDC.
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PMID:Granulocyte-macrophage colony stimulating factor is an anti-apoptotic cytokine for thymic dendritic cells and a significant modulator of their accessory function. 1260 Jul 52

Therapeutic cancer vaccination is based on the finding that tumors in both humans and experimental animals, such as mice, express potential immunological targets, some of which have high selectivity for cancer cells. In contrast to the successful vaccination against some infectious diseases, where most vaccines induce neutralizing antibodies that act prophylactically, the aim of therapeutic cancer vaccines is to treat established tumors (primarily micrometastases). Since most tumor-destructive immune responses are cell-mediated, therapeutic cancer vaccination needs to induce and expand such responses and also to overcome "escape" mechanisms that allow tumors to evade immunological destruction. Tumor antigens (as with other antigens) are presented by "professional" antigen-presenting cells, most notably dendritic cells (DC). Therefore DC that have been transfected or "pulsed" to present antigen provide a logical source of tumor vaccines, and some encouraging results have been obtained clinically as well as in preclinical models. An alternative and more physiological approach is to develop vaccines that deliver tumor antigen for in vivo uptake and presentation by the DC. Vaccines of the latter type include tumor cells that have been modified to produce certain lymphokines or express costimulatory molecules, as well as cDNAs, recombinant viruses, proteins, peptides and glycolipids which are often given together with an adjuvant. Several studies over the past 5 years have demonstrated dramatic therapeutic responses against established mouse tumors as a result of repeated injections of agonistic monoclonal antibodies (MAbs) to the costimulatory molecule CD137 (4-1BB). However, the clinical use of such MAbs may be problematic since they depress antibody formation, for example, to infectious agents. The alternative approach to transfect tumor cells to express the CD137 ligand (CD137L) increases their immunogenicity, but vaccination with tumor cells expressing CD137L is ineffective in several systems where injection of anti-CD137 MAb produces tumor regression. Recent findings indicate that a more effective way to engage CD137 towards tumor destruction is to transfect tumor cells to express a cell-bound form of anti-CD137 single-chain Fv fragments (scFv). Notably, tumors from melanoma K1735, growing either subcutaneously or in the lung, could be eradicated following vaccination with K1735 cells that expressed anti-CD137 scFv. This was in spite of the fact that K1735, as with many human neoplasms, expresses very low levels of MHC class I and has low immunogenicity. Similar results were subsequently obtained with other tumors of low immunogenicity, including sarcoma Ag104. We hypothesize that the concomitant expression of tumor antigen and anti-CD137 scFv effectively engages NK cells, monocytes and dendritic cells, as well as activated CD4(+) and CD8(+) T cells (all of which express CD137) so as to induce and expand a tumor-destructive Th1 response. While vaccines in the form of transfected tumor cells can be effective, at least in mouse models, the logical next step is to construct vaccines that combine genes that encode molecularly defined tumor antigens with a gene that encodes anti-CD137 scFv. Before planning any clinical trials, vaccines that engage CD137 via scFv need to be compared in demanding mouse models for efficacy and side effects with vaccines that are already being tested clinically, including transfected DC and tumor cells producing granulocyte-macrophage colony-stimulating factor.
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PMID:Therapeutic vaccination with tumor cells that engage CD137. 1260 23

A pilot vaccine study was conducted to test the safety and immunological efficacy of four monthly immunizations of an MHC class I peptide vaccine, the E75 HLA-A2 epitope from HER-2/neu, using flt3 ligand as a systemic vaccine adjuvant. Twenty HLA-A2-expressing subjects with advanced stage prostate cancer were randomly assigned to one of four immunization or treatment schedules: (a) Flt3 ligand (20 microg/kg per day) administered subcutaneously daily for 14 days on a 28-day cycle, monthly for four months; (b) flt3 ligand course as above with the E75 peptide vaccine administered on day 7 of each flt3 ligand cycle; (c) flt3 ligand course as above with the E75 peptide vaccine administered on day 14 of each flt3 ligand cycle; or (d) E75 peptide admixed with granulocyte-macrophage colony-stimulating factor and administered intradermally once every 28 days, as has previously been reported. The primary endpoints of the study were the determination of safety and immunological efficacy in generating E75-specific T cells as determined by peptide-specific interferon-gamma ELIspot. Adverse events included one grade 3 skin reaction and the development of grade 2 autoimmune hypothyroidism in two subjects with preexisting subclinical autoimmune hypothyroidism. Dendritic cells were markedly increased in the peripheral blood of subjects receiving flt3 ligand with each repetitive cycle, but augmentation of antigen-presenting cells within the dermis was not observed. Apart from a single subject, no significant peptide-specific T-cell responses were detected by ELIspot, whereas delayed-type hypersensitivity responses were detectable in control subjects and in subjects receiving peptide vaccine early in the course of flt3 ligand administration. The absence of robust peripheral immune responses in the current study may be attributable to the small numbers of subjects or differences in the subject population. In addition, the inability of fit3 ligand to augment the number of peripheral skin antigen-presenting cells may have contributed to the absence of robust peptide-specific immunity detectable in the peripheral blood of immunized subjects treated with flt3 ligand.
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PMID:Pilot study of an HLA-A2 peptide vaccine using flt3 ligand as a systemic vaccine adjuvant. 1264 61

