Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of the hematoregulatory peptide SK&F 107647 were examined in a persistently and profoundly neutropenic rabbit model of disseminated candidiasis in order to determine its potential to enhance resistance against infection and its role as an adjunct to conventional antifungal chemotherapy. In healthy animals, SK&F 107647 elicited a time-dependent increase in CD11b-positive monocytes and neutrophils. When administered to neutropenic rabbits infected with Candida albicans, no significant differences in the number of CFU per gram in any of the tissues tested compared with the number in untreated control rabbits were detected. However, when SK&F 107647 was administered in combination with low doses of amphotericin B, there was a significant reduction in organism burden in the lungs, liver, spleen, and kidneys compared with the burdens in the organs of untreated control animals and in the lungs and kidneys compared with the burdens in the lungs and kidneys of animals treated with amphotericin B alone. These data suggest a potential role for this peptide as adjunctive therapy in combination with conventional antifungal agents in the treatment of disseminated candidiasis in the setting of profound and persistent neutropenia.
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PMID:Effects of the hematoregulatory peptide SK&F 107647 alone and in combination with amphotericin B against disseminated candidiasis in persistently neutropenic rabbits. 1047 59

Autoimmune neutropenia (AIN) in children can be divided into 2 forms. In primary AIN, neutropenia is the sole abnormality, and although neutrophil counts are generally below 500 microL(-1), mild bacterial infections occur. Primary AIN is mostly seen in young children and shows a self-limited course. AIN occurring in association with autoimmune diseases (secondary AIN) often shows more severe infectious complications. We analyzed clinical and serological data from 28 pediatric patients with AIN to evaluate whether there is a possible relationship between specificity of the neutrophil autoantibodies and the clinical course of the disease. Specificity of the circulating antibodies was determined with the indirect granulocyte immunofluorescence test (GIFT) and a panel of phenotyped donor neutrophils. The samples were further analyzed in the monoclonal antibody immobilization of granulocyte antigens assay (MAIGA) for neutrophil antigen (NA)1, NA2, CD11a, and CD11b specificity. With the indirect GIFT, an antibody specificity was deduced in 26 of the 28 analyzed samples. In all but 3 sera from patients with primary AIN, NA1-(76%) or NA2-(10%) specific antibodies were detected with the indirect GIFT. In 2 samples, the reactivity in the indirect GIFT was too weak to draw conclusions, but the MAIGA showed NA1 and/or NA2 specificity of the antibodies. One serum, from a patient with primary AIN with a persistent neutropenia for more than 6 years, contained NA1, possibly pan-FcgammaRIIIb, and CD11a antibodies. In 4 sera from patients with primary AIN, weak antibodies with CD11a or CD11b specificity were detected with the MAIGA. Sera from 7 patients with secondary AIN contained in all cases antibodies with pan-FcgammaRIIIb specificity, as deduced from the indirect GIFT results and absorbance/elution experiments performed with 2 sera. The MAIGA confirmed this for only 1 of the 5 tested sera. Furthermore, CD11a antibodies were detected in 1 of the 5 tested sera. In conclusion, our results indicate that primary AIN is usually associated with NA-specific antibodies, whereas secondary AIN seems to be associated with pan-FcgammaRIIIb antibodies. Thus, characterization of the antibodies in sera from children with AIN discriminates patients with primary AIN from those with secondary AIN.
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PMID:Neutrophil antibody specificity in different types of childhood autoimmune neutropenia. 1047 6

