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)

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

Leucocyte functions and the influence of chemoradiotherapy were examined in three age groups of patients with oral cancer. The groups consisted of 66 patients below 65 years old (group A): 40 patients between 65 and 80 years old (group B); 20 patients over 80 years old (group C). 20 healthy individuals (45.8 +/- 9.6 years old) were chosen as controls. Originally, no significant differences in leucocyte count, CD3 population, CD4/CD8 ratio, natural killer activity or phagocytosis of polymorphonuclear leucocytes (PMNL) were found in the patients. However, T cell blastogenesis, lymphokine-activated killer cell activity and superoxide production of PMNL were all suppressed. These functions were further suppressed by cancer therapy, the greatest suppression being seen in group C. Compared to controls and group A, the generation of interleukin-1, interleukin-6, tumour necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor were markedly suppressed in group C. These results show that very old cancer patients are already in an immunologically suppressed condition and that the leucocyte functions of these patients are further impaired by cancer therapy.
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PMID:Influence of aging and chemoradiotherapy on leucocyte function in oral cancer patients. 763 87

Interleukin-2 (IL-2)-dependent large granular lymphocytes (LGL) with a distinctive surface phenotype were generated from histologically normal duodenal biopsy tissues. Immunoperoxidase staining of the mucosa with an anti-CD56 monoclonal antibody revealed LGL localized in the lamina propria rather than in the epithelium. Light and electron microscopy demonstrated azurophilic and electron-dense cytoplasmic granules. Flow cytometry analysis revealed that these cells express CD45, CD56, CD2, CD7, CD11a, CD18, CD69 and the intermediate affinity (p70) IL-2 receptor (IL-2R) but not CD57, CD16, CD3, CD4, CD5, CD8, CD45RA, CD25, or the high affinity p55 IL-2R. The LGL proliferated when cultured in the presence of human rIL-2 but not in the presence of human rIL-4. Functional studies demonstrated that the LGL had strong cytotoxicity against natural killer (NK) target cells, K562, but not NK-resistant targets such as Colo 205, Melanoma and Epstein-Barr virus (EBV)-transformed B-cell lines. The LGL expressed genes for IL-5, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor-alpha (TNF-alpha) and the corresponding cytokines were detected in culture supernatant. These results provide evidence for an important role of gut mucosal LGL in the induction and regulation of inflammation and immunity in the gut.
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PMID:Morphological, phenotypic and functional characteristics of a pure population of CD56+ CD16- CD3- large granular lymphocytes generated from human duodenal mucosa. 769 28

We used retroviral mediated gene transfer and gene knockout technologies to explore the in vivo functions of murine granulocyte-macrophage colony-stimulating factor (GM-CSF) [1, 2]. In tumor vaccination experiments, GM-CSF was the most potent molecule of a large number of cytokines, adhesion molecules and other immunomodulators for the induction of specific and long-lasting anti-tumor immunity. Vaccination required activities of both CD4 and CD8 positive lymphocytes, and likely involved the augmentation by GM-CSF of host professional antigen-presenting cell function. Mice engineered by homologous recombination techniques in embryonic stem cells to lack GM-CSF demonstrated no significant perturbations in steady-state hematopoiesis. All mutant animals, however, developed the accumulation of surfactant proteins and lipids in the alveolar space, the defining feature of the idiopathic human disorder pulmonary alveolar proteinosis. Surfactant lipid and protein content were increased in the absence of alterations in surfactant protein mRNA, supporting the concept that surfactant clearance or catabolism was perturbed. Extensive lymphoid hyperplasia associated with lung airways and blood vessels was also found, yet no infectious agents could be isolated. These results demonstrate that GM-CSF is not an essential growth factor for basal hematopoiesis and reveal an unexpected, critical role for GM-CSF in pulmonary homeostasis. It is tempting to speculate that the ability of GM-CSF to modulate the uptake and processing of particulate material underlies the mechanisms of immunostimulation and surfactant accumulation.
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PMID:Activities of granulocyte-macrophage colony-stimulating factor revealed by gene transfer and gene knockout studies. 769 61

