UNIPROT:P04141 - FACTA Search

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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)

Expression of major histocompatibility complex (MHC) class II molecules is developmentally regulated and lineage dependent. Their role in hematopoiesis is not well defined. Previous studies in a canine model showed that dogs given 920 cGy of total body irradiation, transplanted with autologous marrow, and treated with anti-MHC class II monoclonal antibody (MoAb) immediately posttransplant experienced only a transient granulocyte recovery that was followed by graft failure. In the present study, the effect of anti-MHC class II MoAbs on canine in vitro hematopoiesis was investigated. Anti-MHC class II MoAb H81.9 or B1F6 (both recognizing nonpolymorphic determinants) had no inhibitory effect when added directly to colony-forming unit-granulocyte-macrophage (CFU-GM) grown in agar. However, the addition of intact MoAb or as F(ab')2 fragments to long-term marrow cultures (LTMCs) resulted in a dose-dependent inhibition of the generation of CFU-GM among nonadherent cells. Inhibition was most profound with MoAb added at the time of initiation of culture. However, even if MoAb was added 3 weeks after recharging LTMCs, CFU-GM generation rapidly decreased. In addition, the number of adherent cells in LTMCs decreased; predominantly fibroblast-like cells with prominent cytoplasmic vesiculation remained. Acridine orange/ethidium bromide staining and TdT-mediated deoxyuridine triphosphate-digoxigenin nick end labeling (TUNEL) tests showed an increase in the proportion of apoptotic cells in both the nonadherent and adherent compartments. Binding of anti-MHC class II MoAb to unfractionated marrow cells resulted in an increase in free (Ca2+)i; no changes in tyrosine phosphorylation pattern were observed. The addition of stem cell factor (SCF), but not granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor, to LTMCs prevented apoptosis, and the generation of CFU-GM was indistinguishable from controls. Similarly, a supportive adherent layer was maintained. Thus, anti-MHC class II MoAbs interfere with hematopoiesis both in vitro and in vivo. The mechanism involves programmed cell death in subpopulations of adherent and nonadherent cells. Inhibition of hematopoiesis is abrogated by exogenous SCF.
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PMID:Major histocompatibility complex class II-mediated inhibition of hematopoiesis in long-term marrow cultures involves apoptosis and is prevented by c-kit ligand. 861 36

Alterations in the ras p21 protein have been associated with both rodent and human neoplasia. Thus, mutated ras p21 proteins may bear unique antigenic epitopes for immune recognition, such as by T cells, which have been implicated in host antitumor activity. Synthetic peptides that mimic segments of mutated ras p21 have been reported to be immunogenic in mice in vivo, although detailed functional analyses remains undefined. Here, in a murine model, we explored and characterized distinct effector properties of host-derived T lymphocytes reactive to mutated ras peptides, which was consistent with the CD4+ T helper type 1 (Th1) subset. BALB/c mice (H-2d) were immunized with a purified peptide, 13 amino acids in length, containing the substitution of Gly (G12) to Val (V12) at position 12, which is commonly found in human carcinomas. An alpha beta T cell receptor-positive, CD3+, CD4+, CD8- T cell line was established, which expressed peptide-specific proliferation. Cytokine assays revealed the production of interleukin-2, interferon-gamma, tumor necrosis factor and granulocyte-macrophage colony-stimulating factor. Moreover, antigen-specific cytotoxicity was demonstrable against: (1) Iad-bearing A20 tumor cells incubated with exogenously bound V12 peptide; and (2) A20 tumor cells transduced with the K-ras p21 oncogene encoding the corresponding point mutation. CD4(+)-mediated cytotoxicity was major histocompatibility complex (MHC) class II-restricted, as revealed by the absence of lysis against MHC class II- P815 targets, inhibition of A20 lysis with anti-Iad monoclonal antibodies, and induction of lysis against L cell targets transfected with E alpha A beta d. Independent isolation of a second CD4+ V12 line revealed a very similar cytolytic and MHC class II-restricted profile. Overall, these data demonstrated that peptide immunization produced a CD4+ Th1 response that specifically recognized tumor cells expressing endogenous activated K-ras epitopes, which may have implications for the development of peptide-based active immunotherapies.
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PMID:Peptide-specific activation of cytolytic CD4+ T lymphocytes against tumor cells bearing mutated epitopes of K-ras p21. 758 31