Complement activation, neutrophil stimulation, increased cellular adhesiveness, transient leukocyte margination and pulmonary leukostasis take place during hemodialysis with cellulosic dialysis membranes. Several investigators have hypothesized that complement activation is primarily responsible for the acute neutropenia occurring during the early phase of bio-incompatible hemodialysis. We have investigated the relationship between complement activation, levels of expression of CD11b and CD61 integrins on neutrophils and platelets, neutrophil counts and blood gas measurements in patients dialyzed with three types of membranes, known to activate the complement system to a different extent. Polysulfone, cellulose acetate and cuprophane membranes were used subsequently in six patients in a prospective cross-over trial design to reduce inter-individual variability. Increased levels of CD61 and CD11b, as well as neutropenia, were detected regardless of the type of membrane used. We observed a high inter-individual variation with regard to complement activation suggesting varying susceptibility to dialysis membranes. We also report that the kinetics of anaphylatoxin generation were dissociated from those of the upregulation of adhesion molecules, early neutrophil margination and decrease in PaO2 during the first 30 min of hemodialysis. Similar results were obtained with all three types of dialysis membranes. The data strengthen the hypothesis that factors other than complement are involved in the induction of dialysis-related neutropenia and hypoxemia.
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PMID:Dissociation between complement activation, integrin expression and neutropenia during hemodialysis. 1051 74

The etiology of drug-induced agranulocytosis is poorly understood. Many drugs that induce neutropenia or agranulocytosis can be metabolized to reactive intermediates that covalently bind to macromolecules. Until now, the myeloid precursor cell or an earlier committed progenitor cell has been favoured as the target for toxicity, due to evidence in some cases of cytotoxic action or antibodies against neutrophils. In the bone marrow, where neutrophils mature, certain components of the stromal microenvironment, e.g. intracellular adhesion molecule 1, vascular cell adhesion molecule 1, CD11b/CD18, heparan sulfate proteoglycans, fibronectin and hemonectin are essential for normal myeloid maturation. This article proposes that drugs implicated in agranulocytosis, or more likely their reactive metabolites, interact with specific components of the extracellular matrix and interfere with the normal regulation of granulopoiesis.
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PMID:Drugs that induce neutropenia/agranulocytosis may target specific components of the stromal cell extracellular matrix. 1053 10

Despite the increasing use of granulocyte colony-stimulating factor (G-CSF) for the mobilization of stem cells and neutrophils, its pharmacodynamic actions are not fully understood. Because of the roles of G-CSF and gelatinase B in leucokinetics, we set out to characterize the interaction of G-CSF with its receptor in humans and its effects on gelatinase B release. G-CSF was infused at bolus doses of 1 microg/kg and 5 microg/kg, and compared to placebo and dexamethasone (1 mg/kg b.i.d), which enhances the plasma levels of endogenous G-CSF. The study was randomized, double-blind, four-way crossover, in eight healthy male volunteers. G-CSF dose-independently induced profound neutropenia (> 95%) within minutes and downregulated its own receptor (CD114) on neutrophils by 75%. The G-CSF/CD114 interaction dose-independently induced degranulation of neutrophils as evidenced by a 300-400% increase in CD11b expression. Degranulation induced up to a 10-fold increase in plasma levels of gelatinase B, an enzyme known to precipitate neutropenia and subsequent neutrophilia in animals. In this study, it was shown that G-CSF downmodulates CD114 expression on the surface of neutrophils in humans and the consequent degranulation enhances gelatinase B release into plasma, which may contribute to mobilization of neutrophils or stem cells.
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PMID:Granulocyte colony-stimulating factor (G-CSF) downregulates its receptor (CD114) on neutrophils and induces gelatinase B release in humans. 1109 Dec 18

