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Results for “complement C3 inhibitor”

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PubMed2006

Complement plays an important role in spinal cord injury and represents a therapeutic target for improving recovery following trauma.

Initiation of an inflammatory cascade following traumatic spinal cord injury (SCI) is thought to cause secondary injury and to adversely impact functional recovery, although the mechanisms involved are not well defined. We report on the dynamics of complement activation and deposition in the mouse spinal cord following traumatic injury, the role of complement in the development of SCI, and the characterization of a novel targeted complement inhibitor. Following traumatic injury, mice deficient in C3 had a significantly improved locomotor score when compared with wild-type controls, and analysis of their spinal cords revealed significantly more tissue sparing, with significantly less necrosis, demyelination, and neutrophil infiltration. Wild-type mice were also treated with CR2-Crry, a novel inhibitor of complement activation that targets to sites of C3 deposition. A single intravenous injection of CR2-Crry 1 hour after traumatic injury improved functional outcome and pathology to an extent similar to that seen in C3-deficient animals. CR2-Crry specifically targeted to the injured spinal cord in a distribution pattern corresponding to that seen for deposited C3. As immunosuppression is undesirable in patients following SCI, targeted CR2-Crry may provide appropriate bioavailability to treat SCI at a dose that does not significantly affect systemic levels of serum complement activity.

Animals↗

PubMed2003

Compstatin, a peptide inhibitor of complement, exhibits species-specific binding to complement component C3.

Although activation of complement protein C3 is essential for the generation of normal inflammatory responses against pathogens, its unregulated activation during various pathological conditions leads to host cell damage. Previously we have identified a 13-residue cyclic peptide, Compstatin, that inhibits C3 activation. In this study, we have examined the species-specificity of Compstatin. Bimolecular interaction analysis using a real-time surface plasmon resonance-based assay showed that Compstatin exhibits exclusive specificity for primate C3s and does not bind either to C3s from lower mammalian species or to two structural homologs of C3, human C4 and C5. Furthermore, it showed that although the kinetics of binding of Compstatin to non-human primate C3s were distinctly different from those to human C3, like human C3 its mechanism of binding to non-human primate C3 was biphasic and did not follow a simple 1:1 interaction, suggesting that this binding mechanism could be important for its inhibitory activity. Analysis of Ala substitution analogs of Compstatin for their inhibitory activities against mouse and rat complement suggested that the lack of binding of Compstatin to mouse and rat C3s was not a result of sterically hindered access to the binding pocket due to individual bulky side chains or the presence of charge on the Compstatin molecule. These results suggest that Compstatin's exclusive specificity for primate C3s could be exploited for the development of species-specific complement inhibitors.

Amino Acid Substitution↗

PubMed2006

The use of TP10, soluble complement receptor 1, in cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) for cardiac surgery or lung transplantation initiates a systemic inflammatory response characterized by increased vascular permeability, generalized edema, abnormal lung function and oxygenation and impaired ventricular function. This post-CPB syndrome significantly contributes to postoperative morbidity and mortality. Activation of complement during CPB is a key component that initiates and augments this process. TP10, soluble complement receptor 1, is a novel complement inhibitor that is a potent inhibitor of C3 and C5 convertases, blocking activation of the complement cascade at the nexus of all three complement pathways. Recent controlled trials in humans have demonstrated that TP10 effectively inhibits complement activation during CPB. In high-risk adult patients, TP10 decreases the incidence of mortality and myocardial infarction in males but not in females following cardiac surgery. TP10 is also well tolerated and protects vascular function in infants undergoing CPB. In addition, TP10 leads to early extubation in adult lung transplant recipients. TP10 is currently positioned for clinical development in a male-only indication of cardiac surgery on CPB.

Cardiopulmonary Bypass↗

PubMed2000

Degradation of antiproteinases, complement and fibronectin in chronic leg ulcers.

