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)

Frequent complications of human immunodeficiency virus infection are hematopoietic failure and poor tolerance of myelosuppressive drugs. Reasons for neutropenia resulting from hematopoietic failure are infection of the bone marrow and hematotoxicity of treatment with zidovudine, ganciclovir, sulfonamides, and interferons. Moreover, tumor necrosis factor-alpha, transforming growth factor-beta and interferon-gamma have been shown to suppress proliferation of bone marrow cells. Both granulocyte (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) increase neutrophil counts and ameliorate phagocytic and bactericidic function of neutrophils. We report eight cases of AIDS patients with serious infections and neutropenia (< 750 cells/microliters), who were treated concomitantly with recombinant human G-CSF (3-4 micrograms subcutaneously per kilogram body weight daily). G-CSF treatment was well tolerated in all patients and showed no side effects or disturbances of other lineages than neutrophils. Life-threatening bacterial infections were treated successfully by stimulating the neutrophil immune system. This therapy shortened the duration of subsequent treatment with antibiotics. Since human immunodeficiency virus infects CD4-positive monocytes and macrophages, which are stimulated by GM-CSF, G-CSF seems to be the cytokine of choice, if stimulation of the neutrophil lineage is warranted.
 ...
PMID:Granulocyte colony-stimulating factor treatment in AIDS patients. 128 Apr 96

Hematopoietic growth factors may mitigate the cytopenias that frequently complicate HIV disease or its treatment. Clinical and in vitro studies have indicated the ability of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) or erythropoietin (EPO) to overcome the myelosuppression of HIV or many of the drug therapies used in the care of HIV-infected individuals. In addition, neutrophil or monocyte functional abnormalities observed in AIDS patients may be improved by the use of GM-CSF. Issues which may distinguish the use of hematopoietic growth factors in AIDS as compared with in other clinical settings include: 1) interaction of the growth factor with other cytokines which are aberrantly expressed, 2) direct effects of the growth factor on the replicative activity of HIV, and 3) potential interactions of the growth factor with other concurrently administered medications. This review focuses on the potential roles and limitations of growth factor use in AIDS and reviews the clinical studies using GM-CSF in HIV-infected individuals.
 ...
PMID:The use of GM-CSF in AIDS. 128 4

In this paper, the release of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the lung of patients with HIV-1 infection was evaluated. This cytokine has well recognized effects on granulocyte and macrophage growth and differentiation and plays some role in the mechanisms leading to the accumulation of alveolar macrophages (AM) in patients with interstitial lung disease. Detectable levels of GM-CSF (up to 10 pg/ml) were demonstrated in unconcentrated bronchoalveolar lavage fluid retrieved from HIV-1-seropositive patients, thus suggesting that the GM-CSF is released in vivo in the lung during HIV-1 infection. A statistically significant correlation was demonstrated between the bronchoalveolar lavage concentrations of GM-CSF and the absolute numbers of AM and lung neutrophils. Cell-free supernatants obtained from unstimulated 24-h cultured AM isolated from HIV-1-infected patients contained discrete amounts of GM-CSF, as demonstrated by an immunoenzymatic assay. AM lost the capability of releasing GM-CSF after 72 h of culture, thus suggesting that the production of GM-CSF is not constitutive in AM. After exposition of AM with LPS, the release of GM-CSF and the expression of its mRNA significantly increased with respect to the baseline values; interestingly, the amount of GM-CSF released by LPS-stimulated AM was more than 10-fold higher in HIV-1-infected patients than in healthy subjects. As demonstrated by flow cytometry analysis, more than 70% of freshly isolated AM efficiently bound phycoerythrin-GM-CSF, thus indicating that they express the receptor for GM-CSF. Determination of AM in G1, S, and G2+M by flow cytometry showed that, after 48 h of culture with GM-CSF, 5.5 to 7% of AM entered the proliferative phase of the cell cycle. Taken together, these findings suggest that AM might represent an important source of GM-CSF production in HIV-1 infection. In particular, the hypothesis is formulated that pulmonary opportunists might trigger AM to synthesize GM-CSF in situ. The local overproduction of this cytokine is likely to play a role in the pathogenic events leading to the local proliferation of AM and recruitment of neutrophils in AIDS-associated interstitial lung disease.
 ...
PMID:Release of granulocyte-macrophage colony-stimulating factor by alveolar macrophages in the lung of HIV-1-infected patients. A mechanism accounting for macrophage and neutrophil accumulation. 143 Nov 12

Granulocyte-macrophage colony-stimulating factor (GMCSF) is a hematopoietic protein that has been studied both in vitro and in vivo in human immunodeficiency virus (HIV) infection. Since both HIV infection primarily and zidovudine (formerly AZT) treatment secondarily may result in neutropenia, administration of GMCSF to persons with HIV infection is generating considerable interest. Despite in vitro studies demonstrating that the agent may stimulate HIV replication, in the presence of zidovudine a synergistic inhibition of replication occurs. Early clinical studies in patients with the acquired immunodeficiency syndrome indicate that GMCSF can raise neutrophil counts with or without concurrent zidovudine treatment. The long-term safety and tolerance of the combination has to be established.
 ...
PMID:Granulocyte-macrophage colony-stimulating factor and zidovudine in the treatment of neutropenia and human immunodeficiency virus infection. 149 10

