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 use of immunomodulating gene therapy in the treatment of malignant disease is under intensive investigation. In this study, we examined the potential of melanoma-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) to inhibit melanoma progression in a murine model. The HGH18 murine melanoma cell line was transfected with the murine GM-CSF gene in a SV40 expression vector that resulted in melanoma clones that produced varying amounts of GM-CSF. Syngeneic mice inoculated s.c. with HFH18 parental melanoma cells or HFH18 cells transfected with the GM-CSF gene n the noncoding 3'-5' orientation [HFH18/GM-CSF(-) cells] develop large tumors that reach a mean tumor volume of 3300 mm3 by day 30. In contrast, animals inoculated with two melanoma clones producing high levels of GM-CSF [HFH18/GM-CSF(++) and HFH18/GM-CSF(+ + +)] either completely reject the tumor cells or develop tumors with a mean volume of only 40 mm3. In comparison, animals inoculated with a melanoma clone producing low levels of GM-CSF [HFH18/GM-CSF(+)] develop large tumors averaging 2000 mm3, thus demonstrating a dose-response effect of tumor inhibition by melanoma-derived GM-CSF. Additionally, vaccination with irradiated GM-CSF-producing melanoma cells conferred optimal immunogenicity against a subsequent challenge with HFH18 cells. Tissue sections from excised GM-CSF-producing tumor cell inoculation sites but not from HFH18 parental or HFH18/GM-CSF(-) inoculation sites demonstrate a dense inflammatory infiltrate composed of neutrophils, tissue macrophages, and numerous CD4- and CD8-positive lymphocytes but few melanoma cells. Large numbers of dendritic cells and cells expressing the B7-2 costimulatory molecule are detected only within HFH18/GM-CSF(+ + +) melanoma inoculation sites. Our results lend further support to clinical trials of GM-CSF gene therapy in the treatment of advanced malignant melanoma, possibly by the recruitment of dendritic antigen-presenting cells.
 ...
PMID:Antitumor effects of granulocyte-macrophage colony-stimulating factor production by melanoma cells. 861 71

CD3- granulated leucocyte clones have been generated from human first-trimester decidualized endometrial tissue following culture in interleukin-2 (IL-2). Supernatants from both CD3- decidual granulated leucocyte (dGL) and CD3- peripheral blood natural killer (PBNK) cell clones inhibited the proliferation of choriocarcinoma cell lines. A panel of CD3- dGL clones, with or without phytohaemagglutinin stimulation, was assayed for cytokine secretion compared with CD3- PBNK clones and fresh tissue extracts. Levels of interferon-gamma, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor-alpha (TNF-alpha) and IL-10 produced by stimulated CD3-CD8- dGL clones were greater than those produced by stimulated CD3-CD8+ dGL clones. In contrast, CD8+ dGL clones were more effective in production of IL-6 than CD8- dGL clones. Immunoreactive transforming growth factor-beta 2 (TGF-beta 2) was undetectable in supernatants from CD3- dGL and PBNK clones. CD3- dGL clones generally produced higher levels of all cytokines than PBNK clones. Some unstimulated CD3- dGL and PBNK clones spontaneously produced these cytokines, but usually at a reduced level. Fresh extracts of first-trimester decidual tissue contained detectable GM-CSF, TNF-alpha, IL-10,IL-6 and TGF-beta 2. Cytokine production by fresh CD3- dGL and CD3- dGL clones indicates that these cells could play an important role in the regulation of placental growth.
 ...
PMID:Soluble mediators and cytokines produced by human CD3- leucocyte clones from decidualized endometrium. 866 42