It has been proposed that excessive and uncontrolled proteolytic activity is an important pathogenetic factor for chronic wounds. Identification of molecules that either control or reflect proteolysis in wounds may prove to be useful in determining wound healing activity. In this study wound fluid was sampled under a polyurethane dressing or on hydrophilic glass filters. Multiple chronic wound fluid components were identified; viz. the previously described alpha2-macroglobulin, alpha1-antitrypsin and fibronectin, as well as "novel" wound fluid molecules such as complement factor C3, inter-alpha-inhibitor, kininogen, IgG, IgA, C-reactive protein, tetranectin, orosomucoid and ceruloplasmin. There appeared to be a highly variable degradation of alpha1-antitrypsin in the wounds; furthermore, the activation of C3 appeared to correlate with the appearance of fibronectin breakdown products. In wound fluid, inter-alpha-inhibitor was degraded. The influence of the sampling procedures was studied. It was shown that contact phase activation must be taken into account in the study of molecules (such as kininogens) activated by hydrophilic charged surfaces.

Blood Proteins↗

PubMedDate not supplied

Humoral and cellular immunity in chronic urticaria.

In chronic recurrent urticaria of months' or years' duration, it is difficult to identify the causative factor. From an immunological point of view, various authors have attempted to demonstrate alterations in levels of immunoglobulins and complement fractions. We do not know of any previous studies of cellular immunity in this disorder. Fifty-one patients with chronic urticaria were studied, 22 females and 29 males, with ages ranging from 8 to 70 years. The patients were considered to be affected by recurrent or chronic urticaria with no clear allergic etiology. In all subjects a determination was made of serum levels of immunoglobulins G, A, M and E and of the complement fractions: C1 inhibitor, C1q, C3, C4 and C5. In addition, a study of cellular immunity was carried out on these patients. The results of tests of humoral immunity in the group of chronic urticarial patients studied showed only an increase of IgM in 41.7%. No significant changes were noted among the complement fractions. The study of cellular immunity gave normal figures for total and for B and T lymphocytes. The only finding which may be worthy of is a slight decrease in active T lymphocytes. The lymphocyte transformation test also gave a normal response to PHA and overall a normal cellular immunity was shown in these patients. At present we do not consider that the increased IgM in 40 to 45% of the cases has any pathogenic diagnostic value.

Adolescent↗

PubMed1992

Peripheral edema due to increased vascular permeability: a clinical appraisal.

The release of vasoactive substances produces reversible changes of endothelial permeability with consequent edematous syndromes. We present 899 patients referred to our clinic for "non-hydrostatic non-hyponcotic" recurrent edema problems. Personal and family histories were recorded and a complete physical examination was carried out for each patient. In chronic situations laboratory tests [blood cell count, cryoglobulins, thyroid hormones, complement components (C3, C4, C1 inhibitor), total IgE, skin testing] were performed. Four subgroups of angioedema are identified for relevant clinical and etiopathogenetic differences. Seventy-three percent of patients had an urticaria-angioedema syndrome responding to antihistamine and/or corticosteroid treatment (histamine-dependent angioedema). Twenty-three percent had an angioedema related to a deficiency in C1 esterase inhibitor (complement-dependent angioedema). In a minority of patients, angioedema was due to the pharmacological effect of a drug (pharmacological angioedema) or was of a totally unknown origin (idiopathic angioedema). A generalized increase in vascular permeability was reported in 3 patients (systemic capillary leak syndrome). A brief survey of the literature is given with the review of our patients.

Adolescent↗

PubMedDate not supplied

[Effect of dietotherapy on the blood serum protein content of patients with torpid and latent recurrent rheumocarditis].

A group of 85 patients with a minimal activity of rheumatic process received the diet with a high protein content (130 to 140 g). The effect of the high protein diet was evaluated according to the time-course of changes in the content of individual blood serum proteins (albumin, prealbumin, alpha1-antitrypsin, alpha2-macroglobulin, transferrin, ceruloplasmin, orosomucoid, fibrinogen, haptoglobin, IgG, IgM, IgA, IgD, IgE, complement components: C1-inhibitor, C3, C4, C5 and C9). It was revealed that the dietetic management brought about not only the improvement of the general status and reduction of the clinical manifestations of the disease but also exerted a favourable action on the concentration of serum proteins assayed.

Adult↗

PubMed1999

Ureteral obstruction reverses glomerular proliferation in immune complex glomerulonephritis.

