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PubMed2001

Complement activation in circulation and central nervous system after rituximab (anti-CD20) treatment of B-cell lymphoma.

Rituximab (IDEC-C2B8, Mabthera, Rituxan), a chimeric monoclonal antibody against the B-cell specific CD20-antigen, has been demonstrated to be effective in the treatment of non-Hodgkin's B-cell lymphoma (B-NHL). Previous in vitro studies have shown that direct complement-dependent cytotoxicity (CDC), ADCC and apoptosis are important in the rituximab-induced killing of lymphoma cells. It is, however, unknown whether rituximab penetrates the blood-brain barrier. Therefore, we studied rituximab levels and complement (C) activation in blood and cerebrospinal fluid (CSF) following intravenous rituximab therapy in a patient with relapsing non-Hodgkin's lymphoma with central nervous system (CNS) involvement. Longitudinal samples from blood and CSF were taken at 13 time-points during the treatment period. The results show that the C cascade becomes activated in blood during the first mAb infusion (C3a-desArg concentration rose from 55 to 138 microg/ml during the first 2 hours). After the first infusion the proportions of lymphocytes positive for the CD19- and CD20-antigens in the peripheral blood were reduced from 41% and 35%, respectively, to a level of 2% (for both). In CSF the rituximab concentration increased after successive infusions, but remained below 0.55 microg/ml (compared to a Cmax of 400 microg/ml in peripheral blood). Although a minor and delayed C activation response was seen in the CSF the treatment did not clear CD20-positive cells away from the CNS. Thus, it appears that an intact blood-brain barrier restricts the entry of rituximab into the CNS. Possible options to circumvent this would be dose escalation or intrathecal rituximab treatment.

Antibodies, Monoclonal↗
PubMed1982

Inhibition of secondary in vitro antibody responses by the third component of complement.

Purified human C3 was found to inhibit rat in vitro secondary antibody responses. Fifty percent inhibition of antibody-forming cell development occurred with C3 concentrations of 26 micrograms/ml. This decrease was not the result of a general toxicity or a shift in the antibody response kinetics. Using cell mixing experiments, we could not detect a C3-induced suppressor lymphocyte or macrophage. C3 was active when added to culture early (day 0 or 1 or during a 24-hr antigen prepulse) or late (day 3, 5, or 7)--the early addition being more suppressive. Regardless of the addition time, there was a characteristic 48- to 72-hr lag before the inhibitory effect was manifested. C3 could inhibit antibody-forming cell development after stimulation with the thymus-independent antigens, trinitrophenyl-Brucella abortus and dinitrophenyl-Ficoll, as well as the thymus-dependent antigens, dinitrophenyl-bovine gamma-globulin and chicken gamma-globulin suggesting that C3 was not selective for B memory cell subpopulations. Further characterization of our C3 preparation indicated that the majority of the suppressive activity resided in a small m.w. protein resembling the C3a fragment of C3. Human C3a preparations generated either by trypsin cleavage or zymosan activation of C3 were also tested in our antibody response system and were able to inhibit antibody-forming cell development. These data implicate C3 cleavage products as negative regulators of antibody formation.

Anaphylatoxins↗
PubMed2001

Complement and its implications in cardiac ischemia/reperfusion: strategies to inhibit complement.

Although reperfusion of the ischemic myocardium is an absolute necessity to salvage tissue from eventual death, it is also associated with pathologic changes that represent either an acceleration of processes initiated during ischemia or new pathophysiological changes that were initiated after reperfusion. This so-called "reperfusion injury" is accompanied by a marked inflammatory reaction, which contributes to tissue injury. In addition to the well known role of oxygen free radicals and white blood cells, activation of the complement system probably represents one of the major contributors of the inflammatory reaction upon reperfusion. The complement may be activated through three different pathways: the classical, the alternative, and the lectin pathway. During reperfusion, complement may be activated by exposure to intracellular components such as mitochondrial membranes or intermediate filaments. Two elements of the activated complement contribute directly or indirectly to damages: anaphylatoxins (C3a and C5a) and the membrane attack complex (MAC). C5a, the most potent chemotactic anaphylatoxin, may attract neutrophils to the site of inflammation, leading to superoxide production, while MAC is deposited over endothelial cells and smooth vessel cells, leading to cell injury. Experimental evidence suggests that tissue salvage may be achieved by inhibition of the complement pathway. As the complement is composed of a cascade of proteins, it provides numerous sites for pharmacological interventions during acute myocardial infarction. Although various strategies aimed at modulating the complement system have been tested, the ideal approach probably consists of maintaining the activity of C3 (a central protein of the complement cascade) and inhibiting the later events implicated in ischemia/reperfusion and also in targeting inhibition in a tissue-specific manner.

