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)

We have reported previously that heat-shock protein 60 kDa (hsp60) of Helicobacter pylori is an important antigen in the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. In order to investigate associations with host immune reactions and hsp60 antigen, CD40 ligand (CD40L) expression and cytokine production were analysed following stimulation with hsp60. To provide a clear antigen-driven immune response, peripheral blood mononuclear cells (PBMC) from patients with low-grade MALT lymphoma and gastritis and those from healthy volunteers were stimulated with recombinant H. pylori hsp60 and H. pylori cell lysate in the presence of cytokines (IL4 and granulocyte-macrophage colony-stimulating factor). mRNA expression was also analysed by a cDNA microarray containing 1100 genes. Expression of CD40L on PBMCs of patients with MALT lymphoma was increased by cytokines or by combination with stimulation with hsp60 antigens. The production of IL4 in PBMC cultures was increased in patients with MALT lymphoma; however, production of IFN-gamma was at low levels. DNA microarray analysis indicated increased levels of HLA-DR and integrin mRNAs. In cases of low-grade MALT lymphoma, adaptive immune responses against hsp60 may be enhanced by host factors, such as antigen presentation and T-cell activation, resulting in B-cell proliferation, which can be demonstrated during chronic H. pylori infection.
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PMID:Immune response in Helicobacter pylori-induced low-grade gastric-mucosa-associated lymphoid tissue (MALT) lymphoma. 1466 1

Chemokines orchestrate trafficking of immune effector cells during inflammation. Here we demonstrate that chemokines also serve to potentiate effector cell-mediated antineoplastic immune responses in vaccination strategies. As a critical mediator of inflammation, macrophage inflammatory protein 1alpha (CCL3/MIP-1alpha) attracts and stimulates both antigen-presenting and cytotoxic cells. In the A20 leukemia/lymphoma vaccine model, we explored the efficacy of MIP-1alpha in combination with interleukin-2 (IL-2) or granulocyte-macrophage colony-stimulating factor (GM-CSF). After subcutaneous injection of the MIP-1alpha + IL-2 or MIP-1alpha + GM-CSF combination vaccine, focal but pronounced infiltrates of CD4+ and CD8+ T cells were observed at the vaccination sites. In mice with preestablished leukemia/lymphoma, survival is significantly improved in animals treated with MIP-1alpha + GM-CSF- and MIP-1alpha + IL-2-secreting vaccines. Protection is superior in the MIP-1alpha + GM-CSF group, with the effects of MIP-1alpha and GM-CSF being synergistic. In contrast, suppression of lymphoblast proliferation by single-immunogen vaccines secreting MIP-1alpha, GM-CSF, or IL-2 alone does not translate to improved survival. The systemic protective effects afforded by the MIP-1alpha + IL-2 or MIP-1alpha + GM-CSF combination are mediated by different effector cell populations. In the MIP-1alpha + IL-2 group, antineoplastic defense is mediated by CD8+ T and NK cells, whereas in the MIP-1alpha + GM-CSF group CD4+ T cells are involved in addition to CD8+ cytotoxic T cells, underscoring that T cell help is critical for long-term protection. Thus combination of MIP-1alpha with different cytokines recruits different sets of effector cells into a potent antineoplastic immune response.
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PMID:CCL3/MIP-1alpha is a potent immunostimulator when coexpressed with interleukin-2 or granulocyte-macrophage colony-stimulating factor in a leukemia/lymphoma vaccine. 1496 75

The ability of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) administration to increase the content of blood leucocytes and hematopoietic progenitor cells (HPCs) is well established, yet the effect of these cytokines on immune function is less well described. Recent data indicate that plasmacytoid dendritic cells (DC2) may inhibit cellular immune response. We hypothesized that administration of the combination of G-CSF and GM-CSF after chemotherapy would reduce the type 2, or plasmacytoid, DC2 content of the autologous blood HPC grafts compared with treatment with G-CSF alone. To test this hypothesis, 35 patients with lymphoma and myeloma were randomized to receive either G-CSF or the combination of G-CSF plus GM-CSF after chemotherapy, and blood HPC grafts were collected by apheresis. Cytokine-related adverse events between the 2 groups were similar. More than 2 x 10(6)CD34 + cells per kilogram were collected by apheresis in 14 of 18 subjects treated with G-CSF and in 16 of 17 subjects treated with GM-CSF plus G-CSF ( p = not significant). There were minor differences between the 2 groups with respect to the content of T cells and CD34 + cells in the apheresis products. However, grafts collected from recipients of the combination of GM-CSF plus G-CSF had significantly fewer DC2 cells and similar numbers of DC1 cells compared with recipients treated with G-CSF alone. A third cohort of patients received chemotherapy followed by the sequential administration of G-CSF and the addition of GM-CSF 6 days later. Grafts from these patients had a markedly reduced DC2 content compared with those from patients treated either with G-CSF alone or with the concomitant administration of both cytokines. These data, and recent data that cross-presentation of antigen by DC2 cells may induce antigen-specific tolerance among T cells, suggest that GM-CSF during mobilization of blood HPC grafts may be a clinically applicable strategy to enhance innate and acquired immunity after autologous and allogeneic HPC transplantation.
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PMID:A randomized trial comparing the combination of granulocyte-macrophage colony-stimulating factor plus granulocyte colony-stimulating factor versus granulocyte colony-stimulating factor for mobilization of dendritic cell subsets in hematopoietic progenitor cell products. 1557 Feb 53