We investigated an effect of ureteral obstruction on a progressive immune complex glomerulonephritis in murine lupus erythematosus. Unilateral ureteral obstruction for 8 days significantly decreased the expanded glomerular mesangial area, as measured by computer-assisted morphometry (4.44 +/- 0.33 x 10(-4) mm2 to 3.60 +/- 0.34 x 10(-4) mm2, P < .05), and reduced the staining for IgG, C3, and extracellular matrix components, whereas the nephritis was exacerbated in the contralateral non-obstructed kidney. The renal concentration of prostaglandin E2 (PGE2) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) in the obstructed kidneys 8 days after obstruction significantly exceeded that of kidneys in sham-operated controls (344.2 +/- 83.9 pg/mg tissue protein vs 50.0 +/- 27.5 pg/mg tissue protein, P < .01; 71.9 +/- 11.4 pg/mg tissue protein vs 9.5 +/- 2.3 pg/mg tissue protein, P < .01), whereas thromboxane B2 (TxB2) levels were similar in the two groups (33.9 +/- 4.5 pg/mg tissue protein vs 31.3 +/- 2.6 pg/mg tissue protein). Next, an experiment was performed to evaluate the role of renal eicosanoids in the amelioration in the immune complex glomerulonephritis after ureteral obstruction. Treatment with the cyclooxygenase inhibitor indomethacin abolished the decrease in mesangial area induced by ureteral obstruction (7.7% +/- 6.9%). CV-4151, a thromboxane synthetase inhibitor, had no effect on the decrease in mesangial area (-25.8% +/- 6.8%, P < .05). We conclude that unilateral ureteral obstruction quickly decreased the mesangial expansion in immune complex glomerulonephritis, and vasodilatory eicosanoids such as PGE2 and PGI2 at least partly contribute to the amelioration of glomerular histology.

6-Ketoprostaglandin F1 alpha↗

PubMed1981

An immunofluorescence assay for complement activation by the classical pathway.

The functional integrity of classical complement pathway components was determined by an immunofluorescence (IFL) assay based on the capacity of cytoskeletal intermediate filaments (IMF) to bind C1q and to activate the complement pathway. The assay uses IMF-rich capillary endothelium of human term placentae as complement-activating substrate. IFL staining for bound C1q, C4 and C3 was demonstrated after incubation of the tissue sections with normal human sera in dilutions up to 1 : 80. Known inhibitors of C1q binding and inhibitors fo C3 convertase formation prevented binding of complement components. Eight of 100 sera from patients showed negative or reduced binding of complement whereas all of 100 control sera from healthy individuals were positive in the assay. Four negative patients' sera were studied further: 3 had markedly reduced hemolytic activity and normal levels of C3 and C4. The IFL assay for complement activation provides a simple method of evaluating complement deficiencies and of studying mechanisms and inhibitors of complement activation.

Autoantibodies↗

PubMedDate not supplied

[The immunological reactivity indices (the humoral component) in persons in contact with mycotoxin-contaminated food products].

Blood serum levels of immunoglobulins (IgG, IgA, IgM, IgD, IgE), concentration of complement components (C1-inhibitor, C3, C4, C5, C9) as well as the content of some protein fractions (transferrin, ceruloplasmin, haptoglobin, orosomucoid, alpha 1-antitrypsin, alpha 2-macroglobulin, albumin and prealbumin) in the plasma were assayed in subjects exposed (due to their occupational necessity) to food raw materials (wheat, corn, barley, combined fodder) contaminated with mycotoxins. A total of 50 subjects, who have been working from 1 to 15 years at grain-treating factories, were investigated. It has been shown that a long-term exposure to food and fodder products containing mycotoxins induces a growth of IgE level attended by a drop in IgG content, and a decrease in the concentration of the complement components C3 and C9, transferrin and orosomucoid.

Antibody Formation↗

PubMedDate not supplied

[The effect of dietotherapy on the clinico-immunological indices of rheumatoid arthritis patients].