We studied human megakaryocytes to determine if they both expressed and synthesized Fc gamma and CD4 membrane receptors. The strategy employed relied on demonstration of receptor protein and mRNA in megakaryocytes present in freshly made marrow smears, or in megakaryocytes isolated from aspirated normal bone marrow by counterflow centrifugal elutriation. Protein was detected immunochemically, whereas mRNA was detected either by in situ hybridization, or by reverse transcription, polymerase chain reaction (RT-PCR). Using these methods CD4 and Fc gamma RII protein and mRNA were detected in most megakaryocytes. Fc gamma RI and Fc gamma RIII protein was not detected in these cells. Megakaryocytes were also cultured with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to determine the effect of this growth factor on Fc gamma RII expression. As has been noted in cells of the monocyte-macrophage lineage, exposure to rhGM-CSF resulted in a significant increase in the level of megakaryocyte Fc gamma RII mRNA and protein. These observations are significant because they provide a physiologic basis for known viral trophism displayed by megakaryocytes. They are also of interest because they suggest that alternative portals exist for entry of human immunodeficiency virus (HIV-1) into megakaryocytes and that such infection may play a role in acquired immunodeficiency syndrome (AIDS)-related thrombocytopenia.
 ...
PMID:Expression of Fc gamma RII and CD4 receptors by normal human megakaryocytes. 153 89

Chronically immunosuppressed individuals are susceptible to lymphoreticular tumors. Up to 15% of patients with congenital deficiencies such as ataxia=telangiectasia may develop malignancies, mainly high-grade B cell non=Hodgkin's lymphomas (NHLs). AIDS lymphomas are comprised of NHLs including Burkitt's lymphoma (BL) and primary cerebral lymphomas (PCLs). Almost 3% of all AIDS patients (2824 of 97,258 cases) developed NHL. Epstein-Barr virus (EBV) as a co-factor in AIDS lymphomagenesis has been studied: in 12 cases of 24 AIDS lymphomas EBV by DNA in situ hybridization was found. In an analysis of 6 primary cerebral lymphomas, .5 were positive for EBV DNA by Southern blotting. In Burkitt's lymphoma the characteristic genetic alteration affects the c-myc oncogene. In 1/3 of BL p53 mutations were found but none in the 43 NHLs suggesting that p53 mutations and c-myc activation act synergistically in the pathogenesis of these tumors. Cytotoxic agents dideoxyinosine, dideoxycytosine, and zidovudine may cause secondary neoplasia. 8 of 55 AIDS patients under zidovudine treatment developed high-grade lymphoma 23.8 months subsequently; recently doses were reduced. PCL was found in 21 of 90 patients. A 5.2 months survival was associated with combined treatment with cyclophosphamide, Oncovin (vincristine), methotrexate, etoposide, and cytosine arabinoside compared with 11.3 months with chemotherapy. Colony-stimulating factors (CSFs) alleviate drug-induced myelotoxicity and zidovudine-induced neutropenia, however, l8 of 11 patients receiving granulocyte-macrophage CSF developed hematological toxicity. Interleukine-2 produced by T-helper cells enhancing tumor cells cytotoxicity has been used in AIDS-associated cryptosporidial diarrhea and in 4 patients with AIDS lymphoma with modest response, but its stimulation of the HIV-infected substrate may increase viral proliferation.
Int J STD AIDS
PMID:AIDS lymphomas. 161 63

The expression "immunocompromised host" refers to an individual who has one or more defects in the body's natural defense, which leads to severe, often life-threatening, infections. Alcoholism, diabetes mellitus, advanced age, the use of antacids, and viral infections have immune-modulating effects. The human immunodeficiency virus, cytomegalovirus, Epstein-Barr virus, and Non A, Non B hepatitis virus also contribute to immunosuppression. The lung has a special vulnerability to infection, and pneumonia accounts for more than 40% of deaths in the immunosuppressed population. Diagnostic methods include detection of microbial antigens by monoclonal antibodies, DNA sequences by the polymerase chain-reactions or DNA probes, and unique metabolites of pathogens by gas chromatography. Transtracheal aspiration was used to obtain uncontaminated respiratory secretions, but fiberoptic bronchoscopy with shielded brush and bronchoalveolar lavage (BAL) is a better means of diagnosis because of a 90% sensitivity in diagnosing pneumocystis infection. Percutaneous aspiration and open lung biopsy are reserved for more complicated cases. Empiric treatment is justified in far advanced AIDS or relapsed myelogenous leukemia with limited life expectancy, or when there is uncontrollable bleeding diathesis or impaired pulmonary function as invasion diagnostic procedures will not be tolerated. The most important antiinfective measure is careful hand washing, while prophylactic antibiotics, selective decontamination, and antifungal, antiviral, and antiparasitic agents can be used. Active and passive immunization against specific pathogens, immunological reconstitution with granulocyte-macrophage colony-stimulating factor (GM-CSF) and reducing the dosage of immunosuppression are the other strategies for prevention. In the last several decades there has been substantial progress in the management of chronic diseases which used to be fatal.
 ...
PMID:Pulmonary infections in the immunocompromised host. 166 54