Immunization of BALB/c mice with human cartilage proteoglycan (aggrecan) produces a progressive polyarthritis, similar in many aspects to human rheumatoid arthritis, and autoreactive T cells are necessary for initiation of the disease. To study the immunopathological mechanisms operating in the synovium of arthritic mice, we isolated a proteoglycan (PG)-specific arthritogenic T-cell hybridoma, 5/4E8, and examined the presentation of PG to this T-cell hybridoma by mouse synovial cells and chondrocytes. Both cell types expressed very low levels of major histocompatibility complex (MHC) class II following isolation and culture and were unable to present PG to the hybridoma. However, following stimulation with interferon-gamma (IFN-gamma), both synovial cells and chondrocytes showed a marked increase in MHC class II expression and consequently were able to present PG very effectively. The PG-specific responses of the hybridoma were abrogated by an anti-Ia monoclonal antibody. Granulocyte-macrophage colony-stimulating factor (GM-CSF), one of the most abundant cytokines in the rheumatoid synovium, had no effect on the antigen-presenting capacity of synovial cells and chondrocytes, either on its own or together with IFN gamma.
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PMID:Interferon-gamma but not granulocyte/macrophage colony-stimulating factor augments proteoglycan presentation by synovial cells and chondrocytes to an autopathogenic T cell hybridoma. 762 93

Langerhans cells (LC), the dendritic antigen presenting cells of the skin, mature into potent immunostimulatory cells during migration to regional lymph nodes, where they are identified as interdigitating cells (IDC). Since mature Langerhans cells (mLC) resemble IDC in phenotype and immunostimulatory capacity, we examined whether these cells were susceptible to infection with macrophagetropic and lymphotropic strains of human immunodeficiency virus type 1 (HIV-1). Highly purified cell preparations of mLC migrating from human epidermis expressed high amounts of major histocompatibility complex (MHC) class I and II antigens and of the accessory molecules CD40, CD80 and CD86, indicative of the phenotype of potent immunostimulatory cells. CD4 expression was upregulated on mLC during cultivation, independent of the presence of tumour necrosis factor alpha (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the culture medium. The macrophagetropic HIV-1 strain SF162 replicated to higher titres in mLC than the lymphotropic strain IIIB. Both strains induced syncytia, with SF162 showing a more rapid cytopathic effect. Addition of TNF-alpha enhanced virus production, due to better cell viability under TNF-alpha treatment, whereas GM-CSF did not significantly influence viability of cells and replication pattern of the virus. These findings suggest that in the infected individual IDC in lymph nodes may function as target cells for HIV-1.
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PMID:Replication pattern of human immunodeficiency virus type 1 in mature Langerhans cells. 778 62

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) are weak inducers of major histocompatibility complex (MHC) class II expression on purified human blood monocytes. The glucocorticoid dexamethasone synergizes with GM-CSF or IL-3 for the upregulation of HLA-DR, -DP and -DQ antigen mRNA and cell-surface expression by these cells. The purpose of the present study was to address the mechanism of dexamethasone action. We demonstrate that the capacity of dexamethasone to up-regulate GM-CSF-induced MHC class II expression correlates with the capacity to up-regulate GM-CSF receptor, but not the interferon-gamma (IFN-gamma) receptor, in a highly dose-dependent manner on monocytes. Although dexamethasone induces GM-CSF receptor expression, it does not confer responsiveness to IL-5, a cytokine that shares a common chain of its heterodimeric cytokine receptor signalling molecule with IL-3 and GM-CSF. Three other steroid hormones, beta-oestradiol, vitamin D3 and dehydroepiandosterone (DHEA), were also tested for their capacity to up-regulate MHC class II expression. All three mediators failed to enhance MHC class II expression or GM-CSF receptor expression on the surface of human monocytes. These experiments suggest that dexamethasone may act to up-regulate GM-CSF-induced MHC class II antigen expression on monocytes by up-regulating cytokine receptor expression.
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PMID:Dexamethasone up-regulates granulocyte-macrophage colony-stimulating factor receptor expression on human monocytes. 783 47