Previous studies have demonstrated that Pseudomonas exotoxin A stimulated the proliferation of immature T lymphocytes within the splenocytes of athymic mice. These studies were performed to determine which lymphokines were involved in the proliferation of the immature T cells. The results of this study indicate that exotoxin A does not induce the production of interleukin-2 or tumor necrosis factor from B cell-depleted splenotypes from athymic mice. However, exotoxin A does induce the production of granulocyte-macrophage colony-stimulating factor (GM-CSF) from B cell-depleted splenocytes. Furthermore, the GM-CSF was shown to be produced by a Thy1+, CD4-, CD8- T lymphocyte. The addition of anti-GM-CSF antibody abrogates the exotoxin A-induced proliferation of B cell-depleted splenocytes from athymic mice. Thus, these data indicate that exotoxin A induces the production of GM-CSF from immature T lymphocytes within the splenocytes of athymic mice and the exotoxin A-induced proliferation of these immature T cells is dependent on the presence of GM-CSF.
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PMID:GM-CSF is required for the Pseudomonas exotoxin A-induced proliferation of immature T cells in athymic mice. 784 87

Human autologous tumor-specific T-helper 2 (Th2) cells were investigated in melanoma tumor-infiltrating lymphocytes (TILs). Both a CD4+ T-cell line and its 5 potential T-cell clones established from TILs of a patient with metastatic melanoma produced significant levels of IL-4, IL-6, IL-10 and granulocyte-macrophage colony-stimulating factor (GM-CSF) in response to autologous, but not any of 12 allogeneic, melanoma cell lines. They also produced IL-3 and IL-8 but not IL-2, IFN-gamma, TNF-alpha or TNF-beta in response to autologous tumor cells. Furthermore, they showed autologous melanoma-specific cytotoxicity only in an 18-hr 51Cr-release assay. Specific IL-4, IL-6 or IL-10 production by the CD4+ M73 T-cell line and its clone was inhibited by anti-class II DR (but not anti-class I) MAb, whereas their specific cytotoxicity was inhibited by anti-class I (but not anti-class II) MAb. Anti-CD3 and -CD4 MAb (but not anti-CD8) abrogated both IL-4, IL6 and IL-10 production and cytotoxicity, while anti-IL-4 antibody did not inhibit cytotoxicity. CD4+ potential T-cell clones, but not CD8+ clones, that were established from freshly isolated TILs without in vitro sensitization by autologous tumor cells also produced IL-4, IL-6 and IL-10 but not IFN-gamma or tumor necrosis factor (TNF) alpha in an autologous tumor-specific fashion. These Th2 cells were neither reactive to EBV-B cells nor suppressive against CD8+ T-cell clones. PMA and PHA stimulated these potential T-cell clones, regardless of their specific lymphokine production, to produce IL-3, IL-4, IL-6, IL-8, IL-10, GM-CSF, TNF alpha and IFN-gamma. Our results demonstrate the presence of autologous tumor-specific Th2 cells at the melanoma sites.
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PMID:Characterization of autologous tumor-specific T-helper 2 cells in tumor-infiltrating lymphocytes from a patient with metastatic melanoma. 791 81

Recombinant human granulocyte-macrophage colony-stimulating factor therapy significantly reduces serum hepatitis B virus DNA levels, associated with increased 2',5'-oligoadenylate synthetase activity in cultured mononuclear cells of patients with chronic hepatitis B. To assess changes in immune function during therapy of chronic hepatitis B patients, spontaneous and mitogen-induced production of tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, interferon-alpha and interferon-gamma were measured-along with serum levels of soluble CD4, soluble CD8, soluble interleukin-2 receptor and beta 2-microglobulin-before, during and after a 6-wk course of granulocyte-macrophage colony-stimulating factor in nine patients with chronic hepatitis B. Treatment statistically enhanced spontaneous production of tumor necrosis factor-alpha (p < 0.05) and interleukin-1 beta (p < 0.02). Furthermore, spontaneous interleukin-6 production correlated negatively with hepatitis B virus DNA levels (p < 0.03), and spontaneous interleukin-1 beta production correlated positively with 2',5'-oligoadenylate synthetase activity (p < 0.0005). In addition, statistically significant increases were found during therapy in serum levels of soluble interleukin-2 receptor (p < 0.01), soluble CD4 (p < 0.01) and beta 2-microglobulin (p < 0.05). Levels of soluble interleukin-2 receptor and soluble CD4 correlated negatively with levels of hepatitis B virus DNA (p < 0.05), and levels of soluble interleukin-2 receptor and beta 2-microglobulin correlated positively with 2',5'-oligoadenylate synthetase activity (p < 0.003 and p < 0.02, respectively). Thus recombinant human granulocyte-macrophage colony-stimulating factor administration may induce reductions in hepatitis B virus DNA levels, perhaps by altering the immune status and increasing cytokine production.
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PMID:Changes in cytokine production during therapy with granulocyte-macrophage colony-stimulating factor in patients with chronic hepatitis B. 792 47