MDA-MB-231, an HLA-A2(+), HER2/neu(+) allogeneic breast cancer cell line genetically modified to express the costimulatory molecule CD80 (B7-1), was used to vaccinate 30 women with previously treated stage IV breast cancer. Expression of CD80 conferred the ability to deliver a costimulatory signal and thereby improved the antigen presentation capability of the tumor cells to patient T cells in vitro. Patients were vaccinated with 10(7) or 10(8) irradiated gene-modified tumor cells with granulocyte-macrophage colony-stimulating factor (GM-CSF) or BCG, three times at 2-week intervals and then monthly until progressive disease developed. GM-CSF-related flulike symptoms and minor injection site reactions were observed frequently. Prolonged disease stabilization was observed in four patients but no objective tumor regressions were seen. Immune responses were measured in matched peripheral blood samples collected before and after treatment from 9 of 15 patients treated at the 10(8) tumor cell dose. Four patients exhibited MHC class I-restricted cytokine production in response to the parental breast cancer cell line. One patient maintained an increased number of circulating tumor-specific, interferon gamma-secreting CD8(+) T cells for 24 months after the last vaccination. One patient exhibited a tumor-specific interleukin 5 response to an autologous tumor cell line. This immunization strategy proved to be safe and feasible, and induced tumor-specific immune responses in a minority of patients; however, no objective tumor regressions were observed.
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PMID:Vaccination of women with metastatic breast cancer, using a costimulatory gene (CD80)-modified, HLA-A2-matched, allogeneic, breast cancer cell line: clinical and immunological results. 1288 50

Type I interferons (IFNs) are potent regulators of both innate and adaptive immunity. All type I IFNs bind to the same heterodimeric cell surface receptor composed of IFN-alpha receptor (IFNAR-1) and IFN-alpha/beta receptor (IFNAR-2) polypeptides. This study revealed that type I IFN receptor levels vary considerably on hematopoietic cells, with monocytes and B cells expressing the highest levels. Overnight treatment of peripheral blood mononuclear cells (PBMCs) with IFN-alpha2b or IFN-beta led to increased expression on monocytes and B cells of surface markers commonly associated with activated antigen-presenting cells (APCs), such as CD38, CD86, MHC class I, and MHC class II. Five-day exposure of adherent monocytes to granulocyte-macrophage colony-stimulating factor (GM-CSF) plus IFN-alpha or IFN-beta caused the development of potent allostimulatory cells with morphology similar to that of myeloid dendritic cells (DCs) obtained from culture with GM-CSF and interleukin-4 (IL-4) but with distinct cell surface marker profiles and activity. In contrast to IL-4-derived DCs, IFN-alpha-derived DCs were CD14+, CD1a-, CD123+, CD32+, and CD38+ and expressed high levels of CD86 and MHC class II. Development of these cells was completely blocked by an antibody to IFNAR-1. Furthermore, activity of the type I IFN-derived DC in a mixed lymphocyte reaction (MLR) was consistently more potent than that of IL-4-derived DCs, especially at high responder/stimulator ratios. This MLR activity was abrogated by the addition of anti-IFNAR-1 antibody at the start of the DC culture. In contrast, there was no effect of anti-IFNAR-1 on IL-4-derived DCs, indicating that this is a distinct pathway of DC differentiation. These results suggest a potential role for anti-IFNAR-1 immunotherapy in autoimmune diseases, such as systemic lupus erythematosus (SLE), in which the action of excessive type I IFN on B cells and myeloid DCs may play a role in disease pathology.
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PMID:The receptor for type I IFNs is highly expressed on peripheral blood B cells and monocytes and mediates a distinct profile of differentiation and activation of these cells. 1498 77