In a prospective study of 80 patients, we investigated the association of acute kidney graft rejection with pretransplant T helper/suppressor activity, B-cell responses, and in vitro cytokine secretion. Patients' CD4+ or CD8+ T cells were cocultured with control B cells and pokeweed mitogen for 6 days. SAC I was used for T cell- and monocyte-independent B-cell stimulation and pokeweed mitogen was used for T cell-dependent B-cell stimulation. B-cell differentiation was assessed in a reverse hemolytic plaque assay. Cytokine responses of T cells (interleukin [IL]-2, IL-10, gamma-interferon) and B cells/monocytes (IL-6, IL-8, tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor) were determined in culture supernatants using ELISA. Subsets of CD4+ T cells, CD8+ T cells, and B cells were assessed by flow cytometry. None of 12 patients with pretransplant CD4 helper defects (CD4 helper activity < 10%) had acute rejection episodes, in contrast to 32 of 68 (47%) patients with normal pretransplant CD4 helper function (P = 0.001). Patients with pretransplant CD4 helper defects also had better 1-year graft function than patients without CD4 helper defects (serum creatinine 1.2 +/- 0.1 mg/dl and 1.7 +/- 0.1 mg/dl, respectively, P < 0.05). Pretransplant IL-10 responses were significantly associated with the occurrence of acute rejection episodes (P = 0.001) and impaired 1-year graft function (P < 0.001). All 14 patients with low pretransplant IL-10 responses (< 100 pg/ml) had 1-year serum creatinine values of < 1.5 mg/dl. Pretransplant B-cell defects and B cell/monocyte-derived cytokine secretion were not related to the incidence of graft rejection or infectious complications. Pretransplant CD8 suppressor-effector (CD11b+), cell counts were significantly associated with the occurrence of infections (P < 0.05). These results show that pretransplant CD4 helper defects and low IL-10 responses predict a low risk of graft rejection, whereas Th1 (IL-2, gamma-interferon) and B-cell/monocyte responses are not of predictive value.
 ...
PMID:Pretransplant CD4 helper function and interleukin 10 response predict risk of acute kidney graft rejection. 897 Jun 16

Thymocytes show differential cytokine responses, depending on the stage of differentiation. Whether these responses are due to preferential cytokine receptor expression or due to downstream signaling mechanisms is unknown. In this study, we examined the relationship between receptor expression and T-cell proliferation or differentiation using thymocytes from transgenic mice constitutively expressing the human granulocyte-macrophage colony-stimulating factor (hGM-CSF) receptor. Transgenic CD4- CD8-, CD4+ CD8-, and CD4- CD8+ cells proliferated when cultured with hGM-CSF in vitro, whereas CD4+ CD8+ cells failed to proliferate. To examine the effect of hGM-CSF receptor signaling on T-cell development, we used fetal thymic organ cultures. The addition of exogenous hGM-CSF resulted in the failure of CD4- CD8- cells to differentiate into CD4+ CD8+ cells. To more closely identify this maturational inhibition, we reconstituted normal fetal lobes with sorted pro-T-, pre-T-, or post-pre-T-precursor cells from transgenic mice. The addition of hGM-CSF to these cultures led to a block in both pro-T- and pre-T-cell differentiation, whereas the more mature post-pre-T cells differentiated normally. We propose that hGM-CSF receptor signaling during T-cell development results in a stage-specific inhibition of thymic precursor maturation.
 ...
PMID:Human granulocyte-macrophage colony-stimulating factor (hGM-CSF) induces inhibition of intrathymic T-cell development in hGM-CSF receptor transgenic mice. 902 58

Granulocyte-macrophage colony-stimulating factor, mobilized peripheral blood stem cell (PSC) products, and peripheral blood leukocytes posttransplantation contain cells that cause allogeneic and autologous T cell apoptosis. Isolation and characterization of these cells demonstrated that they were low-density (Percoll fractionation) CD14+ monocytes. T cells in PSC products have a depressed phytohemagglutinin (PHA) mitogenic response; however, purified CD4+ or CD8+ T cells exhibit a statistically normal mitogenic function. Furthermore, no T cell inhibitory activity was observed in CD14+, CD4+, and CD8+ cell-depleted fractions enriched in CD4- CD8- TCR alpha/beta+ T cells. Inhibition of T cell function by CD14+ monocytes required cell-cell contact, and the analyses of DNA fragmentation by Southern and TUNEL analysis demonstrates an activation-induced T cell apoptosis in the presence of CD14+ monocytes. Reverse-transcriptase polymerase chain reaction studies suggested that high levels of interleukin-10 or tumor necrosis factor gene transcripts in the PSC products may contribute to the inhibition of T cell function.
 ...
PMID:Monocytes from mobilized stem cells inhibit T cell function. 912 7

