RESUMO
Twenty-four healthy male volunteers received either placebo or 75, 150, or 300 microg filgrastim (recombinant methionyl human granulocyte colony-stimulating factor) for 12 days to study effects on monocytes and lymphocytes. In all filgrastim-treated groups, tumor necrosis factor alpha (TNF-alpha), interleukin-12 (IL-12), and interferon gamma (IFN-gamma) release by whole blood in response to endotoxin (lipopolysaccharide) was reduced. IL-12 added in vitro to lipopolysaccharide-stimulated blood of filgrastim-treated donors restored IFN-gamma and TNF-alpha release, suggesting that the anti-inflammatory effect of granulocyte colony-stimulating factor is exercised through IL-12 suppression. Phytohemagglutinin- or anti-CD3 antibody-induced lymphocyte proliferation ex vivo was reduced by 60% from day 5 to day 15, after a 50% increase at day 2 with concomitant doubled IL-2 release. In vivo, filgrastim induced doubling of all T-cell populations by day 8. Filgrastim decreased proinflammatory cytokine production and lymphocyte proliferation ex vivo throughout prolonged treatment at all doses. This indicates that endogenous granulocyte colony-stimulating factor may counterregulate the inflammatory cytokine cascade and implies a potential indication for filgrastim in chronic inflammatory conditions.
Assuntos
Citocinas/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Linfócitos/efeitos dos fármacos , Adulto , Divisão Celular/efeitos dos fármacos , Método Duplo-Cego , Filgrastim , Humanos , Interferon gama/efeitos dos fármacos , Interleucina-12/sangue , Células Matadoras Naturais/efeitos dos fármacos , Contagem de Leucócitos/efeitos dos fármacos , Lipopolissacarídeos , Masculino , Monócitos/efeitos dos fármacos , Proteínas Recombinantes , Valores de Referência , Fatores de Tempo , Fator de Necrose Tumoral alfa/efeitos dos fármacosAssuntos
Fator Estimulador de Colônias de Granulócitos/farmacologia , Granulócitos/efeitos dos fármacos , Leucocitose/induzido quimicamente , Esquema de Medicação , Filgrastim , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Contagem de Linfócitos/efeitos dos fármacos , Proteínas Recombinantes , Subpopulações de Linfócitos T/efeitos dos fármacosRESUMO
Based on 1,2-O-isopropylidene-sn-glycerol five chiral building blocks containing differently modified glycerol residues were required for the synthesis of the target molecule 2. One of these building blocks is diacylglyceryl beta-gentiobioside carrying a phosphite residue at 6b-O position. Ligation of these five building blocks led to the desired glycerol phosphate backbone to which d-alanyl residues were attached, thus generating after O-deprotection the target molecule 2, a bisamphiphilic structural variant of Staphylococcus aureus LTA. This compound displayed higher potency in terms of cytokine release by human blood leukocytes than the monoamphiphilic variant LTA.
Assuntos
Diglicerídeos/química , Lipopolissacarídeos/química , Staphylococcus aureus/química , Ácidos Teicoicos/química , Configuração de Carboidratos , Sequência de Carboidratos , Citocinas/biossíntese , Citocinas/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Leucócitos/efeitos dos fármacos , Lipopolissacarídeos/síntese química , Lipopolissacarídeos/farmacologia , Conformação Molecular , Dados de Sequência Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Ácidos Teicoicos/síntese química , Ácidos Teicoicos/farmacologiaRESUMO
We examined leukocyte counts and ex vivo cytokine response of whole blood to lipopolysaccharide (LPS) or lipoteichoic acid (LTA) in patients under low-dose molgramostim therapy. Patients were injected subcutaneously daily for ten days with 1 microg/kg (n=9) or 2 microg/kg (n=14) molgramostim. Leukocytosis was observed in all patients, but only the eosinophil fraction was significantly increased in relation to other leukocyte populations. Ex vivo IFN-gamma release was decreased and IL-10 and IL-1ra secretion were increased in response to LPS or LTA. Thus, in non-neutropenic patients, leukocytosis can already be initiated by low doses of molgramostim. The ex vivo cytokine data suggest that these doses prime blood towards a systemic anti-inflammatory response.