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)

Report of a T-cell rich B-cell lymphoma (TCRBCL) in a 43 years old man with an associated haemophagocytic syndrome (HS). At presentation the haemophagocytic cells involved the same organs as the lymphoma, i.e. spleen, liver, abdominal lymph nodes and bone marrow. As supportive measure to alleviate chemotherapy-induced granulocytopenia the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) was given. After an initial improvement of the blood granulocyte count pancytopenia developed again, resulting in fatal sepsis. Autopsy demonstrated massive proliferation of macrophages in the bone marrow with haemophagocytosis as morphological correlation to the pancytopenia. The observation that exogenous GM-CSF enhanced the preexistent HS primarily reactive to the TCRBCL raises the question if endogenous GM-CSF may play a role in triggering a HS. The observed association of TCRBCL and HS has not been reported so far.
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PMID:[T-cell rich B-cell lymphoma associated with hemophagocytic syndrome]. 128 41

Lymphokine requirements for the in vitro proliferation of the spleen-dependent B cell lymphoma BCL1 have been analysed. Cells were found to respond by proliferation to added recombinant (r) interleukin-4 (IL-4), r-IL-5 and recombinant granulocyte-macrophage colony-stimulating factor (r-GM-CSF). Inhibition by antibodies specific for each of these lymphokines has confirmed growth factor-dependent growth. Anti-GM-CSF has, however, been found to inhibit the proliferation of BCL1 cells induced by r-IL-4 and r-IL-5, as well as r-GM-CSF, suggesting that BCL1 cells may express receptors for GM-CSF and that GM-CSF may be able to act synergistically with IL-4 and IL-5 in promoting cell proliferation. Anti-IL-6 antibody was also found to be a very effective inhibitor of BCL1 proliferation induced by either IL-4 or IL-5 but not by GM-CSF. Added IL-6 did not stimulate BCL1 proliferation, suggesting that endogenous IL-6 may regulate the autocrine growth of BCL1 cells. BCL1 cell proliferation in vitro appears to be regulated by interactions between multiple growth factors.
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PMID:Proliferation of the BCL1 B cell lymphoma induced by IL-4 and IL-5 is dependent on IL-6 and GM-CSF. 147 97

The present study was undertaken to elucidate whether B cell lymphoma and hybridoma cell lines can be stimulated by lipopolysaccharides (LPS) or by antibodies against immunoglobulin M (IgM) to produce granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF activity was assayed on the basophil/mast cell line PT-18 which is GM-CSF- and interleukin 3-dependent. Antibodies against murine recombinant GM-CSF were used to identify the colony-stimulating factor activity present in the supernatants of the stimulated B cell lines. When these cell lines were stimulated with LPS, two of five lymphoma and five of six hybridoma lines produced GM-CSF. Two cell lines, the B cell lymphoma M12.4.1 and the hybridoma TH2.2, were analyzed more extensively under serum-free conditions. In these two cell lines, the production of GM-CSF was dependent on the dose of LPS used and time of exposure. Antibodies against IgM stimulated the TH2.2 (IgM+) but not the M12.4.1 (IgM-) cells to produce GM-CSF. Northern blot analysis of the M12.4.1 and TH2.2 cells showed that mRNA of GM-CSF can be detected in LPS-stimulated but not in unstimulated cells. Our data show that transformed B cells can be stimulated to produce GM-CSF. The present data and previous studies on GM-CSF production by normal bone marrow-derived B cells suggest a possible participation of B cells in granulopoiesis.
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PMID:Induction of granulocyte-macrophage colony-stimulating factor by lipopolysaccharide and anti-immunoglobulin M-stimulated murine B cell lines. 331 10

Tumor infiltrating lymphocytes (TIL) were cultured from 17 B-cell lymphoma specimens derived from patients with predominantly low-grade malignancies. Specimens included 15 lymph-node biopsies, 1 malignant pleural effusion, and PBL from 1 patient with circulating lymphoma cells. The phenotypic and proliferative characteristics of TIL cultured in interleukin-2 (IL-2) were studied, as well as cytolysis and cytokine secretion in response to autologous tumor. Flow cytometry of fresh tumor suspensions showed that 50% of cells (median) were malignant B cells and 36% were infiltrating T lymphocytes. After culture for approximately 1 month, TIL were 75% +/- 8% CD3+ (mean +/- SEM), 47% +/- 8% CD4+ and 35% +/- 7% CD8+. TIL proliferation was modest in most cases: the median maximum expansion was 32-fold in 25 days. Lysis of autologous tumor in 4-hour 51Cr release assays was mediated by 2 of 12 TIL studied, but was nonspecific. However, these same two TIL, when cocultured with various tumor stimulators, preferentially secreted tumor necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor after autologous tumor stimulation; unstimulated TIL secreted undetectable or barely detectable levels of these cytokines. In one TIL culture, cytokines were secreted by purified CD4+ TIL but not by CD8+ cells, and secretion was completely abrogated by the anti-major histocompatibility complex (MHC) class II antibody IVA12. Thus, although specific cytokine secretion by lymphoma TIL in response to autologous tumor was observed, it occurred in fewer than 20% of patients studied.
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PMID:Tumor-infiltrating lymphocytes derived from select B-cell lymphomas secrete granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha in response to autologous tumor stimulation. 835 84