The aim of the present study was to investigate the patterns of cytokine production by T cell clones raised from in vivo activated synovial fluid (SF) mononuclear cells (MNC) of five patients with oligoarticular juvenile arthritis (JA). Freshly isolated SF T cells were cultured in vitro with low dose recombinant IL-2 and subsequently cloned by limiting dilution. Sixty-four clones were obtained from the five patients studied. Fifty-nine clones were TCR alpha/beta+, either CD4+ (n = 43) or CD8+ (n = 15). The remaining five clones were TCR gamma/delta+, CD4-, CD8-. Clone immunophenotypes differed in the individual patients. Forty-four T cell clones were stimulated with phytohaemagglutinin (PHA) and phorbol myristate acetate (PMA) and supernatants tested for the presence of IL-2, IL-4, IL-5 and interferon-gamma (IFN-gamma) by ELISA or bioassays. Cytokine mRNA accumulation was tested by reverse transcriptase-polymerase chain reaction (RT-PCR). Most of 44 clones tested released large amounts of IFN-gamma irrespective of the immunophenotype. Of these, 27 were classified as Th1-type and 17 as Th0-type based upon the IFN-gamma/IL-4 ratio in culture supernatants. Finally, when 10 representative T cell clones were tested for pro- and anti-inflammatory cytokines, gene expression by RT-PCR, all of them were found to express the granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor-alpha (TNF-alpha), IL-10 and transforming growth factor-beta 1 (TGF-beta1) genes, and half of them IL-6 and IL-8 mRNA. In conclusion, T cell clones, that represent the progeny of in vivo activated SF T cells from oligoarticular JA patients, display heterogeneous immunophenotypes, but all share the ability to produce large amounts of IFN-gamma, with a predominant Th1/Th0 pattern. The expression of pro- and anti-inflammatory cytokine genes in these clones suggests that in vivo activated SF T cells modulate joint inflammation in a complex fashion.
 ...
PMID:Synovial fluid T cell clones from oligoarticular juvenile arthritis patients display a prevalent Th1/Th0-type pattern of cytokine secretion irrespective of immunophenotype. 921 17

The present study investigated the ability of supernatants collected from cultures of healthy donor-derived peripheral blood mononuclear cells (HD-PBMCs) stimulated with anti-CD3 monoclonal antibody (MAb) (allogeneic CD3 supernatants; ACD3S) to induce, upon brief exposure, tumour-reactive cytotoxic lymphocytes in cancer patients' PBMCs. ACD3S enhanced natural killer (NK) and lymphokine-activated killer (LAK) cell-mediated cytotoxicity. ACD3S contained increased levels of interleukins (IL) 1, 2, 6, 7 and 12, as well as of granulocyte-macrophage colony-stimulating factor (GM-CSF), gamma-interferon (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha). MAbs against these cytokines significantly reduced the ACD3S-induced cytotoxicity. ACD3S-induced cytotoxicity was not inhibited by anti-CD4, CD8 and MHC class I MAbs, but was markedly reduced in the presence of MAb against CD18. In contrast to HD-PBMC, ACD3S derived from cancer patients' lymphocytes exhibited lower levels of the above-mentioned cytokines and exerted reduced biological activity. In conclusion, ACD3S are able to activate, upon short-term incubation, tumour-reactive lymphocytes from cancer patients' PBMCs that lyse a variety of tumour targets, including autologous tumours. ACD3S contain high levels of certain cytokines that positively influence the induction of autologous tumour-reactive lymphocytes. Such supernatants can be collected easily from healthy donors and stored until use in clinical trials for adoptive cellular therapy of cancer. They may also be indicated in the construction of cytokine cocktails that have the ability to induce anti-tumour cytotoxicity.
 ...
PMID:Induction of anti-tumour lymphocytes in cancer patients after brief exposure to supernatants from cultures of anti-CD3-stimulated allogeneic lymphocytes. 937 69