To test the role of immune reactivity in the pathogenesis of hepatitis C, serum soluble immune factors were measured in a cohort of 57 patients with chronic hepatitis C, and in 20 healthy subjects. Levels of interleukin-1 beta, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, and interleukin-6 were detected in some, but not all, HCV patients and were in general undetectable in healthy subjects. Patients had significantly higher concentrations of neopterin (P = 0.0026), beta 2-microglobulin (P = 0.046), soluble interleukin-2 receptor (P = 0.021), and soluble CD8 (P < 0.039), than healthy controls; conversely, interferon-gamma levels were significantly lower (P = 0.023). Significant correlations were observed between beta 2-microglobulin concentration and Knodell's index (r = 0.638, P = 0.00045), the score of piecemeal necrosis (r = 0.572, P = 0.0023), and the degree of fibrosis (r = 0.527, P = 0.0056). Interleukin-2 levels correlated significantly with Knodell's index (r = 0.412, P = 0.037), and the degree of lobular cytolysis (r = 0.389, P = 0.048). According to therapeutic outcome, pretreatment levels of soluble CD8 were only significantly elevated (P = 0.042) in patients with a sustained biochemical response. On interferon-alpha treatment, the levels of beta 2-microglobulin, neopterin, and soluble interleukin-2 receptor increased significantly (P < 0.05), irrespective of therapy outcome. In summary, HCV patients have an altered immune reactivity that might play a role in the pathogenesis of chronic hepatitis C, and might influence the therapeutic outcome to interferon-gamma.
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PMID:Serum levels of soluble immune factors and pathogenesis of chronic hepatitis C, and their relation to therapeutic response to interferon-alpha. 795 20

We have reported previously that IL-1 induces murine thymocyte proliferation in the absence of artificial comitogens, provided that the cells are cultured at high densities. In the present study, we show that, in these conditions, TdR uptake in response to IL-1 is diminished significantly by anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) Abs. Indeed, a substantial production of this growth factor occurs when thymocytes are cultured in the presence of IL-1. Maximal GM-CSF levels are attained within 3 days of culture, and mRNA expression is detected after a 48-h stimulation. Both GM-CSF production and IL-1-induced thymocyte proliferation are decreased considerably by the depletion of I-A+ Mac-1+ accessory cells. Yet, addition of exogenous GM-CSF to accessory cell-depleted thymocytes does not restore the proliferative response to IL-1 alone, suggesting the implication of another accessory cell-derived mediator. Our data design IL-7 as the endogenous factor required in our culture system because: 1) GM-CSF can reverse the decrease in the proliferation after accessory cell depletion when IL-7 is provided together with IL-1, and 2) the proliferative response to IL-1 plus IL-7 is diminished as much by neutralization of GM-CSF by its specific Abs as by accessory cell removal (approximately 30%). Finally, the cells responding to IL-1 + IL-7 were identified as mature CD4-CD8-TCR+ thymocytes by the use of bromodeoxyuridine (BrdUrd), suggesting that the GM-CSF produced by thymic accessory cells in response to IL-1 participates in IL-7-dependent, intrathymic expansion of the CD4-CD8-TCR+ compartment.
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PMID:Endogenous granulocyte-macrophage colony-stimulating factor is involved in IL-1- and IL-7-induced murine thymocyte proliferation. 805 2

Interleukin-12 (IL-12) is a heterodimeric cytokine produced primarily by antigen-presenting cells (monocytes, macrophages, dendritic cells, and B cells). Its production is stimulated by bacteria, bacterial products, and intracellular parasites and enhanced by priming with granulocyte-macrophage colony-stimulating factor (CM-CSF) and interferon-gamma (IFN-gamma) or inhibited by IL-10. The major biological activity of IL-12 is on T and natural killer (NK) cells in which it increases cytokine production, proliferation, and cytotoxicity. Its production occurs several hours after exposure to infections agents, which induces a rapid production of IFN-gamma by NK and later by T cells. This IFN-gamma potentiates antigen-presenting cell functions important in clearing infections agents (phagocytosis, oxidative burst, and production of nitrous oxide) and also increases further production of IL-12. IL-12 has been clearly demonstrated to be important in the generation of CD4 and CD8 type 1 T cells both in vivo and in vitro. Our data reveals that IL-12 primes naive T cells for high IFN-gamma and IL-10 production, whereas IL-4 is required for IL-4 priming, thus suggesting that these genes and possibly others are independently regulated. IL-12 is therefore involved in the skewing of cytokine production toward a type 1 and has been implicated in being involved in selective mechanisms of established T cells. It is now becoming clear that the IL-12 acts as both a proinflammatory cytokine and an immunomodulator and therefore bridges the innate and adaptive immune responses.
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PMID:Immunoregulation by interleukin-12. 861 97


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