The human interleukin-3 receptor (IL-3R) is expressed on myeloid, lymphoid, and vascular endothelial cells, where it transduces IL-3-dependent signals leading to cell activation. Although IL-3R activation may play a role in hematopoiesis and immunity, its aberrant expression or excessive stimulation may contribute to pathologic conditions such as leukemia, lymphoma, and allergic reactions. We describe here the generation and characterization of a monoclonal antibody (MoAb), 7G3, which specifically binds to the IL-3R alpha-chain and completely abolishes its function. MoAb 7G3 immunoprecipitated and recognized in Western blots the IL-3R alpha-chain expressed by transfected cells and bound to primary cells expressing IL-3R alpha. MoAb 7G3 bound the IL-3R alpha-chain with a kd of 900 pmol/L and inhibited 125I-IL-3 binding to high- and low-affinity receptors in a dose-dependent manner. Conversely, IL-3 but not granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibited 125I-7G3 binding to high- and low-affinity IL-3Rs, indicating that MoAb 7G3 and IL-3 bind to common or adjacent sites. In keeping with the inhibition of IL-3 binding, MoAb 7G3 antagonized IL-3 biologic activities, namely stimulation of TF-1 cell proliferation, basophil histamine release, and IL-6 and IL-8 secretion from human endothelial cells. Two other anti-IL-3R alpha-chain MoAbs failed to inhibit IL-3 binding or function. Epitope mapping experiments using truncated IL-3R alpha-chain mutants and IL-3R alpha/GM-CSFR alpha chimeras revealed that 31 amino acids in the N-terminus of IL-3R alpha were required for MoAb 7G3 binding. MoAb 7G3 may be of clinical significance for antagonizing IL-3 in pathologic conditions such as some myeloid leukemias, follicular B-cell lymphoma, and allergy. Furthermore, these results implicate the N-terminal domain of IL-3R alpha in IL-3 binding. Since this domain is unique to the IL-3/GM-CSF/IL-5 receptor subfamily, it may represent a novel and common binding feature in these receptors.
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PMID:Monoclonal antibody 7G3 recognizes the N-terminal domain of the human interleukin-3 (IL-3) receptor alpha-chain and functions as a specific IL-3 receptor antagonist. 854 80

Idiotypic determinants of the immunoglobulin expressed on the surface of B-cell lymphomas are tumor-specific antigens (TSAs), which can be targeted by immunotherapy. Immunization with DNA constructs encoding the idiotype (ld) of a murine B-cell lymphoma induced specific anti-ld antibody responses and protected mice against tumor challenge. Use of DNA encoding an ld/GM-CSF (idiotype/granulocyte-macrophage colony-stimulating factor) fusion protein improved vaccine efficacy, and xenogeneic immunoglobulin constant region determinants were required for immunogenicity. These results indicate that DNA may be a simple and efficacious means of inducing immune responses against a weak, otherwise unrecognized tumor antigen, provided that additional stimuli are included with the DNA.
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PMID:DNA immunization induces protective immunity against B-cell lymphoma. 878 65

The idiotypic determinants of B cell lymphoma provide a tumor-specific Ag and a target for immunotherapy. We have developed several generations of idiotype vaccines that were tested in an animal model, the 38C13 mouse B cell lymphoma. Initially we showed that effective tumor immunity was elicited by the syngeneic Id when it was conjugated to a carrier protein and mixed with an adjuvant. A subsequent generation of Id vaccines eliminated the need for a carrier protein and for an adjuvant by incorporating cytokines into fusion proteins containing the Id. A third generation of vaccines consisting of naked DNA encoding the Id-granulocyte-macrophage colony-stimulating factor (GM-CSF) fusion proteins was equally effective in inducing tumor immunity. To determine whether Ig variable regions, in the absence of constant regions, could be immunotherapeutic in this model, we tested the use of single-chain Fv (scFv). scFv proteins, produced in bacteria, and naked DNA encoding scFv were used in this study. scFv was tested alone or fused to GM-CSF or an immunoenhancing peptide derived from IL-1beta. Here we demonstrate that scFv-GM-CSF was effective only when injected as a protein, not as a DNA vaccine. In contrast, both scFv-IL-1beta peptide fusion protein and naked DNA encoding it induced tumor immunity that protected mice from tumor challenge.
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PMID:A nine-amino acid peptide from IL-1beta augments antitumor immune responses induced by protein and DNA vaccines. 895