T-cell receptor (TCR) alpha beta+ CD4- CD8- (double-negative; DN) T cells appear in the peritoneal cavity at an early stage of intraperitoneal (i.p.) infection with the intracellular pathogen Listeria monocytogenes. In the present report, we analysed the developmental pathway and functions of the TCR alpha beta+ DN T cells using the L. monocytogenes infection system. The TCR alpha beta+ DN T cells appeared in the peritoneal cavity after L. monocytogenes i.p. infection in adult-thymectomized lethally irradiated bone marrow chimeras and p56lck-deficient mice. The results demonstrated that the TCR alpha beta+ DN T cells can develop extrathymically in a p56lck-independent manner. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that the TCR alpha beta+ DN T cells expressed genes for interferon-gamma (IFN-gamma), the macrophage chemotactic factors MCP-1 and Eta-1, and granulocyte-macrophage colony-stimulating factor (GM-CSF) but lacked expression of genes for interleukin-2 (IL-2), IL-4 and IL-10. As expected from the RT-PCR analysis, the TCR alpha beta+ DN T cells produced IFN-gamma in response to anti-TCR beta monoclonal antibody (mAb), anti-CD3 mAb and L. monocytogenes-infected macrophages but IL-4 was undetectable after the stimulation. Furthermore, the intracellular cytokine staining analysis demonstrated that approximately half of the TCR alpha beta+ DN T cells detectable at the early stage of L. monocytogenes infection were IFN-gamma-producing cells. All of the results suggest that the TCR alpha beta+ DN T cells develop through a unique extrathymic p56lck-independent pathway and participate in early protection against bacterial infection through activation and accumulation of macrophages.
 ...
PMID:TCR alpha beta+ CD4- CD8- T cells differentiate extrathymically in an lck-independent manner and participate in early response against Listeria monocytogenes infection through interferon-gamma production. 937 88

Eosinophilia associated with the expansion of cloned T-cells is reviewed in relation to cytokine production. It has been proved that eosinophilopoiesis is caused by eosinophil-stimulating cytokines, including interleukin-5 (IL-5), granulocyte-macrophage colony-stimulating factor and interleukin-3, which are secreted from T-cells. Recently, we and other groups have reported several cases of eosinophilia including hypereosinophilic syndrome (HES) accompanied with proliferation of abnormal T-cells with an unusual phenotype CD3- CD4+ or CD3+ CD4- CD8- in the peripheral blood. The T-cells clonally proliferate, as confirmed by clonal rearrangements of the T-cell receptor (TCR) gene, and produce eosinophil-stimulating cytokines, especially IL-5, with or without stimulation in vitro. Although HES is defined by the combination of unexplained prolonged eosinophilia and evidence of organ involvement, these observations suggest that increased production of eosinophil-stimulating cytokines from the abnormal T-cells with phenotype CD3- CD4+ or CD3+ CD4- CD8- may cause eosinophilia, some of which have been diagnosed as HES.
 ...
PMID:Eosinophilia associated with clonal T-cell proliferation. 940 31

T-cell large granular lymphocyte (T-LGL) leukemia is clinically indolent, but is associated with severe neutropenia in approximately 50% of cases. The pathogenesis of the neutropenia is unclear. We report reversal of severe neutropenia associated with T-LGL leukemia in five patients treated with cyclosporine (CSA). All five had persistent neutrophil counts below 0.5 x 10(9)/L, two had agranulocytosis, and four had recurrent infections. Increased populations of LGL were present in blood and marrow, with a T-LGL immunophenotype (CD3(+)CD8(+)CD16(+/-)CD56(+/-)CD57(+)) shown by multiparameter flow cytometry, and clonal T-cell receptor (TCR) gene rearrangements in two of two pretreatment blood samples studied. CSA was initiated at doses of 1 to 1.5 mg/kg orally every 12 hours, with subsequent dose adjustments based on trough serum levels. Four patients attained normal neutrophil counts with CSA alone; one required addition of low-dose granulocyte-macrophage colony-stimulating factor. Time to attainment of 1.5 x 10(9)/L neutrophils ranged from 21 to 75 days. Attempts to taper and withdraw CSA resulted in recurrent neutropenia. Three patients have maintained normal neutrophil counts on continued CSA therapy for 2, 8, and 8.5 years. Two patients died 1.7 and 4.6 years after initiation of CSA despite normal neutrophil counts-one of metastatic melanoma and one of complications after aortofemoral bypass surgery. Despite resolution of neutropenia, increased populations of T-LGL cells have persisted in all patients during CSA therapy, as shown by morphology and flow cytometry and by the presence of clonal TCR gene rearrangements in four patients' posttreatment blood samples. We conclude that CSA is an effective therapy for neutropenia associated with T-LGL leukemia, and that resolution of neutropenia despite persistence of abnormal cells implies that CSA may inhibit T-LGL secretion of yet unidentified mediators of neutropenia.
 ...
PMID:Neutropenia associated with T-cell large granular lymphocyte leukemia: long-term response to cyclosporine therapy despite persistence of abnormal cells. 955 95


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