Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
Mais filtros








Base de dados
Intervalo de ano de publicação
1.
J Allergy Clin Immunol ; 147(4): 1420-1429.e7, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32926878

RESUMO

BACKGROUND: Activation of the classical and lectin pathway of complement may contribute to tissue damage and organ dysfunction of antibody-mediated diseases and ischemia-reperfusion conditions. Complement factors are being considered as targets for therapeutic intervention. OBJECTIVE: We sought to characterize ARGX-117, a humanized inhibitory monoclonal antibody against complement C2. METHODS: The mode-of-action and binding characteristics of ARGX-117 were investigated in detail. Furthermore, its efficacy was analyzed in in vitro complement cytotoxicity assays. Finally, a pharmacokinetic/pharmacodynamic study was conducted in cynomolgus monkeys. RESULTS: Through binding to the Sushi-2 domain of C2, ARGX-117 prevents the formation of the C3 proconvertase and inhibits classical and lectin pathway activation upstream of C3 activation. As ARGX-117 does not inhibit the alternative pathway, it is expected not to affect the antimicrobial activity of this complement pathway. ARGX-117 prevents complement-mediated cytotoxicity in in vitro models for autoimmune hemolytic anemia and antibody-mediated rejection of organ transplants. ARGX-117 exhibits pH- and calcium-dependent target binding and is Fc-engineered to increase affinity at acidic pH to the neonatal Fc receptor, and to reduce effector functions. In cynomolgus monkeys, ARGX-117 dose-dependently reduces free C2 levels and classical pathway activity. A 2-dose regimen of 80 and 20 mg/kg separated by a week, resulted in profound reduction of classical pathway activity lasting for at least 7 weeks. CONCLUSIONS: ARGX-117 is a promising new complement inhibitor that is uniquely positioned to target both the classical and lectin pathways while leaving the alternative pathway intact.


Assuntos
Anticorpos Monoclonais/farmacologia , Complemento C2/antagonistas & inibidores , Inativadores do Complemento/farmacologia , Animais , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/farmacocinética , Cálcio , Ativação do Complemento/efeitos dos fármacos , Complemento C2/análise , Complemento C2/metabolismo , Inativadores do Complemento/sangue , Inativadores do Complemento/farmacocinética , Mapeamento de Epitopos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Macaca fascicularis , Masculino
2.
J Autoimmun ; 42: 94-104, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23410585

RESUMO

Activation of complement components is crucial in the progression and severity of myasthenia gravis and experimental autoimmune myasthenia gravis (EAMG). Mice deficient in complement component C4 or treated with monoclonal antibody to C1q are resistant to EAMG. In this study, we show that inhibition of complement cascade activation by suppressing the expression of a critical low-abundant protein, C2, in the classical complement pathway, significantly improved clinical and immunopathological manifestations of EAMG. Two weeks after a second booster immunization with acetylcholine receptor, when mice exhibit muscle weakness, i.p. injection of C2 siRNA significantly suppressed C2 mRNA in the blood cells and liver of EAMG mice. Treatment of EAMG mice with C2 siRNA, once a week for 5 weeks, significantly improved muscle strength, which was further evidenced by functional AChR preservation in muscle, reduction in number of C3 and membrane-attack complexes at neuro-muscular junctions in forelimb muscle sections, and a transient decrease in serum IgG2b levels. Our study shows for the first time that siRNA-mediated suppression of C2, a component of the classical complement system, following established disease, can effectively contribute to the remission of EAMG. Therefore, C2 siRNA mediated therapy can be applied in all complement mediated autoimmune diseases.


Assuntos
Complemento C2/antagonistas & inibidores , Fígado/imunologia , Músculos/imunologia , Miastenia Gravis Autoimune Experimental/terapia , RNA Interferente Pequeno/genética , Animais , Ativação do Complemento/genética , Complemento C2/genética , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Feminino , Humanos , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos C57BL , Músculos/patologia , Receptores Colinérgicos/imunologia
3.
FEBS Lett ; 470(2): 131-4, 2000 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-10734221

RESUMO

Human complement regulatory (also called inhibitory) proteins control misdirected attack of complement against autologous cells. Trypanosome and schistosome parasites which survive in the host vascular system also possess regulators of human complement. We have shown Sh-TOR, a protein with three predicted transmembrane domains, located on the Schistosoma parasite surface, to be a novel complement regulatory receptor. The N-terminal extracellular domain, Sh-TOR-ed1, binds the complement protein C2 from human serum and specifically interacts with the C2a fragment. As a result Sh-TOR-ed1 pre-incubated with C2 inhibits classical pathway (CP)-mediated haemolysis of sheep erythrocytes in a dose-dependent manner. In CP-mediated complement activation, C2 normally binds to C4b to form the CP C3 convertase and Sh-TOR-ed1 has short regions of sequence identity with a segment of human C4b. We propose the more appropriate name for TOR of CRIT (complement C2 receptor inhibitory trispanning).