The main requirements for the dietotherapy of rheumatoid arthritis (RA) patients have been formulated, and for the first time a pathogenetically balanced diet has been developed that produces antiinflammatory and immunocorrective effects. The effectiveness of the dietotherapy included into the combined treatment was studied in 41 patients with classic and proved RA. The authors have studied the influence of the dietotherapy on the clinical signs characterizing the activity of inflammation in the joints, and laboratory immunological parameters (IgG, IgM, IgA, IgD, the complement components: C1-inhibitor, C3, C4, C5, C9; haptoglobin, orrhozomucoid, transferrin, ceruloplasmin, alpha 1-antitrypsin, alpha 2-macroglobulin, prealbumin). The results of the study have shown that the dietotherapy is not only conducive to the improvement of the clinical picture of the disease, that permits diminishing the amount of nonsteroid antiinflammatory drugs used, but also produces a favourable effect on the RA patients' immunological state. It has been concluded that inclusion of the dietotherapy into the combined treatment of RA patients is advisable.

Adult↗

PubMed1982

Complement activation and complement control proteins in acute pancreatitis.

Serum levels of the complement proteins C3, C4, C1 inhibitor (C1 INH), factor I (C3b inactivator) and factor H (BIH) and plasma levels of cleavage products of C3 (C3c) and factor B were measured in 26 patients with acute pancreatitis. Breakdown of C3 occurred in 19 patients, as shown by a reduction in C3 level and the presence of C3c. C4 levels, however, did not fall and factor B breakdown products were not detected, thus suggesting that enzymatic cleavage of C3 occurred without significant involvement of either the early classical pathway or the alternative pathway. C1 INH and factor H both showed increases, presumably reflecting an acute phase response. Factor I showed an initial fall followed by a rise. There was no correlation between the presence or extent of C3 breakdown and the clinical condition of the patients. It is concluded that C3 cleavage in pancreatitis probably results from tryptic activity and that the measurement of complement components has no part to play in the management of the disease.

Acute Disease↗

PubMed1990

Peptide inhibitors of C3 breakdown.

We have investigated the development of substrate-based inhibitors of complement enzymes. Sequences around the scissile Arg77-Ser78 bond of C3 have been synthesized and tested as inhibitors of C3 convertase. The best inhibition was found with the tetrapeptide Ac-Arg-Ser-Asn-Leu-OH (H-576); extending this sequence in either direction reduced inhibitory activity. Preliminary experiments with peptides in which the scissile bond--CO--NH--was replaced with non-hydrolysable moieties such as--CO--CH2--(H-497) and--CH2--NH--(H-336) failed to show enhanced inhibition. One of the longer chain inhibitors H-416 containing DArg77-Ser78 was unexpectedly found to potentiate iC3 cleavage by factors I and H but did not inhibit the intact alternative pathway. The same peptide also bound to factor H. It is concluded that the binding requirements of the C3 convertase are more sophisticated than can be satisfactorily imitated simply by linear sequences around the scissile bond of C3.

Complement Activating Enzymes↗

PubMed2004

The role of complement in the antiphospholipid syndrome.

The anti-phospholipid syndrome (APS) is characterized by recurrent fetal loss, vascular thrombosis and thrombocytopenia occurring in the presence of antiphospholipid (aPL) antibodies. We hypothesized that aPL antibodies activate complement in the placenta, generating split products that mediate placental injury and lead to fetal loss and growth restriction, and that complement activation by aPL antibodies in other vascular areas causes inflammation and thrombophilia. Here we review studies in a murine model of APS in which human aPL antibodies are passively transferred into pregnant mice. Blockade of complement activation using a C3 convertase inhibitor or genetic deletion of C3 protected mice from pregnancy complications induced by aPL antibodies. These findings demonstrate that complement activation is a central mechanism in aPL antibody-induced pregnancy loss and fetal growth restriction. Although the cause of tissue injury in APS is likely to prove multifactorial, we have shown that complement activation is an absolute requirement for the most serious phenotypic outcomes, pregnancy complications and thrombosis, and, therefore, that this pathway acts upstream of other important effector mechanisms.

Abortion, Spontaneous↗

PubMed2002

A tumor-expressed inhibitor of the early but not late complement lytic pathway enhances tumor growth in a rat model of human breast cancer.