We have evaluated a one-hit lentiviral transduction approach to genetically modifying monocytes in order to promote autocrine and paracrine production of factors required for their differentiation into immature dendritic cells (DCs). High-titer third-generation self-inactivating lentiviral vectors expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4) efficiently achieved simultaneous and persistent codelivery of the transgenes into purified human CD14+ monocytes. Coexpression of GM-CSF and IL-4 in CD14+ cells was sufficient to induce their differentiation into a DC-like phenotype, as evidenced by their morphology, immature immunophenotypic profile (CD14-, CD1a+, CD80+, CD86+, MHC-I+, MHC-II+), and their ability to further develop into a mature phenotype (CD83+) on further treatment with soluble CD40 ligand. Mixed lymphocyte reactions showed that the T cell-stimulating activity of lentivirus-modified DCs was superior to that of DCs grown by conventional methods. Lentivirus-modified DCs displayed efficient antigen-specific, MHC class I-restricted stimulation of autologous CD8+ T cells, as shown by IFN-gamma production and CTL assays. DCs coexpressing GM-CSF and IL-4 could be kept metabolically active and viable in culture for 14 days in the absence of exogenously added growth factors, unlike conventionally produced DCs. Coexpression of FLT3 ligand did not improve the viability, expansion, or immunologic performance of lentivirus-modified DCs. This article demonstrates the proof-of-concept to genetically convert monocytes to DC-type antigen-presenting cells with lentiviral vectors.
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PMID:Making dendritic cells from the inside out: lentiviral vector-mediated gene delivery of granulocyte-macrophage colony-stimulating factor and interleukin 4 into CD14+ monocytes generates dendritic cells in vitro. 1531 31

Various dendritic cell subsets are induced from bone marrow cells under different cytokine conditions. We have demonstrated previously that the Th1-cytokine-conditioned bone marrow-derived dendritic cell (BMDC) subset BMDC1 (generated in the presence of granulocyte-macrophage colony-stimulating factor [GM-CSF] + interleukin [IL]-3 + interferon [IFN]-gamma+ IL-12) induces a much stronger type 1 immune response than BMDC0 (GM-CSF + IL-3). In the present study, we investigated the effect of 1alpha,25-dihydroxyvitamine D3 (VitD3), which is a known immunomodulating drug, on the differentiation of BMDC subsets. The addition of VitD3 significantly influenced the functional differentiation of BMDC1 compared with BMDC0. Specifically, the addition of VitD3 greatly decreased the expression levels of MHC class I, CD80, CD40 and leukocyte function-associated antigen (LFA)-1 molecules on BMDC1. In addition, VitD3-treated BMDC1 (VD3-BMDC1) almost completely lost their immunostimulating activity for inducing type 1 immunity and cytotoxic T lymphocyte generation. A failure in the induction of type 1 immunity by VD3-BMDC1 appeared to be due to the following: (i) the expression of co-stimulatory molecules on VD3-BMDC1 was strongly downmodulated compared with BMDC1 generated without VitD3; and (ii) VD3-BMDC1 showed significantly lower mRNA expression of IFN-gamma and IFN-beta, factors that are essential for cytotoxic T lymphocyte induction. VitD3 inhibited the differentiation of functionally competent BMDC1 during the early phase of differentiation but not during the late differentiation period. A possible reason for the inhibition of BMDC1 differentiation by VitD3 is reduced phosphorylation of STAT1 during early differentiation. Taken together, VitD3 strongly suppressed T-cell responses by inhibiting functional differentiation of precursor dendritic cells into functional BMDC1 that are feasible for inducing Th1-dependent cellular immunity.
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PMID:1alpha,25-Dihydroxyvitamin D3 downmodulates the functional differentiation of Th1 cytokine-conditioned bone marrow-derived dendritic cells beneficial for cytotoxic T lymphocyte generation. 1644 25