Assuntos
Antígenos de Helmintos , Antígenos de Protozoários/metabolismo , Complemento C2/antagonistas & inibidores , Complemento C2/metabolismo , Proteínas de Helminto , Receptores de Superfície Celular/metabolismo , Schistosoma , Sequência de Aminoácidos , Animais , Antígenos de Protozoários/química , Western Blotting , Cromatografia de Afinidade , Complemento C2/química , Complemento C2/imunologia , Complemento C2a , Convertases de Complemento C3-C5/antagonistas & inibidores , Convertases de Complemento C3-C5/química , Convertases de Complemento C3-C5/imunologia , Convertases de Complemento C3-C5/metabolismo , Complemento C4b/antagonistas & inibidores , Complemento C4b/química , Complemento C4b/imunologia , Complemento C4b/metabolismo , Via Clássica do Complemento/imunologia , Eritrócitos/imunologia , Hemólise/imunologia , Humanos , Modelos Imunológicos , Dados de Sequência Molecular , Peso Molecular , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Receptores de Superfície Celular/química , Schistosoma/imunologia , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Ovinos
4.
Immunology ; 90(1): 115-20, 1997 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9038721

RESUMO

Licorice, the root extract of Glycyrrhiza glabra I., is used as a medicine for various diseases. Anti-inflammatory as well as anti-allergic activities have been attributed to one of its main constituents, glycyrrhizin. These activities are mainly ascribed to the action of the aglycone, beta-glycyrrhetinic acid. beta-Glycyrrhetinic acid has a steroid-like structure and is believed to have immunomodulatory properties. To determine whether interference with complement functions may contribute to the immunomodulatory activity of beta-glycyrrhetinic acid, its effects on the classical and alternative activation pathways of human complement were investigated. We found that beta-glycyrrhetinic acid is a potent inhibitor of the classical complement pathway (IC50 = 35 microM), whereas no inhibitory activity was observed towards the alternative pathway (IC50 > 2500 microM). The anticomplementary activity of beta-glycyrrhetinic acid was dependent on its conformation, since the alpha-form was not active. It was also established that naturally occurring steroids, e.g. hydrocortisone and cortisone, did not inhibit human complement activity under similar conditions. Detailed mechanistic studies revealed that beta-glycyrrhetinic acid acts at the level of complement component C2.


Assuntos
Anti-Inflamatórios/farmacologia , Proteínas Inativadoras do Complemento/farmacologia , Via Clássica do Complemento/efeitos dos fármacos , Ácido Glicirretínico/farmacologia , Administração Tópica , Técnicas de Cultura de Células , Complemento C1q/metabolismo , Complemento C1s/biossíntese , Complemento C2/antagonistas & inibidores , Ácido Glicirretínico/química , Humanos , Tolerância Imunológica/efeitos dos fármacos , Imunoglobulina G/metabolismo
5.
Biochem J ; 226(1): 199-205, 1985 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-3977865

RESUMO

By using a radioimmunoassay, C1-inhibitor was found to accumulate in the supernatants of human monocyte cultures. The production of this protein was inhibited reversibly by cycloheximide. When C1-inhibitor synthesis was compared with C2 synthesis, it was found that C1-inhibitor synthesis continued, whereas synthesis of C2 appeared to cease after about 7 days in culture. Immunoprecipitation of supernatants of monocyte cultures that had been pulsed with [35S]methionine showed a specific band with an Mr of 105 000. Immunoprecipitates of the lysates revealed a band of Mr 83 000; this was thought to represent a partially or non-glycosylated precursor of C1-inhibitor. C1-inhibitor produced by the monocytes was shown, by using a haemolytic assay, to be functionally active. However, the functional activity of C1-inhibitor was reduced by only 44% in the presence of cycloheximide, whereas the concentration of this protein in cycloheximide-treated culture supernatants fell by more than 93%. This finding suggests that monocytes secrete a second molecule, which inhibits C1 activity but is distinct from classical C1-inhibitor.


