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PubMed1978

The immunopharmacologic and anti-inflammatory properties of RMI 9563 with special reference to its effect on the complement system.

The immunopharmacology of RMI 9563 - bis[3-(diethylamino)propyl]fluoranthene-3,9-dicarboxylate dihydrochloride--has been described. The compound, when given parenterally, inhibited several cell-mediated immune responses (EAE, tuberculin skin reaction, adjuvant arthritis) in rats, enhanced IgM and IgG antibody-producing cells in mice, and displayed anti-inflammatory activity in several models (carrageenan paw edema, adjuvant arthritis, direct passive Arthus reaction--a model of inflammation that is immunologically induced and complement-dependent). RMI 9563 suppressed the activation of complement in vitro by the selective inhibition of C1 esterase.

Animals↗
PubMed1991

Comparative study of in vitro inhibition of activation of the classical and alternative pathways of human complement by the magnesium and sodium salts of the anti-inflammatory peptide N-acetyl-aspartyl-glutamic acid (NAAGA).

The inhibitory activity of the sodium salt of the anti-inflammatory peptide N-acetyl-aspartyl-glutamic acid (NAAGA) on activation of the classical and alternative pathways of human complement was compared with that of the clinically used magnesium salt of NAAGA (NAAGA-Mg). Sodium salt of NAAGA (NAAGA-Na) inhibited both pathways of activation in a dose-dependent manner at concentration ranging from 1 to 10 mM by acting on formation and/or function of the C3 convertases as shown by the inhibitory capacity of the peptide on the release of the C3 cleavage fragment C3b and C3a. NAAGA-Na was as effective as NAAGA-Mg in inhibiting classical pathway activation at concentration above 10 mM. NAAGA-Na was more effective than NAAGA-Mg in inhibiting the alternative pathway since the sodium salt did not interfere with Mg-dependent formation of the alternative pathway C3 convertase.

Animals↗
PubMed1984

Immunological variables and acute-phase reactants in patients with ankylosing spondylitis (Bechterew's syndrome) and their relatives.

Serum and EDTA blood from 120 patients with ankylosing spondylitis (Bechterew's syndrome) and serum from 138 first-degree relatives of patients and from 42 adult blood donors were investigated. Increased serum concentrations of IgA and IgG and complement factors C3 and C4 were found in total groups of HLA B27-positive male or female patients compared with controls or relatives. The men had higher serum concentration of IgA and complement factors than the women, whereas IgM concentration was higher in the women. These patterns were found in controls, in relatives and in patients. Increased concentrations of IgA and of C4 were characteristic of all patients whereas IgG and IgM and C3 concentrations were likewise elevated in patients with peripheral joint arthritis/arthropathy. Increased levels of circulating immune complexes (CIC) were associated with peripheral joint arthritis and were strongly correlated with IgG or CRP concentrations in serum. Total haemolytic complement activity in serum was negatively correlated with concentrations of CIC or CRP indicating complement activation in patients with such complexes. No differences in serum concentrations of Ig or complement factor concentrations were seen between HLA B27-positive and negative relatives with normal sacro-iliac joints or between relatives and controls. Strong mutual correlations were seen among IgG, IgM, complement factors, CRP, SAA, sedimentation rate and alpha 2-macroglobulin. When the present findings were combined with our previous results it turned out that AS, and psoriasis with or without arthropathy, and acute anterior uveitis (AAU) in combination with sacro-iliitis, may be described as IgA-related conditions and that increased serum C4 was related to sacro-iliitis in all these disorders.

Adult↗
PubMed1996

Relationship between anticomplement in seminal plasma and complement in follicular fluid associated with outcome in an in vitro fertilization program.

PURPOSE: The study was conducted to evaluate levels of anticomplement in seminal plasma and levels of complement in follicular fluid, in correlation with fertilization and pregnancy rate after in vitro fertilization and intracytoplasmic sperm injection programs. MATERIALS AND METHODS: Anticomplement levels were determined in 70 couples undergoing in vitro fertilization therapy. In 15 of these couples, complement levels were measured. Anticomplement and complement levels were also determined in an additional 21 couples (apart from the 70 couples) undergoing intracytoplasmic sperm injection treatment. RESULTS: A correlation was found between fertilization rate and anticomplement levels in the seminal plasma (r = 0.4, P < 0.01) after standard in vitro fertilization. No correlation was found in the intracytoplasmic sperm injection group, or observed between complement levels and any parameter examined in both groups. Pregnancy occurred only in those couples with an anticomplement:complement ratio below 0.49. CONCLUSIONS: Determination of anticomplement and complement levels may contribute to the assessment of a successful outcome of in vitro fertilization/intracytoplasmic sperm injection.