In all tissues that have been studied to date, dendritic leucocytes constitute only a small proportion of total cells and are difficult both to isolate and purify. This study reports on a method for the propagation of large numbers of dendritic cells (DC) from mouse spleen using granulocyte-macrophage colony-stimulating factor (GM-CSF) and their characteristics. Within a few days of liquid culture in GM-CSF, B10 BR (H-2k, I-E+) mouse splenocytes formed loosely adherent myeloid cell clusters. Mononuclear progeny released from these clusters at and beyond 4 days exhibited distinct dendritic morphology and strongly expressed leucocyte common antigen (CD45), CD11b, heat-stable antigen, Pgp-1 (CD44) and intercellular adhesion molecule-1 (ICAM-1; CD54). The intensity of expression of the DC-restricted markers NLDC 145 and 33D1, the macrophage marker F4/80, and Fc gamma RII (CDw32) was low to moderate, whereas the cells were negative for CD3, CD45RA and NK1.1. High and moderate levels, respectively, of cell surface staining for major histocompatibility complex (MHC) class II (I-Ek) and the B7 antigens (counter-receptors of CTLA4, a structural homologue of CD28) were associated with potent stimulation of unprimed, allogeneic T cells (B10; H-2b, I-E-). DC propagated in a similar fashion from DBA/2 mouse spleen proved to be strong antigen-presenting cells (APC) for MHC-restricted, syngeneic T-helper type 2 (Th2) cell clones specifically responsive to sperm whale myoglobin. Footpad or intravenous injection of GM-CSF-stimulated B10.BR spleen-derived DC into B10 (H-2b, I-E-) recipients resulted in homing of the allogeneic cells to T-cell-dependent areas of lymph nodes and spleen, where they strongly expressed donor MHC class II antigen 1-2 days later. These findings indicate that cells can be propagated from fresh splenocyte suspensions that exhibit distinctive features of DC, namely morphology, motility, cell-surface phenotype, potent allogeneic and syngeneic APC function and in vivo homing ability. Propagation of DC in this manner from progenitors present in lymphoid tissue provides an alternative and relatively convenient source of high numbers of these otherwise difficult to isolate but functionally important APC.
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PMID:Generation of DC from mouse spleen cell cultures in response to GM-CSF: immunophenotypic and functional analyses. 789 Feb 96

Epidermal Langerhans cells (LC) are major histocompatibility complex (MHC) class II (Ia)-positive dendritic cells that act as potent antigen-presenting or accessory cells for primary and secondary T cell-dependent immune responses. Recent studies have disclosed that the morphological, functional, and phenotypic characteristics of LC are variably and drastically modulated by external stimuli both in vivo and in vitro. However, little is known of the biological significance of diverse cytokines in regulating the surface molecules of LC. To determine the regulatory properties of ICAM-1, Ia, and MHC class I (H-2K) molecules in LC, we have examined the effects of interleukin (IL)-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-10, interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and granulocyte-macrophage colony-stimulating factor (GM-CSF) on the expression of these molecules. Among the cytokines examined, IFN-gamma markedly and reproducibly up-regulates the expression of H-2K, but not ICAM-1, in Ia+ LC in a time- and dose-dependent manner. TNF-alpha consistently up-regulates the expression of ICAM-1, but not H-2K, in a time- and dose-dependent manner. IL-10 slightly but reproducibly inhibits the expression of ICAM-1, but not H-2K, in a time- and dose-dependent manner. IL-10 potently inhibits the TNF-alpha-induced ICAM-1 up-regulation, but not the IFN-gamma-induced H-2K up-regulation. Moreover, no cytokine consistently affects the Ia expression of LC. In addition, slight enhancing effects have been observed on H-2K expression by IL-4, and on ICAM-1 expression by IL-1 alpha, IL-1 beta, or GM-CSF. The present data suggest that the selective regulation is operative in a certain cell surface moiety of LC by various cytokines. These results further facilitate our understanding of immunobiology of LC.
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PMID:Selective regulation of ICAM-1 and major histocompatibility complex class I and II molecule expression on epidermal Langerhans cells by some of the cytokines released by keratinocytes and T cells. 795 79

Staphylococcal enterotoxin superantigens (SAg) bind class II major histocompatibility complex (MHC) molecules on antigen-presenting cells (APC) and upon cell-to-cell contact stimulate proliferation of T cells expressing appropriate V beta gene products. In addition, SAg can also deliver negative signals to Ag-specific T cells resulting in a state of unresponsiveness or a loss of viability. The present study examines the functional consequences of a direct interaction of SAg with alloAg-specific class II MHC+ CD4+ T cell lines (TCL). Our results demonstrate that SAg induce programmed death (apoptosis) in a majority of Ag-specific CD4+ T cells accompanied by genomic DNA fragmentation. SAg binding to Ag-specific TCL resulted in a rapid mobilization of intracellular free calcium ([Ca2+]i) and transcription of a number of cytokine genes including interleukin-2(IL-2), IL-4, interferon-gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), and granzyme B indicating the activation of primed T cells. Both SAg-induced cytokine gene expression as well as subsequent death were significantly inhibited by a tyrosine kinase inhibitor herbimycin A and also by cyclosporin A. SAg-induced death of primed T cells was also inhibited by monoclonal antibodies (mAb) directed at the CD11a/CD18 molecule but not those reactive with other T cell surface molecules such as CD2, CD7, CD28, CD29 or CD49d. None of these mAb, including anti-CD11a/CD18, had any effect on SAg-induced expression of IL-2 and IL-4 genes or SAg-induced [Ca2+]i response. Addition of cytokines such as IL-1 alpha, IL-2, IL-4, IL-6, GM-CSF, IFN-gamma, tumor necrosis factor (TNF-alpha, or TNF-beta), or neutralizing Ab to these cytokines had no effect on SAg-induced death of Ag-specific TCL. The T cells which survived the death-inducing effects of SAg showed down-regulation of the CD3/T cell receptor and up-regulation of CD2 and HLA-DR expression, and upon re-exposure to the same SAg upregulated expression of mRNA for IL-2 and IFN-gamma. Presentation of SAg by B7+ ICAM-1+ LFA-3+ DR+ professional APC was also able to induce the death of Ag-specific TCL. Together these results suggest that the activation with SAg causes programmed death of Ag-specific TCL cells via a mechanism that requires late participation of the CD11a/CD18 molecule.
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PMID:Activation with superantigens induces programmed death in antigen-primed CD4+ class II+ major histocompatibility complex T lymphocytes via a CD11a/CD18-dependent mechanism. 810 Jul 73

