Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027947 (neutropenia)
 17,527 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

Proliferation and differentiation of hematopoietic progenitor cells are regulated by a network of stimulatory and inhibitory cytokines. An understanding of the molecular mechanisms of growth control may provide a physiologic basis for the innovative therapy of bone marrow disorders. Among various accessory cells, bone marrow T lymphocytes are capable of stimulating, as well as inhibiting, hematopoietic progenitor cells. We have now elucidated molecular mechanisms regulating the differential expression of T cell genes encoding for the stimulatory and inhibitory hematopoietic programs. Stimulation of hematopoiesis requires granulocyte-macrophage colony stimulating factor (GM-CSF), whereas inhibition requires interferon-gamma (IF gamma). Both cytokines can be induced by interleukin-2 (IL2). The T cell IL2 receptor consists of a 75 kD chain (p75) mainly expressed on a subset of resting T cells and a 55 kD chain (p55) which is strongly expressed upon T cell activation. P55 and p75 associate on activated T cells to form a dimeric receptor molecule exhibiting high affinity for IL2. The p75 monomer has an intermediate affinity for IL2. Expression of p55 in the context of the high affinity IL2 receptor constitutes a requirement for T cell IFg release. In contrast, p75 alone is capable of mediating the production of GM-CSF. Thus, T cells may be capable of selective production of cytokines with specific effects in hematopoietic growth control. Utilizing a human peripheral blood leukocyte genomic library, we identified various clones containing the entire GM-CSF gene, including coding and regulatory regions. Cloning of the GM-CSF gene allowed clinical studies utilizing recombinant DNA-derived GM-CSF. Chemotherapy-induced neutropenia contributes to both complications of cytotoxic therapy as well as increased relapse incidence of underlying disease. In a prospective randomized study, we have demonstrated that GM-CSF abrogates neutropenia following aplasiogenic chemotherapy in children and adolescents with solid tumors, and that GM-CSF may reduce the duration of infectious episodes after cytotoxic therapy. Next, we escalated the cumulative doses of cytotoxic therapy in an ablative regimen followed by hematopoietic stem cell transplantation to treat patients with poor prognosis pediatric tumors. Morbidity of this highly toxic ablative regimen depends on the duration of myeloid aplasia. Median duration of aplasia following hyper-VAMP was 13 days with CM-CSF and 29 days without GM-CSF. In addition, we have employed p55 blocking monoclonal antibody for prevention of graft vs. host disease in bone marrow transplantation. The understanding of specific molecular mechanisms of hematopoietic immuno-regulation can thus be utilized to provide novel approaches to the treatment of bone marrow failure and cancer.
 ...
PMID:Molecular regulation of hematopoietic cytokines: implications and indications for clinical use in pediatric oncology. 130 80

The chemiluminescent (CL) response of interferon-gamma-treated U937 (IFN-U937) cells to sensitized target cells has been used to detect red cell, platelet and granulocyte antibodies. A clone of U937 cells was selected which expressed Fc receptor I (Fc gamma RI) and which, after incubation with IFN-gamma for 72 h, was capable of generating high levels of lucigenin-enhanced CL. The CL responses of IFN-U937 cells and peripheral blood human monocytes to sensitized red cells, platelets or granulocytes were then compared. Assays using monocytes or IFN-U937 cells were of comparable sensitivity for detection of antibodies against all three types of target cell. In addition, the use of IFN-U937 cells reduced interassay variation and simplified assay performance. The potential clinical usefulness of these CL assays was suggested by the ability of both monocytes and IFN-U937 cells to respond to red cells, platelets or granulocytes sensitized with sera from pregnant women whose babies had either haemolytic disease of the newborn (HDN), alloimmune thrombocytopenia or alloimmune neutropenia respectively. In addition, monocytes and IFN-U937 cells both responded to red cells sensitized with antibodies against a variety of specificities of assumed (although not documented) clinical significance for blood transfusion recipients. In contrast, monocytes and IFN-U937 cells responded only weakly to red cells sensitized with either anti-D in sera from mothers of babies unaffected by HDN, or with antisera containing high titre antibodies with specificities not normally associated with significantly reduced red cell survival.
 ...
PMID:The use of interferon-gamma-treated U937 cells in chemiluminescence assays to detect red cell, platelet and granulocyte antibodies of potential clinical significance. 147 11

Thirty-seven patients with advanced malignancies were treated sequentially with recombinant interferon-gamma (rIFN-gamma) and recombinant interleukin-2 (rIL-2) in an outpatient dose escalation clinical trial. rIFN-gamma (0.1 or 0.25 mg/m2/day) was administered by intramuscular injection, days 1-7 and rIL-2 (12, 18, or 24 x 10(6) IU/m2/day) was administered by a 15-min intravenous bolus, days 8-12. Common toxicities encountered included fever, chills, fatigue, neutropenia, and elevations of SGOT, bilirubin, or creatinine. Hypotension and cardiac and pulmonary toxicities were rare. With repeated cycles of therapy, nausea/vomiting and diarrhea associated with the administration of rIL-2 were seen in greater frequency. There were no treatment-related deaths, and no patient required intensive care unit admission for toxicity management. A complete response was observed in one of 11 patients with renal cancer and a partial response was observed in one of seven patients with malignant melanoma. Due to problems with drug supply, further dose escalation could not be continued, and maximum tolerated doses (MTD) were not determined by strict criteria. However, the combination of rIFN-gamma, 0.25 mg/m2/day, and rIL-2, 24 x 10(6) IU/m2/day, appeared to be beyond the MTD, as three of six patients at this dose level could not complete one cycle of therapy due to toxicity. It is unlikely that higher doses of either agent would be tolerated, and for further study using this schedule, we recommend the doses: rIFN-gamma, 0.1 mg/m2/day, and rIL-2, 24 x 10(6) IU/m2/day.
 ...
PMID:A Southwest Oncology Group Phase I study of the sequential combination of recombinant interferon-gamma and recombinant interleukin-2 in patients with cancer. 151 22