Assuntos
Proteínas Inativadoras do Complemento 1/biossíntese , Monócitos/imunologia , Células Cultivadas , Proteínas Inativadoras do Complemento 1/antagonistas & inibidores , Complemento C2/antagonistas & inibidores , Complemento C2/biossíntese , Cicloeximida/farmacologia , Eletroforese em Gel de Poliacrilamida , Hemólise , Humanos , Cinética , Monócitos/efeitos dos fármacos
6.
Clin Exp Immunol ; 57(2): 454-60, 1984 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-6088136

RESUMO

Adenosine inhibits C2 production by human monocytes. The use of synthetic analogues of adenosine suggested that the action was mediated by receptors of A2 type. EHNA which inhibits the enzyme adenosine deaminase and increases the concentration of intracellular adenosine also reduces C2 production. It is therefore possible that endogenous adenosine regulates C2 synthesis.


Assuntos
Adenosina/farmacologia , Complemento C2/biossíntese , Monócitos/metabolismo , Receptores de Superfície Celular/sangue , Adenina/análogos & derivados , Adenina/farmacologia , Nucleotídeos de Adenina/farmacologia , Adenosina/análogos & derivados , Adenosina-5'-(N-etilcarboxamida) , Complemento C2/antagonistas & inibidores , AMP Cíclico/sangue , Relação Dose-Resposta a Droga , Humanos , Imunossupressores/farmacologia , Monócitos/efeitos dos fármacos , Fenilisopropiladenosina/farmacologia , Receptores Purinérgicos , Tubercidina/farmacologia
7.
J Toxicol Environ Health ; 14(4): 511-23, 1984.
Artigo em Inglês | MEDLINE | ID: mdl-6096571

RESUMO

The inhalation, by grain elevator workers, of airborne grain dusts can lead to pulmonary problems. Complement, which is present in human airways, can interact with various grain dusts, producing activation products that have been shown to participate in the inflammatory reaction. Because of this apparent connection between grain-dust inhalation, complement activation, and respiratory difficulties, we are studying the reaction of an aqueous extract of spring wheat dust (swd) with human complement. The swd extract activates both the classical and alternative pathways; it acts on purified C2 to inhibit it, and it reacts with undiluted serum to consume C4 with kinetics significantly different from those shown by a "typical" antigen-antibody complex (sensitized sheep erythrocytes). Enzyme susceptibility experiments suggest that the alternative and classical pathway activators of swd extract are neither protein nor nucleic acid; periodate oxidation indicates these substances are carbohydrate, and gel filtration suggests they are macromolecular. Enzyme vulnerability also indicates that the C2 inhibitor of swd extract is ribonucleic acid. Although endotoxin is present in swd extract, a gel-filtration experiment showed that a major fraction of the complement reactivity was not associated with this substance.


Assuntos
Ativação do Complemento , Poeira/efeitos adversos , Triticum , Ativação do Complemento/efeitos dos fármacos , Complemento C2/antagonistas & inibidores , Complemento C4/antagonistas & inibidores , Proteínas do Sistema Complemento/análise , Endotoxinas/análise , Humanos , Concentração de Íons de Hidrogênio , Oxirredução , Ácido Periódico , Ribonucleases/farmacologia
8.
Clin Exp Immunol ; 41(3): 497-504, 1980 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-6108172

RESUMO

Histamine produced dose-dependent inhibition of the production of the second complement component (C2) by monocytes in tissue culture. The effect was not associated with either cell death, as ascertained by trypan blue exclusion, or loss of cells from the monolayer, as determined by measuring their DNA content. The specificity of the response was shown by the failure of histidine or histamine metabolites to inhibit C2 production. Preincubation of histamine with histaminase also abrogated the histamine effect. The kinetics of the effect were extremely rapid and irreversible, most of the reduction being achieved during a 5-min exposure to histamine. The H2 receptor antagonist cimetidine was able to prevent the histamine response, whereas chlorpheniramine, the H1 receptor antagonist, had no effect. Dimaprit and 4-methyl histamine, H2 receptor agonists, simulated the effect of histamine whereas the H1 receptor agonist 2-(2-aminoethylthiazole) was ineffective, confirming that the effect of histamine on C2 production by monocytes is mediated by the H2 receptors. Thus histamine, released from basophils or mast cells by the C3 and C5 cleavage products C3a and C5a respectively, may exert a negative feedback on further C3 and C5 cleavage by limiting the formation of the C3 (C42) and C5 (C423b) convertases.