Blastic natural killer (NK) cell lymphoma corresponding to CD4+CD56+ malignancies is a novel disease entity, according to the results of clinical, morphologic, and immunologic studies. It is especially noteworthy that this disease likely arises from plasmacytoid dendritic cells (pDCs), described previously as plasmacytoid T-cells, which have an important role in innate and adaptive immunity. However, the exact relationship between the tumor cells and pDCs remains to be elucidated. We encountered a patient with typical blastic NK cell lymphoma, which later converted to leukemic manifestations, and tried to establish a cell line using the leukemic cells. We succeeded in establishment of a novel cell line, CAL-1, which originated from the primary malignant cells. The genetic and phenotypic features of CAL-1 cells bear a similarity to those of pDCs, namely, plasmacytoid morphology at light and electron microscopy; negative results for CD11c and lineage-associated markers of CD3, CD14, CD19, and CD16; positive results for HLA-DR, CD4, CD56, CD45RA, and CD123; and negative results for TCR and IgH gene rearrangements. An interesting finding was that CAL-1 cells change morphologically into the mature DC appearance with many long dendrites after short-term culture in the presence of granulocyte-macrophage colony-stimulating factor and interleukin 3. CAL-1 cells can secrete tumor necrosis factor alpha but not interferon alpha. Thus although they do not share in part phenotypic and functional features with their normal counterparts, CAL-1 cells mostly exhibit a striking pDC phenotype. We describe the first novel pDC cell line of CAL-1. This cell line should open the opportunity for study not only of CD4+CD56+ tumor cells but also of pDCs in vitro.
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PMID:A novel plasmacytoid dendritic cell line, CAL-1, established from a patient with blastic natural killer cell lymphoma. 1576 84

Human recombinant granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) is traditionally used as supportive care for patients undergoing cytotoxic chemotherapy or haematopoietic cell progenitor mobilisation. Emerging evidence suggests rhuGM-CSF, through activity on monocytes and dendritic cells, acts as a potent modulator of immune responses and has the ability to recruit inflammatory cells and cytokines to local and systemic sites of infection. The immunomodulatory effects of rhuGM-CSF suggest the potential to enhance innate and acquired immune responses against tumour-related antigens. Enhancement of innate antitumour immunity, especially in the context of minimal residual disease, is of central importance and presents the potential for meaningful contributions to long-term disease survival. This article discusses the immunomodulatory effects of rhuGM-CSF in the context of single-agent therapy in solid tumours, as well as combination therapy in lymphoma. In addition, dendritic cell modulation with rhuGM-CSF in haematopoietic progenitor grafts and rhuGM-CSF-transduced tumour vaccines will be discussed.
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PMID:Immunomodulatory effects of human recombinant granulocyte-macrophage colony-stimulating factor (rhuGM-CSF): evidence of antitumour activity. 1583 68

FavId (Favrille, Inc., San Diego, CA, USA) is a personalized therapeutic vaccine product for B cell non-Hodgkin's lymphoma, custom-manufactured from individual patient's tumour cells. This investigational agent consists of recombinant tumour-specific immunoglobulin (idiotype [Id]) chemically conjugated to the highly immunogenic carrier protein keyhole limpet haemocyanin (Id-KLH). The vaccine product is administered by subcutaneous co-injection with the cytokine adjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF) with the goal of stimulating tumour-specific T cell and humoral immunity. Therapeutic Id vaccines have shown promising results in early phase clinical trials in follicular lymphoma, and several Phase III trials are ongoing. FavId's advantages over other Id vaccine formulations include its rapid and efficient manufacturing technology utilising recombinant baculovirus, with a production time of only 8-12 weeks. In Phase II studies, FavId Id-KLH plus GM-CSF vaccines have been found to be safe, immunogenic and clinically active in follicular lymphoma. At present, FavId is being tested in a randomised, placebo-controlled Phase III trial in follicular lymphoma, aimed at improving the time to disease progression when administered following cytoreduction with rituximab. If found to be efficacious in this pivotal trial, FavId would represent a tumour-selective immunotherapy for lymphoma with little toxicity and a novel mechanism of action.
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PMID:Recombinant, tumour-derived idiotype vaccination for indolent B cell non-Hodgkin's lymphomas: a focus on FavId. 1595 14