Complement Inactivator Proteins↗
PubMed2003

Anti-complementary activity of protostane-type triterpenes from Alismatis rhizoma.

Four protostane-type triterpenes, alisol B 23-acetate (1a), alisol C 23-acetate (2a), alisol B (3a), and alisol A 24-acetate (4a), were isolated from the rhizome of Alismatis plantago-aquatice L. var. orientale Samuelson (Alismataceae) and eleven protostane derivatives (compounds 1-11) were obtained by selective modification from alisol B 23-acetate (1a). These compounds were investigated for their anti-complement activity against the classical pathway of the complement system. Alisol B (3a) and alisol A 24-acetate (4a) exhibited anti-complement activity with IC50 values of 150 and 130 microM. Among the synthetic derivatives, the tetrahydroxylated protostane triterpene (9) showed moderate inhibitory activity with IC50 value of 97.1 microM. Introduction of an aldehyde group at C-23 (10; IC50 value, 47.7 microM) showed the most potent inhibitory effect on the complement system in vitro.

Alismataceae↗
PubMed1999

Anticomplement activities of oleanolic acid monodesmosides and bisdesmosides isolated from Tiarella polyphylla.

Seven known oleanolic acid glycosides (1-7) were isolated from the MeOH extract of Tiarella polyphylla. The structures were identified to be 3-O-(beta-D-glucopyranosyl) oleanolic acid (1), 3-O-[beta-D-glucopyranosyl-(1-->3)-beta-D-glucopyranosyl] oleanolic acid (2), 3-O-[beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranosyl] oleanolic acid (3), 3-O-[beta-D-glucopyranosyl-(1-->3)-beta-D-glucopyranosyl] oleanolic acid 28-O-beta-D-glucopyranosyl ester (4), 3-O-[beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranosyl] oleanolic acid 28-O-beta-D-glucopyranosyl ester (5), 3-O-[a-L-rhamnopyranosyl-(1-->3)-beta-D-glucuronopyranosyl] oleanolic acid (6), and 3-O-[alpha-L-rhamnopyranosyl-(1-->3)-beta-D-glucuronopyranosyl] oleanolic acid 28-O-beta-D-glucopyranosyl ester (7) on the basis of physicochemical and spectral data. These triterpene glycosides were tested for the anticomplement activity and hemolytic activity. Bisdesmosidic saponins, 4, 5, and 7, showed anticomplement activity; in contrast, monodesmosidic saponins, 1-3, and 6, showed direct hemolytic activity. Methyl esterified monodesmosidic saponins showed anticomplement activity at a low concentration and hemolytic activity at a high concentration.

Complement Inactivator Proteins↗
PubMed1999

Complement-mediated lysis of cultured osteosarcoma cell lines using chimeric mouse/human TP-1 IgG1 and IgG3 antibodies.

Osteosarcoma is the commonest malignant tumour of the bones. The presence of micrometastases at the time of primary diagnosis is associated with poor prognosis. Despite developments in surgery and aggressive chemotherapy, about 50% of the patients still succumb to the disease. Thus, there is a need to develop alternative treatment modalities. One such strategy is to use antibodies with improved effector functions. The two monoclonal antibodies, TP-1 and TP-3, recognize a tumour-associated antigen on human osteosarcoma cells. In the present study, we describe the cloning of the TP-1 variable genes, and the production of complete chimeric mouse/human monoclonal antibodies. Constructs containing the constant genes from human IgG1, IgG3 or a mutant IgG3 with a shortened hinge region, called m15, were expressed in the mouse myeloma cell line, NS0. The m15 mutant has been shown to be very potent in triggering complement-mediated lysis. Our goal was to investigate whether this mutant could overcome the complement protection on human osteosarcoma cells, which is generally present on all human cells. We found that the target cells expressed several membrane-bound complement inhibitors, and that masking of these inhibitors rendered the cells sensitive to lysis. The m15 mutant exhibited greater lytic activity than both IgG3 and IgG1, although it could not cause extensive killing of the target cells alone.

Animals↗
PubMed1998

Systemic complement depletion reduces inflammation and demyelination in adoptive transfer experimental allergic neuritis.