Leukocyte apoptosis is an energy-dependent process that facilitates resolution of the cellular inflammatory response. Levels of apoptosis can be accelerated or inhibited after exposure to various stimuli. To compare apoptosis in transmigrated leukocytes, two models of peritonitis in mice were used that both cause leukocyte influx into the peritoneal cavity: (1) intraperitoneal thioglycollate administration producing a sterile peritonitis and (2) cecal ligation and puncture (CLP) producing a polymicrobial bacterial peritonitis. Samples of blood and peritoneal exudate cells (PEC) were collected at multiple time points after induction of peritonitis. Leukocytes were either fixed immediately to determine an immediate apoptosis level or cultured for 24 h to determine a delayed apoptosis level. Apoptosis was assessed using terminal uridine-triphosphate nick-end labeling (TUNEL) assay, flow cytometry, and confocal microscopy. Leukocyte influx into the peritoneal cavity was confirmed in both models. At all time points, and in both models, there was increased immediate apoptosis in PEC compared with unmanipulated controls and this increase was maximal in CLP after 18 h, although it appeared to remain at a stable level in the sterile peritonitis model by 3 h. There was also an increase in PEC delayed apoptosis at early time points in both models, again maximal at 18 h for CLP, with the levels being significantly higher than the thioglycollate model at 6 h and 18 h. The mice had a relative peripheral neutropenia at 6 h after CLP, but not post thioglycollate injection, and this persisted until 42 h. Lung and liver MPO levels were elevated in CLP but did not increase after thioglycollate. There was no increase in immediate peripheral leukocyte apoptosis in either model, but an increase in delayed peripheral leukocyte apoptosis was observed by 18 h in both models. Peripheral leukocyte CD1lb expression, which is a marker of activation, was also persistently elevated in the CLP model, but not in sterile peritonitis. In conclusion, CLP is a more potent stimulus for apoptosis of leukocytes than their migration to the site of inflammation alone, as occurs in the thioglycollate model. Blood leukocyte apoptosis also appears not to be dependent on CD11b expression, and therefore activation status.
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PMID:Immediate and delayed leukocyte apoptosis in two models of peritonitis. 1183 42

The early neutropenia that occurs with cellulose-based dialysis membranes is believed to result from a cascade of immune events: complement activation, engagement of leukocyte adhesion molecules, cytokine release, and leukocyte sequestration. The beta2 integrin CR3 (CD11b/CD18) is upregulated during hemodialysis, binds complement factor iC3b, and mediates leukocyte adhesion to endothelium and leukoaggregation. Despite being invoked in dialysis-induced neutropenia, there is no direct evidence of a role for CD11b/CD18 in the neutropenia. A unique animal model of beta2-integrin deficiency was discovered in calves experiencing recurrent infections and a paucity of leukocytes in infected tissue. We hypothesized that beta2 integrins mediate the neutropenia of dialysis and directly tested this hypothesis using beta2-integrin-deficient calves. Two 3-month old beta2-integrin-deficient and two age-matched Holstein calves were dialyzed using cuprophane dialyzers. Beta2-integrin-deficient calves had less than 2% of normal neutrophil CD18 expression by flow cytometry. Normal calves had a marked decrease in circulating neutrophils (P < 0.05) to 15% of normal 15 minutes into dialysis (total, four treatments), as well as a decrease in monocytes to 39% (P < 0.05) and lymphocytes to 58% (P < 0.05). CD18-deficient calves had an attenuated decrease in neutrophils (65%; P = not significant), monocytes (78%; P = not significant), and lymphocytes (105%; P = not significant) at 15 minutes. These data, although obtained in a small sample, show that a bovine model can be used to study the early neutropenia of dialysis. These data also suggest that a direct role of beta2 integrins may be occurring in this process.
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PMID:Use of a bovine model to study the role of adhesion molecule CD11/CD18 in hemodialysis-induced neutropenia. 1187 78