Tumor growth induces phenotypic and functional changes among splenic T cells and macrophages (M phi) that contribute to the immunosuppression observed in tumor-bearing hosts (TBH). These changes partly arise through alterations in immune cell production of and responsiveness to cytokines. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important T cell- and M phi-derived cytokine that is produced during normal host immunogenic challenge, but it's involvement during cancer is poorly defined. In contrast, interleukin-10 (IL-10) is an inhibitory cytokine that is produced by immune cells as a deactivation factor. IL-10 can disrupt GM-CSF synthesis and may be associated with tumor-induced changes in cytokine synthesis. We determined if tumor growth alters T-cell and M phi synthesis of and responsiveness to GM-CSF, and if these alterations occur because tumor growth heightens immune cell sensitivity to IL-10. Tumor growth significantly decreased T-cell synthesis of GM-CSF during activation by concanavalin A, and TBH T cells were more susceptible to GM-CSF synthesis inhibition by IL-10 than their normal host (NH) counterparts. This suppression was observed using both unseparated splenic lymphocyte preparations and purified CD4+ and CD8+ T cells. Similarly, TBH M phi (both splenic and peritoneal) produced less GM-CSF than NH M phi during activation by lipopolysaccharide. Tumor growth also altered major histocompatibility complex (MHC) class II- M phi GM-CSF synthesis. TBH M phi were more susceptible to GM-CSF synthesis inhibition by IL-10 than their NH counterparts. Although TBH T cells demonstrate less proliferation than NH T cells during activation, tumor growth did not compromise T-cell responsiveness to GM-CSF. However, tumor growth did increase TBH T-cell susceptibility to inhibition of proliferation by IL-10. Tumor growth suppressed M phi responsiveness to GM-CSF, and IL-10 further decreased M phi responsiveness to GM-CSF. Collectively, these results suggest that T cell and M phi production of and responsiveness to GM-CSF is disrupted during tumor growth, and that TBH T cells and M phi are more susceptible to the suppressor activity of IL-10 than their NH counterparts.
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PMID:Tumor growth alters T cell and macrophage production of and responsiveness to granulocyte-macrophage colony-stimulating factor: partial dysregulation through interleukin-10. 813 Dec 7

The phenotype and functional characteristics of skin-infiltrating lymphocytes in beta-lactam antibiotic-induced vesiculobullous exanthemas were studied in vivo and in vitro. Immunohistochemical analysis demonstrated that CD8+ T lymphocytes were the predominant epidermal T-cell subset in these reactions. Epidermal T lymphocytes were isolated and expanded for in vitro studies. Fluorescence-activated cell sorter analysis showed the majority of epidermal T cells to be CD3+, T-cell receptor alpha/beta+, CD4-, CD8+, and HLA-DR+, which correlated with the predominance of epidermal CD8+ T lymphocytes found in situ. Three CD8+ epidermal T-cell clones derived from cutaneous lesions proliferated in response to penicillin-pulsed autologous antigen-presenting cells but not allogeneic antigen-presenting cells, indicating that those clones were antigen and major histocompatibility complex specific. All T-cell clones produced significant amounts of interleukin-2, interferon-gamma, and granulocyte-macrophage colony-stimulating factor. Additionally, the T-cell clones displayed cytotoxicity against epidermal cells in lectin-mediated cytotoxicity and against B-cell lines in T-cell receptor-triggered cytotoxicity. These data demonstrate the presence of epidermal drug-specific CD8+ T cells in bullous drug reactions. Because these CD8+ T cells have a cytotoxic potential, they may contribute to the necrosis of keratinocytes associated with drug-induced blister formation.
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PMID:Predominance of epidermal CD8+ T lymphocytes in bullous cutaneous reactions caused by beta-lactam antibiotics. 824 7

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