The effect of systemic complement depletion by cobra venom factor (CVF) was evaluated in adoptive transfer experimental allergic neuritis (AT-EAN). Spleen cells of rats immunized with a neuritogenic peptide SP26 were injected into naive rats. On days 3 and 6 after cell transfer AT-EAN rats were treated with CVF or saline intraperitoneally. AT-EAN rats treated with CVF had significantly lower scores for histological inflammation (0.25 +/- 0.25 vs 1.9 +/- 0.4, mean +/- SEM, P < 0.03) and demyelination (0.13 +/- 0.13 vs 1.6 +/- 1.4, P < 0.02) than saline-treated AT-EAN rats. Immunocytochemistry of lumbosacral nerve roots showed significantly less ED1-positive macrophages (0.5 +/- 0.3 vs 1.6 +/- 0.6, P < 0.04) and CD11bc-positive (expressing complement receptor 3 or CR3) inflammatory cells (0.6 +/- 0.4 vs 1.7 +/- 0.5, P < 0.03). Our data suggest that complement plays a crucial role in inflammatory demyelination since systemic complement depletion significantly reduces recruitment of macrophages into the nerve and subsequent macrophage-mediated demyelination.

Animals↗
PubMed2003

Effect of myasthenic immunoglobulin G on motor end-plate morphology.

This study was undertaken to clarify the role of complement in acetylcholine receptor loss and degeneration of the postsynaptic membrane in myasthenia gravis (MG). We examined the end-plate morphology in rats with passively transferred immunoglobulin G (IgG) from myasthenic patients and the effect of complement by treatment of the rats with cobra venom factor. We injected peroxidase-labeled alpha-BuTx (P-BuTx) into the extensor digitorum longus (EDL) muscle to label the motor end-plates. Three hours later, 100 mg of IgG from MG patients or healthy controls was injected into the tail vein. The EDL was removed 48 hours after the injection of IgG. The presence of macrophages and degeneration of the postsynaptic membrane were seen in 4 of 6 IgG samples from MG patients and a decrease in AChRs in the other 2 samples. These changes were reversed completely by treatment with cobra venom factor in all but one case in which the end-plates were severely degenerated. Injection of MG IgG only never induced end-plate morphology changes. The results suggest that complement has a critical role in degeneration of the postsynaptic membrane and AChR loss at the motor end-plates in the passively transferred model and probably in human MG.

Adolescent↗
PubMed2001

Ultrastructural damage of Trypanosoma cruzi epimastigotes exposed to decomplemented immune sera.

The susceptibility of Trypanosoma cruzi epimastigotes to lysis by normal or immune sera in a complement-dependent reaction has been reported, but the effects induced directly by immune serum depleted of complement remain unstudied. The aim of this work was to study the ultrastructural alterations induced in T. cruzi epimastigotes by immune mouse or rabbit sera with or without complement. A local isolate of T. cruzi (Queretaro) was used in all experiments. Immune sera were raised in both mouse and rabbit by immunization with T. cruzi epimastigote antigens. Light microscopy showed intense agglutination of epimastigotes when incubated with decomplemented mouse or rabbit immune sera. A distinctive ultrastructural feature of this agglutination pattern was the fusion of plasma membranes and a pattern of intercrossing between subpellicular microtubules. Agglutination was associated with fragmentation of nuclear membranes and swelling of cytoplasm, Golgi cisternae, endoplasmic reticulum, mitochondria and kinetoplast membranes. Agglutinated parasites also incorporated trypan blue stain. Results of [3H]-thymidine incorporation confirmed that epimastigotes exposed to specific antibodies in the absence of complement were incapable of proliferating. Ultrastructural changes observed in epimastigote micrographs incubated with decomplemented immune mouse sera were statistically significant (P<0.001) when compared with results obtained from images after incubation with decomplemented normal mouse sera.

Animals↗
PubMed1987

In vitro inhibition of the classical pathway of human complement by polymyxin B.

Polymyxin B was found to be an inhibitor of the classical pathway of the complement system. The main sites of inhibition were the interaction of EAC14 with C2 and EAC142 with C3. It also inhibited EAC1-9 formation from EAC1-3 and C5-9 though slightly less efficiently. It did not inhibit C3/C5 convertase of the alternative pathway or its formation. The inhibition of the classical pathway was reversible since hemolytic activity was almost completely restored after dialysis.

Animals↗
PubMed1986

Studies on the structure of the human C4b-binding protein gene.

Protein and cDNA sequence data have shown human C4b-binding protein to contain eight internally homologous repeat units, each approx. 61 amino acids in length. Repeat units conforming to the same consensus sequence have been found in other complement and non-complement proteins. Southern blot analysis together with isolation, characterisation and sequencing of genomic clones has allowed the study of intron/exon organisation in the human C4b-binding protein gene and the identification of a Bg/II restriction fragment length polymorphism.

Amino Acid Sequence↗