A fusion protein containing a B cell lymphoma idiotype (Id) and granulocyte-macrophage colony-stimulating factor (GM-CSF) is a potent stimulator of tumor immunity. In three different tumor models we show that immunization with autologous lymphoma cells that have been engineered to express the Id in the context of GM-CSF is much more effective than immunization with an equivalent dose of the purified protein. The lymphoma Id could be modified by introducing the GM-CSF gene into the immunoglobulin (Ig) heavy chain locus via gene targeting. This approach circumvents the isolation of the rearranged immunoglobulin variable genes from the tumor and the preparation of tumor-specific vector constructs. The low production of Id/GM-CSF fusion proteins by transfected cells, which is a major obstacle in the use of purified fusion proteins for immunotherapy, is due to the presence of the cytokine gene in the immunoglobulin locus. Low production, however, is not limiting in the cell-based setting, because upon in vivo administration of the modified autologous cells, even minute expression levels are sufficient to induce tumor immunity.
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PMID:Induction of tumor immunity by autologous B lymphoma cells expressing a genetically engineered idiotype. 1050 1

B-cell lymphomas express tumor-specific immunoglobulin, the variable regions of which [idiotype (Id)] can serve as a target for active immunotherapy. Promising results have been obtained in clinical studies of Id vaccination using Id proteins.However, Id protein is laborious and time-consuming to produce. DNA vaccination is an attractive alternative for delivering Id vaccines, because Id DNA can be rapidly isolated by PCR techniques. DNA coding for lymphoma Id can provide protective immunity in murine models. In the present study, we performed a Phase I/II clinical trial to study the safety and immunogenicity of naked DNA Id vaccines in 12 patients with follicular B-cell lymphoma. The DNA encoded a chimeric immunoglobulin molecule containing variable heavy and light chain immunoglobulin sequences derived from each patient's tumor, linked to the IgG2a and kappa mouse immunoglobulin (MsIg) heavy- and light-chain constant regions chains, respectively. Patients in remission after chemotherapy received three monthly i.m. injections of the DNA in three dose escalation cohorts of four patients each (200, 600, and 1800 micro g). After vaccination, 7 of 12 patients mounted either humoral (n = 4) or T-cell-proliferative (n = 4) responses to the MsIg component of the vaccine. In one patient, a T-cell response specific to autologous Id was also measured. Anti-Id antibodies were not detectable in any patient. A second series of vaccinations was then administered using a needle-free injection device (Biojector) to deliver 1800 micro g both i.m. and intradermally (i.d.); 9 of 12 patients had humoral (n = 6) and/or T-cell (n = 4) responses to MsIg. Six of 12 patients exhibited humoral and/or T-cell anti-Id responses; yet, these were cross-reactive with Id proteins from other patient's tumors. Subsequently, a third series of vaccinations was carried out using 500 micro g of human granulocyte-macrophage colony-stimulating factor DNA mixed with 1800 micro g of Id DNA. The proportion of patients responding to MsIg remained essentially unchanged (8 of 12), although humoral or T-cell responses were boosted in some cases. Throughout the study, no significant side effects or toxicities were observed. Despite the modest level of antitumor immune responses in this study, DNA vaccine technology retains potential advantages in developing anti-Id immunotherapies. Additional studies are warranted to optimize vaccine dose, routes of administration, vector designs, and prime-boost strategies. These results will help guide the design of such future DNA vaccine trials.
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PMID:Immunogenicity of a plasmid DNA vaccine encoding chimeric idiotype in patients with B-cell lymphoma. 1238 47

This study was designed to evaluate the feasibility, toxicity, and efficacy of rituximab added to the VNCOP-B (etoposide/mitoxantrone/cyclophosphamide/vincristine/prednisone/bleomycin) combination regimen for the treatment of elderly patients with large B-cell lymphoma. Previously untreated patients > or = 65 years of age with stage II, III, or IV large B-cell non-Hodgkin's lymphoma were treated with a modified VNCOP-B regimen with weekly chemotherapy for 8 weeks. In addition, patients received rituximab 375 mg/m2 intravenously on weeks 1, 2, 3, 4, 6, and 8. All patients received prophylactic granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) during the 8 weeks of treatment. Between August 1999 and February 2002, 41 patients entered this multicenter phase II trial. The median age was 74 years, and 54% of patients had high-risk tumors (age-adjusted International Prognostic Index scores of 2 or 3). Sixty-eight percent of patients completed the 8 weeks of therapy. Overall response rate was 66%; actuarial progression-free survival rate at 2 years was 59%, with a 57% actuarial overall 2-year survival rate. Patients > or = 75 years of age had similar treatment outcomes compared with younger patients. Toxicity with this regimen was predominantly related to chemotherapy; rituximab was well tolerated. Grade 3/4 neutropenia occurred in 83% of patients even with routine use of prophylactic G-CSF or GM-CSF. Treatment-related death occurred in 4 patients (10%). VNCOP-B plus rituximab is efficacious, producing 2-year progression-free survival rates that compare favorably with those of other active regimens in this patient group. Hematologic toxicity was increased compared with previous reports with VNCOP-B alone, as evidenced by the treatment-related mortality rate of 10% in the present study. Differences in toxicity may have been caused by the addition of rituximab, the modified etoposide schedule, or the differences in patient characteristics. This regimen provides a treatment option for elderly patients who are not considered candidates for standard CHOP/rituximab chemotherapy.
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PMID:First-line treatment with brief-duration chemotherapy plus rituximab in elderly patients with intermediate-grade non-Hodgkin's lymphoma: phase II trial. 1283 53


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