Hematologic abnormalities are frequent occurrences in patients with HIV infection. Myelosuppression in AIDS may be due to multiple factors and has significant impact on the treatment of HIV-infected individuals, as it is the major dose-limiting toxicity of a number of antimicrobial compounds and chemotherapy. Both granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) are hematopoietic hormones which effect myeloid progenitor cells and enhance the function of mature neutrophils. Clinical studies of the effects of these agents in patients with AIDS indicate that GM-CSF and G-CSF can increase the production of leukocytes in a dose-dependent fashion. This increase in leukocyte production may allow the continued administration of full doses of antiviral or other myelosuppressive medications in previously hematologically intolerant patients with AIDS. Investigations of the hematopoietic, virologic, and immunologic effects of these agents alone and in combination with other hematopoietins, cytokines, and chemotherapeutic agents will ultimately define their clinical utility in patients with HIV infection.
 ...
PMID:The use of myeloid hematopoietic growth factors in patients with HIV infection. 169 Dec 50

The recombinant cytokines are increasingly important therapeutic agents for patients with AIDS. Recombinant interferon-alpha has demonstrated antitumor and antiretroviral activities in patients with Kaposi's sarcoma. Limited studies with interferon-beta suggest that it also has antitumor effects in patients with Kaposi's sarcoma, but interferon-gamma appears to be ineffective in controlling this tumor. The hematopoietic growth factors, including erythropoietin, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF), have been evaluated in several populations of human immunodeficiency virus (HIV)-infected individuals. The combination of G-CSF and recombinant human erythropoietin completely reversed the zidovudine-induced neutropenia of AIDS patients but was only partially effective in reversing anemia. In several clinical trials, GM-CSF induced marked increases in leukocyte counts and improved neutrophil function in some AIDS patients. In severely immunocompromised patients with disease caused by HIV who were receiving therapy with either G-CSF or GM-CSF, opportunistic infections continued to occur despite increases in circulating white blood cell counts. Recombinant cytokines may be used in the future in AIDS patients as adjunctive treatment with myelosuppressive antibiotics and chemotherapeutic drugs, as a possible means of enhancing host defense, or as agents of immune reconstitution.
 ...
PMID:Use of recombinant interferons and hematopoietic growth factors in patients infected with human immunodeficiency virus. 196 13

To evaluate the effect of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) on patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) who were intolerant to zidovudine because of neutropenia, we performed a randomized, open-label study in which patients were assigned to one of two groups. Zidovudine was discontinued in group A patients before instituting GM-CSF treatment and was restarted in a graduated fashion over 4 weeks. Group B patients continued on full-dose (1,200 mg/d) zidovudine therapy while beginning GM-CSF therapy. A total of 17 patients were entered, eight in group A and nine in group B. Five of eight patients in group A and seven of nine in group B had a history of Pneumocystis carinii pneumonia (PCP). All were homosexual males, except one female in group A who was the sex partner of a bisexual male with AIDS. All patients had neutropenia (absolute neutrophil count [ANC] less than 1,000/microL) while taking full-dose zidovudine. The mean CD4 (+/- SD) lymphocyte level was 37 (+/- 29)/microL and 39 (+/- 44)/microL in groups A and B, respectively. After randomization, patients were begun on subcutaneous GM-CSF at a dose of 1.0 microgram/kg/d. Patients in group A received 2 weeks of daily GM-CSF, at which time zidovudine was restarted if the ANC was greater than 1,000/microL; if the ANC was less than 1,000/microL, the dose of GM-CSF was increased to 3.0 micrograms/kg, and at 2-week intervals either zidovudine was restarted or the dose of GM-CSF was increased to 5 micrograms/kg and then 10 micrograms/kg, to maintain the ANC greater than 1,000/microL. Group B patients received full-dose zidovudine concurrently with GM-CSF administration. The dose of GM-CSF was increased every 2 weeks if necessary to keep the ANC greater than 1,000/microL while maintaining full-dose zidovudine therapy. Patients in each group showed an increase in total white blood cell (WBC) count. Neutrophils and eosinophils were responsible for the majority of this increase. Patients in group A had a more rapid increase in WBC than those in group B; however, by week 8, the WBC in each group was essentially equal. Viral replication as measured by human immunodeficiency virus (HIV) p24 antigen (Ag) was decreased in four patients in each group, increased in one patient in each group, and remained unchanged in the remainder. The ability to culture virus from peripheral blood mononuclear cells was not changed by the regimen. The major toxicities of the regimen were fever and malaise.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Recombinant human granulocyte-macrophage colony-stimulating factor ameliorates zidovudine-induced neutropenia in patients with acquired immunodeficiency syndrome (AIDS)/AIDS-related complex. 174 82


1 2 3 4 5 6 7 8 9 10 Next >>