Assuntos
Complemento C2/biossíntese , Histamina/farmacologia , Monócitos/imunologia , Células Cultivadas , Complemento C2/antagonistas & inibidores , Relação Dose-Resposta a Droga , Antagonistas dos Receptores H2 da Histamina/farmacologia , Humanos , Receptores Histamínicos H2/efeitos dos fármacos
9.
Can J Ophthalmol ; 14(3): 186-9, 1979 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-487256

RESUMO

We wished to determine if inhibitors of the complement system are present in the normal rabbit lens. Soluble less extract in various dilutions was incubated with normal human serum (as source of complement). The residual hemolytic activity was measured using sheep erythrocytes sensitized with antisheep rabbit hemolysin. The lens extract was found to contain two heat stable anticomplementary factors of different molecular weights capable of cleaving C2 and C4. Gel filtration showed that one of these factors was located in the alpha-crystalline region. It is suggested that the anticomplementary factors in the lens may be related to a natural mechanism for the modulation of complement mediated lens injury.


Assuntos
Complemento C2/antagonistas & inibidores , Complemento C4/antagonistas & inibidores , Proteínas Inativadoras do Complemento/imunologia , Cristalino/imunologia , Adulto , Animais , Reações Antígeno-Anticorpo , Autoanticorpos/imunologia , Cromatografia em Gel , Meios de Cultura , Técnicas de Cultura , Temperatura Alta , Humanos , Coelhos
10.
Pediatr Res ; 13(3): 188-93, 1979 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-572960

RESUMO

Recently a soybean oil emulsion (Intralipid) (IL) has been released in the United States for use as a parenteral nutrient. The study reported here was undertaken to determine the effect of ingestion of IL on the synthesis and secretion of the second (C2) and fourth (C4) components of complement by guinea pig peritoneal macrophages in vitro. Cells exposed to IL had extensive Oil Red 0-positive granular-appearing accumulations of neutral lipid within the cytoplasm. Control cells did not stain with Oil Red 0. Incubation of the cells with concentrations of IL from 2.3--37.5 mg/100 ml resulted in a significant decrease in the production of both C2 and C4, which could not be explained by variability between plates. The decrease in total C2 or C4 production by cells incubated with IL for 4 hr was similar to the decrease in production by cells incubated with IL for 48 hr. Several lines of evidence indicated that the decrease of C2 or C4 was the result of decreased synthesis of these proteins and not interference of IL with the detection of the proteins or their secretion from the cells. Exposure of the cells to IL at all concentrations caused reduction of the number of cells having pseudopodia and a rounding-up of the cells. IL did not affect the rate of detachment of the cells from the plates through the 48-hr incubation period or the ability of the cells to exclude trypan blue. Total protein synthesis and total lysozyme production by control and IL-treated cells was similar.


Assuntos
Complemento C2/antagonistas & inibidores , Complemento C4/antagonistas & inibidores , Emulsões Gordurosas Intravenosas/farmacologia , Macrófagos/efeitos dos fármacos , Animais , Líquido Ascítico/citologia , Colesterol/farmacologia , Complemento C2/biossíntese , Complemento C4/biossíntese , Dactinomicina/farmacologia , Feminino , Cobaias , Masculino , Glycine max
11.
Immunology ; 35(2): 369-72, 1978 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-750373

RESUMO

Human and rat alveolar macrophages produce haemolytic C2 during in vitro culture. We conclude that C2 synthetic ability is maintained during in vivo maturation of human monocytes to macrophages and that production of complement components by mature tissue macrophages may be important for optimal generation of inflammatory responses.


Assuntos
Complemento C2/biossíntese , Macrófagos/imunologia , Alvéolos Pulmonares/imunologia , Animais , Células Cultivadas , Complemento C2/antagonistas & inibidores , Cicloeximida/farmacologia , Temperatura Alta , Humanos , Ratos
13.
Pathol Biol (Paris) ; 25(2): 105-8, 1977 Feb.
Artigo em Francês | MEDLINE | ID: mdl-322041

RESUMO

The drug, pentosan-poly-sulfoester (PPS), is a potent in vitro inhibitor of the human complement hemolytic activity. This CH 50 inhibition represents a real anticomplementary activity (ACA), because this drug has no effect on sensitized sheep red blood cells (EA). The inhibition curve of human serum CH 50, by PPS is sigmoidal. The 50% inhibition is obtained for a 1: 650 dilution of PPS, which corresponds to a concentration of 0.08 mg/ml in normal human serum. Hemolytic titrations of C1, C4, C2, C3, and C5 showed a complete inhibition of C4, C2 and C3, and a partial inhibition of C1 (C1q, C1r, C1s, Ca++) and C5, by this drug. The mechanism of such functional inactivation of the different complement components is not yet elucidated.


Assuntos
Proteínas Inativadoras do Complemento , Poliéster Sulfúrico de Pentosana/farmacologia , Polissacarídeos/farmacologia , Complemento C2/antagonistas & inibidores , Complemento C3/antagonistas & inibidores , Complemento C4/antagonistas & inibidores , Hemólise/efeitos dos fármacos , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA