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)

The effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on cytokine profile was evaluated in a case of severe congenital neutropenia. The plasma levels of cytokines were measured before and during rhG-CSF therapy. These included G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 alpha, interleukin-1 beta, interleukin-2 (IL-2), interleukin-3 (IL-3), interleukin-4, interleukin-6 (IL-6), and tumor necrosis factor-alpha. Soluble interleukin-2 receptor (sIL-2R) was measured serially during rhG-CSF therapy. Lymphocyte subpopulations including CD2, CD3, CD4, CD8, CD19, CD20, and CD25 were also measured, rhG-CSF was administered once daily as a 30-min infusion. The patient was treated with increasing dose levels of 100, 200, 400, 800, and 1,600 micrograms/m2/day. The level of endogenous G-CSF was elevated to 334 pg/ml before treatment and GM-CSF, IL-2, IL-3, and IL-6 were slightly elevated. Clinically, he showed a moderate response to a high dose of rhG-CSF (1,600 micrograms/m2/day). Plasma levels of G-CSF markedly increased during therapy but plasma levels of other cytokines did not show significant changes during therapy and lymphocyte subpopulations did not significantly change. A drastic increase in sIL-2R expression was observed after rhG-CSF infusion and an increase in sIL-2R expression occurred even before a major increase in granulocyte counts. These results showed that a high dose rhG-CSF therapy may influence the cytokine network as judged by the increased sIL-2R expression.
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PMID:Cytokine profile during high-dose rhG-CSF therapy in severe congenital neutropenia. 750 1

CD34 is a marker for pluripotent stem cells also present on lineage-committed hematopoietic progenitors from bone marrow and a subpopulation of immature thymocytes. To characterize these early immature thymocytes, we have studied 24 pediatric thymus samples for CD34/7 expression. Three subpopulations could be defined from these T-cell receptor (TcR-) immature thymocytes: CD34+7++ (12.0 +/- 5.8), CD34-7++ (12.6 +/- 8.6), and CD34-7+ (71.5 +/- 17.0%). CD7++ represents upregulation of this antigen and is expressed by cells of a blast-like morphology. Three-color flow cytometric analysis of these three subsets suggests the following ordered differentiation sequence: CD34+7++1-4-8-45RA+-->CD34+7++1+ 4+8-45RA+/- -->CD34-7++1+4+8-+45RO+-->CD34-7+1++4+8+45RO+. Early immature thymocyte cell division is essential in the thymus to generate a large number of precursors before the initiation of the selection process. We observed that both CD2 as well CD28 activation pathways were inefficient to serve as costimulant with phorbol ester 12-O-tetradecanoyl phorbol 13-acetate or interleukin-2 (IL-2) to induce the proliferation of the three CD34/7 subsets isolated by cell sorting. However, whereas IL-1, IL-2, IL-3, IL-4, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor were ineffective, IL-7 was a potent cytokine, alone or in synergy with stem cell factor (SCF) to induce immature thymocyte proliferation. The proliferation induced by IL-7 or IL-7 + SCF is restricted to the CD34+ cells and, after 4 or 8 days of culture with IL-7, some CD34+7++ acquire the expression of CD4 and/or CD8, but remain CD3/TcR-. We also tested the myeloid differentiation capacity of these CD34 immature thymocytes. Using two different approaches, myeloid colony formation in methylcellulose and limiting dilution analysis in the presence of myeloid growth factors, we were unable to detect myeloid differentiation capacity from CD34+ early thymocytes, whereas CD34+7+ from bone marrow contained about 10% of the clonogenic cells present in the CD34+7- fraction. Together, these data support the concept that thymic CD34+7++ represents the earliest thymic subset of fully committed T-lineage cells, capable of proliferating specifically to IL-7.
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PMID:CD34-expressing human thymocyte precursors proliferate in response to interleukin-7 but have lost myeloid differentiation potential. 750 22

In this study, we evaluated the effect of a short-term exposure (2 hours) to two different lymphocytotropic strains of human immunodeficiency virus type 1 (HIV-1; HIVIIIB and ICR-3) on the survival of a factor-dependent CD34+ hematopoietic progenitor cell line (TF-1). At flow cytometry analysis, a significant (P < .05) increase in the frequency of apoptotic cell death was observed in HIV-1-treated TF-1 cells, supplemented with low doses of either interleukin-3 (IL-3; 0.02 to 1 ng/mL) or granulocyte-macrophage colony-stimulating factor (GM-CSF; 0.02 to 0.2 ng/mL) with respect to mock-treated cells. On the other hand, higher doses of both cytokines or combinations of suboptimal concentrations of IL-3 plus GM-CSF (eg, 0.2, plus 0.2 ng/mL) completely reversed the HIV-1-induced increase of apoptosis. Remarkably, no signs of productive or latent virus replication were ever observed in HIV-1-treated TF-1 cells up to 16 days of liquid culture. In parallel experiments, the in vitro exposure to HIVIIIB induced a significant and progressive increase of apoptotic death in purified bone marrow CD34+ cells, seeded in liquid cultures in the presence of 1 ng/mL IL-3. The HIV-1-induced apoptosis of TF-1 cells was likely triggered by the simple interaction of HIV-1 envelope glycoprotein gp120 with CD4 receptor, which was expressed at a low level on the surface of TF-1 cells. In fact, treatment of TF-1 cells with recombinant gp120 plus a polyclonal anti-gp120 antibody or with anti-CD4 monoclonal antibody plus rabbit antimouse IgG significantly increased the percentage of apoptotic death. These data suggest that HIV-1, and perhaps also free gp120 in the presence of anti-gp120 antibody; could play a direct role in the pathogenesis of peripheral blood cytopenias in acquired immunodeficiency syndrome patients by inducing apoptotic death of hematopoietic progenitor cells without the need of a direct infection.
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PMID:In vitro exposure to human immunodeficiency virus type 1 induces apoptotic cell death of the factor-dependent TF-1 hematopoietic cell line. 750 78

It is well established by in vivo and in vitro studies that dendritic cells (DCs) originate from hematopoietic progenitor cells. However, the presumed intermediate of Birbeck granule (BG)+ Langerhans cells (LCs) has not been detected in cultures derived from bone marrow or peripheral blood progenitor cells (PBPCs), thus contrasting with the data obtained with cord blood. We show here that large numbers of BG+ LCs can be generated from human CD34+ PBPCs in vitro, when granulocyte-macrophage colony-stimulating factor and interleukin-4, potent promotors of LC/DC differentiation, are combined with a cocktail of early acting hematopoietic growth factors. LCs were found to emerge from CD33+CD11b+CD14- progenitor cells that they share with the monocytic lineage. During culture, these cells exhibited a sequence of dramatic morphologic changes, starting with a major increase in granularity followed by an increase in size herein exceeding that of all peripheral blood cells. At the same time, CD1a and major histocompatibility complex class II expression were upregulated and virtually all CD1a++ cells were BG+ by electron microscopy. With prolonged culture, CD1a was downregulated on a major population of cells, paralleled by a loss of BG and an increase of CD4, CD25, and CD80 expression that may correspond to the maturation of epidermal LC in vitro. However, these cells were consistently CD5- and did not exhibit changes in the CD45-isoform expression during culture. The availability of large numbers of these highly purified BG+ LCs and mature DCs allows for specific analysis of these subpopulations and provides a source of potent antigen-presenting cells from individual patients for vaccination protocols against infectious or tumor-associated antigens.
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PMID:Delineation of the dendritic cell lineage by generating large numbers of Birbeck granule-positive Langerhans cells from human peripheral blood progenitor cells in vitro. 754 68

Although human eosinophils express low concentrations of CD4, the capacity of mature, non-replicating eosinophils to be infected with human immunodeficiency virus-1 (HIV-1) has not been established. Using peripheral blood eosinophils isolated free of contaminating lymphocytes and mononuclear leukocytes, we evaluated eosinophil infection with HIV-1. Eosinophils could be infected with strains of HIV-1 as evidenced by HIV-induced cytolytic effects, progressive release of p24 antigen in cultures of infected eosinophils, recovery of HIV from infected eosinophils by co-cultivation, and detection of HIV-1 gag viral DNA from infected eosinophils by polymerase chain reaction (PCR) amplification. Greater p24 antigen release from infected eosinophils was elicited by the phorbol ester, PMA; and eosinophil killing by HIV-1 was enhanced by the cytokine GM-CSF. By light and electron microscopy, HIV-infected eosinophils demonstrated apoptosis and necrosis. Apoptotic subdiploid nuclear staining was detected by flow cytometric analyses of propidium iodide-stained nuclei from HIV-infected eosinophils, and DNA isolated from HIV-infected eosinophils showed both nucleosomal fragmentation and diffuse degradation. Thus, mature eosinophils, non-replicating terminally differentiated leukocytes, can be infected with HIV-1. HIV-1 expression in eosinophils is promoted by increased granulocyte-macrophage colony-stimulating factor (GM-CSF) and can cause eosinophils to undergo death due to apoptosis and necrosis.
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PMID:Infection, apoptosis, and killing of mature human eosinophils by human immunodeficiency virus-1. 757 98

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

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


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