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

A newborn with fatal neonatal listeriosis developed septic shock, neutropenia, thrombocytopenia and profound hypoxaemia due to severe pulmonary hypertension. Tumour necrosis factor alpha, interleukin-1-beta and interferon-gamma serum concentrations were markedly elevated, suggesting the participation of these cytokines in the aetiopathogenesis of shock induced by Listeria monocytogenes in the neonate.
 ...
PMID:Tumour necrosis factor in neonatal listeriosis: a case report. 274 36

Treatment of neoplastic diseases is followed by a variety of infectious complications. Neutropenia and functional defects of phagocytes are common consequences of cancer and its treatment and contribute to an increased susceptibility to infections. Cytokines with hematopoietic growth stimulatory and/or immunoenhancing properties, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interleukin-3, interferon-gamma, macrophage colony-stimulating factor, interleukin-1, and interleukin-6 have been shown to either have clinical utility in patients with cancer and neutropenia or offer the promise to do so. GM-CSF and G-CSF, for example, have been shown to reduce the incidence of fever and infectious complications in patients with cancer and neutropenia. The role of cytokines for the treatment of defined infections (e.g., invasive mycoses) is under investigation.
 ...
PMID:Perspectives on the use of cytokines in the management of infectious complications of cancer. 750 61

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have recently been introduced in the treatment of chemotherapy-induced neutropenia. Effects of these CSFs on the cellular immune system were evaluated in 38 neutropenic gynecological cancer patients during chemotherapy. In addition to restoring the leukocyte count, GM-CSF--to a greater extent than G-CSF--also induced neopterin, a sensitive marker of macrophages activated by interferons. This effect was confirmed in vitro by investigating the effects of these CSFs on interferon-gamma-mediated pathways in THP-I human myelomonocytic cells. The results suggest activation of immune effector cells by GM-CSF.
 ...
PMID:Increased production of immune activation marker neopterin by colony-stimulating factors in gynecological cancer patients. 751 25

Peripheral blood neutrophils from germ-free (GF), specific-pathogen-free (SPF) and conventional (CV) rats were compared. Besides neutropenia and impaired superoxide anion generation as previously reported, it was found that GF rats had lower phagocytic function (70%) and generated less nitric oxide than the other rats. GF and SPF rats were injected with recombinant human granulocyte-colony-stimulating factor (rhG-CSF), or were transferred to natural environment. It was found that total number, phagocytosis, intracellular killing, ratio of phagocytosis versus killing (killing efficiency) and nitric oxide production induced by recombinant rat interferon-gamma (rrIFN-gamma) were normalized upon injection of rhG-CSF. These results indicate that rhG-CSF may stimulate neutrophil production and induce the expression of neutrophil receptors for phagocytosis and nitric oxide production in GF rats. Although lower than in CV rats, the level of superoxide produced was sufficient for normal neutrophil-killing efficiency in SPF and GF rats. In SPF rats, this could be amended by exposure to natural environment. However, neither rhG-CSF injection nor transfer to natural environment could increase the generation of superoxide anion in GF rats.
 ...
PMID:Peripheral blood neutrophils of germ-free rats modified by in vivo granulocyte-colony-stimulating factor and exposure to natural environment. 1002 60

Following intravenous inoculation with horse blood-infected with the agent of human granulocytic ehrlichiosis (HGE) from a human fatality, two rhesus macaques (Macaca mulatta) exhibited pyrexia and lethargy on days 4-12 postinfection (PI). Hematology revealed neutropenia, thrombocytopenia, and anemia, with ehrlichial morulae in monocytes and neutrophils on days 4-12. Blood was polymerase chain reaction (PCR)-positive on days 4-12 and bone marrow was PCR-positive on day 11. There was a minor increase in gamma-glutamyl transpeptidase on day 12 and serum interferon-gamma levels increased by day 18. Seroconversion occurred on day 20 PI to a titer of 100 by day 22. Western blot bands characteristic of HGE included 25-, 44-, 80-, 94-, 105-, and 125-kD bands. There was generalized lymphohistiocytic infiltration in the liver, spleen, lymph nodes, and other tissues. The liver had focal hepatocyte apoptosis. There was HGE DNA (by PCR) only in the spleen. Comparable findings were not observed in a monkey that received uninfected horse blood as a control. This animal model of human disease is important for further studies of HGE diagnosis, management, and pathogenesis.
 ...
PMID:A simian model of human granulocytic ehrlichiosis. 1040 32


1 2 3 Next >>