Membrane-bound complement inhibitors protect host cells from inadvertent complement attack, and complement inhibitors are often up-regulated on tumors, possibly representing a selective adaptation by tumors to escape elimination by a host antitumor immune response. Relevant in vivo studies using rodent models of human cancer have been hampered by the fact that human complement inhibitors are not effective against rodent complement. Using nude rats and MCF7 cells expressing different rat complement inhibitors, a model of human breast cancer was established to investigate the role of complement and complement inhibitors in tumor progression. Expression of rat CD59, an inhibitor of the terminal cytolytic membrane attack complex of complement, had no effect on the incidence or growth rate of MCF7 tumors. In contrast, expression of rat Crry, an inhibitor of complement activation, dramatically enhanced the tumorigenicity of MCF7 cells. The expression of rat Crry on MCF7 inhibited the in vivo deposition of complement C3 fragments that serve as opsonins for receptors on phagocytes and natural killer cells. These data provide direct in vivo evidence that an inhibitor of complement activation can facilitate tumor growth by modulating C3 deposition. These data indicate an important role for complement opsonization in promoting cell-mediated antitumor immune function, a conclusion further supported by the demonstration that expression of rat Crry, but not rat CD59, on MCF7 cells inhibits rat cell-mediated cytotoxicity in vitro. Rat complement activation on MCF7 tumors was mediated by tumor-reactive antibodies present in the serum of naïve nude rats, but there was also an IgM response to MCF7 tumors, a situation with similarities to some human cancers. These data support a hypothesis that blocking complement inhibitor function on tumor cells will not only enhance monoclonal antibody-mediated immunotherapy but may also be effective at enhancing a normally ineffective humoral immune response in the absence of administered antitumor antibody.

Animals↗

PubMed1998

Solution structure of Compstatin, a potent complement inhibitor.

The third component of complement, C3, plays a central role in activation of the classical, alternative, and lectin pathways of complement activation. Recently, we have identified a 13-residue cyclic peptide (named Compstatin) that specifically binds to C3 and inhibits complement activation. To investigate the topology and the contribution of each critical residue to the binding of Compstatin to C3, we have now determined the solution structure using 2D NMR techniques; we have also synthesized substitution analogues and used these to study the structure-function relationships involved. Finally, we have generated an ensemble of a family of solution structures of the peptide with a hybrid distance geometry-restrained simulated-annealing methodology, using distance, dihedral angle, and 3J(NH-Halpha)-coupling constant restraints. The Compstatin structure contained a type I beta-turn comprising the segment Gln5-Asp6-Trp7-Gly8. Preference for packing of the hydrophobic side chains of Val3, Val4, and Trp7 was observed. The generated structure was also analyzed for consistency using NMR parameters such as NOE connectivity patterns, 3J(NH-Halpha)-coupling constants, and chemical shifts. Analysis of Ala substitution analogues suggested that Val3, Gln5, Asp6, Trp7, and Gly8 contribute significantly to the inhibitory activity of the peptide. Substitution of Gly8 caused a 100-fold decrease in inhibitory potency. In contrast, substitution of Val4, His9, His10, and Arg11 resulted in minimal change in the activity. These findings indicate that specific side-chain interactions and the beta-turn are critical for preservation of the conformational stability of Compstatin and they might be significant for maintaining the functional activity of Compstatin.

Binding, Competitive↗

PubMed2006

Bacterial complement evasion.

The human complement system is elemental to recognize bacteria, opsonize them for handling by phagocytes, or kill them by direct lysis. However, successful bacterial pathogens have in turn evolved ingenious strategies to overcome this part of the immune system. In this review we discuss the different stages of complement activation sequentially and illustrate the immune evasion strategies that various bacteria have developed to evade each subsequent step. The focus is on bacterial proteins, either surface-bound or excreted, that block complement activation. The underlying molecular mechanism of action and the possible role in pathophysiology of bacterial infections are discussed.

Animals↗

PubMed2003

Complement components and their autoantibodies.

The purpose of the immune system is to defend the host from constantly changing microbial pathogens. Autoimmune diseases develop as a consequence of the production of antibodies and/or cells that react with self-antigens, and may recruit other effector mechanisms that result in tissue damage. Thus, in this context, autoimmunity represents an immune response to self-antigens that is sufficient to cause disease. This article is specifically devoted to autoantibodies directed against complement components.

Algorithms↗