Granulocyte (neutrophil) antibodies can cause autoimmune neutropenia, drug-induced neutropenia, immune neutropenia after bone marrow transplantation, neonatal immune neutropenia, refractoriness to granulocyte transfusions as well as febrile and pulmonary transfusion reactions. In the last decade, considerable progress has been made in the characterization of the implicated antigens. In 1998, the Granulocyte Antigen Working Party of the ISBT introduced a new nomenclature for human neutrophil alloantigens (HNA), which is based on the antigens' glycoprotein location. In the HNA nomenclature the immunogenic (glyco-) proteins are indicated by arabic numbers followed by a letter of the alphabet which identify the (glyco-) proteins' polymorphisms, i.e. the specific antigens. Currently, seven HNA antigens are assigned to five systems. The HNA-1a, HNA-lb and HNA-1c antigens, the former NA1, NA2, and SH antigens, have been identified as polymorphic forms of the neutrophil Fc gamma receptor IIIb (CD16b) encoded by three alleles. Recently, we could elucidate the primary structure of the HNA-2a antigen, the former NB1. We could identify the HNA-2a-bearing glycoprotein as a novel member of the Ly-6/uPAR superfamily which has been clustered meanwhile as CD177. The HNA-3a antigen, the former 5b, is located on a 70-95 kDa glycoprotein. However, its molecular basis is still unknown. Finally, the HNA-4a and HNA-5a antigens, the former MART and OND, were found to be caused by single nucleotide mutations in the alphaM (CD11b) and alphaL (CD11a) subunits of the leucocyte adhesion molecules (beta2 integrins). The glycoproteins CD11b, CD16b, and CD177 have been found to be also frequent targets of autoantibodies - approximately 30% of neutrophil autoantibodies are directed against CD16b. Characterization of granulocyte antigens have expanded our diagnostic tools by the introduction of genotyping techniques and immunoassays for antibody identification. In addition, it allowed new insights in the pathophysiology of immune neutropenias and transfusion reactions. Ongoing studies will further improve the prevention and management of granulocyte antibody-mediated diseases.
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PMID:Molecular nature of antigens implicated in immune neutropenias. 1243 Aug 90

This is a novel case report of alloimmune neonatal neutropenia (ANN) linked to the neutrophil antibody anti-HNA-4a (MART). Since its discovery, the HNA-4a antigen has never been associated with any clinical neutropenia. A first-born neonate with respiratory distress was found to be severely neutropenic, because of ANN. The broad reactivity of the antibody together with its capture by CD11b and CD18 in monoclonal antibody immobilization of granulocyte antigen test suggested HNA-4a specificity. DNA sequencing confirmed that the father is HNA-4a-positive and that the mother is HNA-4a-negative, supporting the diagnosis of ANN linked to MART.
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PMID:Alloimmune neonatal neutropenia linked to anti-HNA-4a. 1258 54

The use of granulocyte colony stimulating factor (G-CSF) for recovery from neutropenia has been established; however, acute lung injury due to G-CSF-induced polymorphonuclear leukocyte (PMN) activation is a serious complication. This study was designed to compare the activation of PMN with single bolus administration and continuous administration of G-CSF. Healthy volunteers (age 33.8 +/- 1.4 yr; n = 6) received a single bolus injection of 50 microm/m2 of G-CSF (SI; n = 6) or continuous subcutaneous injection of 50 microm/m2 of G-CSF for 24 h (CI; n = 6) and were followed for 48 h. Circulating leukocyte counts, markers of activation on PMN, and circulating levels of G-CSF, IL-6, and PMN elastase were measured. SI rapidly increased serum G-CSF levels, which peaked at 4 h, whereas CI gradually increased G-CSF levels, which remained at a steady level from 8 to 24 h. SI caused a rapid decrease in PMN counts at 0.5 h followed by sustained increase to peak at 12 h. CI gradually increased PMN counts, which peaked at 24 h, but the peak values were not significantly different between the groups. SI-induced activation of PMN, which was characterized by increased expression of CD11b, decreased expression of L-selectin, and increased F-actin content, led to increases in serum IL-6 and PMN elastase level. Such changes were all attenuated with CI (P < 0.05). We conclude that continuous subcutaneous injection of G-CSF resulted in a marrow response similar to that to a single injection but yielded reduced PMN activation.
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PMID:Continuous subcutaneous injection reduces polymorphonuclear leukocyte activation by granulocyte colony-stimulating factor. 1452 31


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