Standard practice in older patients with acute myeloid leukemia (AML) is induction chemotherapy (ICT) followed by post-remission chemotherapy (PRT). We previously reported a median disease-free survival (DFS) and overall survival (OS) for patients in complete remission (CR) of 7.5 and 13.5 months, respectively, in 30 older patients treated with standard ICT and PRT (study A). We designed a subsequent trial excluding PRT (study B). Forty patients with AML age > or =60 years were treated with ICT consisting of standard dose cytosine arabinoside and mitoxantrone followed with granulocyte-macrophage colony-stimulating factor subcutaneously starting day 11 if the bone marrow aspirate and biopsy was hypocellular. Median age was 68 years. Myelodysplasia preceded AML in 37% of patients. Favourable, normal, and unfavourable karyotypes were seen in 7.5%, 55%, and 37.5% of patients, respectively. Twenty-one patients (52.5%) achieved CR. Median DFS and OS for patients in CR were 6.2 and 10.8 months, respectively. Study A and B differed by the addition of PRT in study A. However, DFS and OS did not differ significantly between patients treated in study A or study B (P = 0.21 and P = 0.15, respectively). PRT has not clearly improved survival in older patients with AML, and therefore the routine addition of chemotherapy to older patients in complete remission is not indicated.
Leuk Lymphoma 2006 Apr
PMID:The role of post-remission chemotherapy for older patients with acute myelogenous leukemia. 1688 71

The unique antigenic determinants, termed idiotype, of the immunoglobulin expressed on a given B-cell malignancy can serve as a tumor-specific antigen for active immunotherapy. Administration of autologous tumor-derived idiotype protein conjugated to a carrier protein, keyhole limpet hemocyanin, together with granulocyte-macrophage colony-stimulating factor to follicular lymphoma patients in complete clinical remission was associated with induction of tumor-specific cellular and humoral immunity, molecular remissions, and prolonged disease-free survival. Idiotype vaccination in patients with mantle cell lymphoma following rituximab-containing chemotherapy induced tumor-specific T-cell immunity in the absence of B cells, suggesting that vaccines may be used in combination with rituximab. Three double-blind, randomized, Phase III idiotype vaccine trials are currently ongoing to definitively determine the clinical benefit of idiotype-keyhole limpet hemocyanin plus granulocyte-macrophage colony-stimulating factor vaccination in patients with lymphoma. Results from early clinical trials with idiotype vaccines suggested that both humoral and cellular immune responses may be independently associated with tumor regression and improved progression-free survival. With the increased use of rituximab for the treatment of follicular lymphoma and other B-cell non-Hodgkin's lymphomas, further improvement in the potency of the vaccines would require strategies to enhance T-cell responses, as rituximab depletes normal B cells and impairs the generation of antibody responses.
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PMID:Therapeutic lymphoma vaccines: importance of T-cell immunity. 1682 22

The capacity to generate effective dendritic cells (DC) from adult acute lymphoblastic leukemia (ALL) patients in complete remission (CR) and off-therapy was investigated. Monocyte-derived DC cultured in the presence of granulocyte-macrophage colony-stimulating factor, interleukin (IL)-4 and tumor necrosis factor (TNF)-alpha expressed maturation markers, produced IL-12 and loaded apoptotic bodies to a similar extent to normal DC. Patients' circulating T and NK lymphocytes were normally represented and, after stimulation, were capable of producing TNF-alpha and interferon-gamma to a similar extent to control lymphocytes. DC loaded with leukemia-derived apoptotic bodies increased their ability to stimulate both allogeneic and autologous lymphocytes, and to generate specific anti-leukemic CD3 + cells. These findings offer a rationale for the design of DC-based vaccine programs for adult ALL patients in CR with the aim of controlling/eradicating the disease.
Leuk Lymphoma 2007 Feb
PMID:Generation of functional dendritic cells (DC) in adult acute lymphoblastic leukemia: rationale for a DC-based vaccination program for patients in complete hematological remission. 1732 76

Although advanced-stage follicular lymphoma (FL) has been considered incurable with standard therapy, novel strategies that utilize immunotherapy provide opportunities for prolonging disease-free survival. While passive immunotherapy with antibodies targeting the CD20 antigen on B cells has been the most widely applied lymphoma immunotherapy, active immunization with vaccines derived from the immunoglobulin idiotype present on the surface of FL provides an opportunity to induce specific humoral and cellular immune responses to the tumor, and have been demonstrated to produce significant benefits in prolonging disease-free survival. Promoting the benefits of all forms of immunotherapy will likely depend upon improving complete remission rates with initial treatment. BiovaxID, a patient-specific idiotype vaccine, has demonstrated durable remissions when administered to FL patients in first complete remission along with keyhole limpet hemocyanin and granulocyte-macrophage colony-stimulating factor, and is now undergoing evaluation in a pivotal Phase III clinical trial.
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PMID:BiovaxID idiotype vaccination: active immunotherapy for follicular lymphoma. 1754 46


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