The goal of vaccination against tumors is the induction of effector T cells mediating tumor destruction and memory T cells providing long-term immunity. Several previous studies in patients vaccinated with major histocompatibility complex (MHC) class I peptides failed to show induction of central memory T cells, which are considered important to provide long-term memory. This study examined the subset composition and function of specific T cells generated by immunization with MHC class I binding tyrosinase peptides in combination with the adjuvants granulocyte-macrophage colony-stimulating factor and keyhole limpet hemocyanin in peripheral blood (PB) and bone marrow (BM) of melanoma patients. Most of the tyrosinase-specific T cells in PB had a CD45RA(+)CCR7(-) effector phenotype. In contrast to this, a large subset of tyrosinase-specific T cells in BM were memory T cells, including CD45RA(+)CCR7(-) central and CD45RA(-)CCR7(-) effector memory T cells. BM tyrosinase-specific T cells were functional, because they produced interferon-gamma and had a high proliferative potential. This study suggests that peptide vaccination can generate a fully functional memory T-cell response characterized by central and effector memory phenotypes, proliferative potential, and BM tropism.
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PMID:Specific central memory T cells in the bone marrow of patients immunized against tyrosinase peptides. 1653 20

Downregulation of MHC class I molecules is believed to be often the cause of tumor immune escape and at the same time it is the major obstacle to T-cell based immunotherapy of tumors. In our experimental model, the C57BL/6 mice bearing tumors induced by TC-1/A9 cells characterized by expression of HPV16 oncogenes and downregulation of H-2b molecules were immunized with highly immunogenic E7GGG.GUS DNA vaccine expressing the fused gene of modified HPV16 E7 (E7GGG) with E.coli beta-glucuronidase (GUS). The DNA vaccine was administered by gene gun on days 7 and 14 after s.c. injection of tumor cells. The tumors in situ were injected with recombinant vaccinia virus MVA expressing the gene for murine granulocyte-macrophage colony-stimulating factor (MVA-GM-CSF). Two doses of the DNA vaccine combined with at least two consecutive local treatments with MVA-GM-CSF were able to inhibit significantly the growth of tumors. We have shown by ELISPOT-IFNgamma that in situ expression of the GM-CSF gene did not enhance the E7 specific systemic Tcell response. We found that local injections of MVA-GM-CSF induced an increase of intratumoral CD3+ T cell counts and that the DNA vaccination resulted in up-regulation of MHC type I molecules on tumor cells in vivo. We suppose that i.t. delivery of MVA-GM-CSF changed the local tumor microenvironment and rendered tumors more attractive and better accessible to effector T cells.
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PMID:Combination of intratumoral injections of vaccinia virus MVA expressing GM-CSF and immunization with DNA vaccine prolongs the survival of mice bearing HPV16 induced tumors with downregulated expression of MHC class I molecules. 1782 23

We investigated the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on biologic signals induced by interferon-alpha (IFN-alpha) and IFN-gamma. In hematopoietic cell lines, IFN-induced signaling was investigated by Western blotting, electrophoretic mobility shift assays (EMSA), flow cytometry, protein-tyrosine phosphatase (PTP) assays, and RT-PCR. GM-CSF inhibited IFN-alpha-induced and IFN-gamma-induced Stat1 tyrosine phosphorylation in a time-dependent manner. EMSA showed that GM-CSF inhibited IFN-alpha-induced and IFN-gamma-induced IFN-gamma activator sequence (GAS) binding activity. As a consequence, IFN-induced transcription of the early response gene, IFN-stimulated gene 54 (ISG54), was inhibited. The expression of IFN regulatory factor-1 (IRF-1) and MHC class I antigens was downregulated at protein levels in hematopoietic cell lines (U937, THP1). In contrast to GM-CSF, granulocyte colony-stimulating factor (G-CSF) and interleukin-3 (IL-3) did not influence the IFN-induced Stat1 activation. To explore the molecular mechanism of suppression of Stat1 tyrosine phosphorylation, we investigated the induction and activation of cytokine-inducible SH2-containing protein/suppressor of cytokine signaling (CIS/SOCS) molecules and phosphatases on GM-CSF treatment. In contrast to G-CSF and IL-3, GM-CSF strongly induced the expression of CIS1 and SOCS2 at mRNA levels, but overexpression of CIS1 or SOCS2 in HEK293 cells did not show inhibition of Stat1 tyrosine phosphorylation upon IFN treatment. In PTP assays, on GM-CSF incubation, no enhanced src homology 2 domain tyrosine phosphatase 1 and 2 (SHP1 and SHP2) activity was detectable. However, GM-CSF-induced downregulation of Tyk2 and Jak1 tyrosine phosphorylation as well as Tyk2 protein levels likely contributed to the reduced Stat1 tyrosine phosphorylation. In hematopoietic cells, GM-CSF antagonizes IFN-induced signals by a block in Stat1 activation.
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PMID:Cross-inhibition of interferon-induced signals by GM-CSF through a block in Stat1 activation. 1805 29


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