Complement Activation↗
PubMed1998

Mechanisms of severe, immediate reactions to iodinated contrast material.

PURPOSE: To measure and elucidate the mechanisms of presumed mediators of unexpected severe, immediate reactions to iodinated contrast materials. MATERIALS AND METHODS: In a multicenter study, 20 patients with mild to severe reactions to iodinated contrast material and 20 control subjects without reactions were evaluated. Ionic contrast material was associated with 18 (90%) of 20 reactions. Concentrations of plasma histamine, tryptase, urinary methylhistamine, specific immunoglobulin E (IgE) against ioxitalamate or ioxaglate, and the anaphylatoxins C3a and C4a were measured with radioimmunoassays; complement C3 and C4 levels were measured with nephelometry. RESULTS: Histamine levels were increased in 14 patients; tryptase levels, in 16; and methylhistamine levels, in six. Histamine and tryptase values correlated with the severity of the reaction (P < .02 and P < .004, respectively). Significantly higher levels of specific IgE against ioxaglate (P < .005) and ioxitalamate (P = .045) were found in patients. No differences were found for complement fractions. Skin test results in two patients with life-threatening reactions were positive for the administered contrast material. CONCLUSION: Histamine release and mast cell triggering are related to severe reactions. An IgE-related mechanism is strongly suspected. Radiologists should be trained to identify and treat anaphylactic shock in patients who react to iodinated contrast material.

Adult↗
PubMed2004

Cloning, expression, cellular distribution, and role in chemotaxis of a C5a receptor in rainbow trout: the first identification of a C5a receptor in a nonmammalian species.

C3a, C4a, and C5a anaphylatoxins generated during complement activation play a key role in inflammation. C5a is the most potent of the three anaphylatoxins in eliciting biological responses. The effects of C5a are mediated by its binding to C5a receptor (C5aR, CD88). To date, C5aR has only been identified and cloned in mammalian species, and its evolutionary history remains ill-defined. To gain insights into the evolution, conserved structural domains, and functions of C5aR, we have cloned and characterized a C5aR in rainbow trout, a teleost fish. The isolated cDNA encoded a 350-aa protein that showed the highest sequence similarity to C5aR from other species. Genomic analysis revealed the presence of one continuous exon encoding the entire open reading frame. Northern blot analysis showed significant expression of the trout C5a receptor (TC5aR) message in PBLs and kidney. Flow cytometric analysis showed that two Abs generated against two different areas of the extracellular N-terminal region of TC5aR positively stained the same leukocyte populations from PBLs. B lymphocytes and granulocytes comprised the majority of cells recognized by the anti-TC5aR. More importantly, these Abs inhibited chemotaxis of PBLs toward a chemoattractant fraction purified from complement-activated trout serum. Our data suggest that the split between C5aR and C3aR from a common ancestral molecule occurred before the emergence of teleost fish. Moreover, we demonstrate that the overall structure of C5aR as well as its role in chemotaxis have remained conserved for >300 million years.

Amino Acid Sequence↗
PubMed1976

Modulation of human eosinophil polymorphonuclear leukocyte migration and function.

Eosinophil migration toward a concentration gradient of a chemotactic factor is regulated at four levels. Diverse immunologic pathways generate stimuli with eosinophil chemotactic activity, including the complement products C5a and a fragment of C3a and the peptide products of mast cells and basophils activated by IgE-mediated reactions, such as eosinophil chemotactic factor of anaphylaxis (ECF-A) and other oligopeptides. The intrinsic preferential leukocyte activity of the chemotactic stimuli represents the second level of modulation, with ECF-A and other mast cell-derived peptides exhibiting the most selective action on eosinophils. The third level of control of eosinophil chemotaxis is composed of inactivators and inhibitors of chemotactic stimuli and is exemplified by degradation of C5a by anaphylatoxin inactivator or chemotactic factor inactivator and of ECF-A by carboxypeptidase-A or aminopeptidases. The activity of ECF-A is uniquely suppressed by equimolar quantities of its NH2- terminal tripeptide substituent, presumably by eosinophil membrane receptor competition. Factors comprising the fourth level of regulation, which alter eosinophil responsiveness to chemotactic stimuli, include the chemotactic factors themselves, through deactivation; nonchemotactic inhibitors such as the COOH-terminal tripeptide substituent of ECF-A, the neutrophil-immobilizing factor (NIF), the phagocytosis-enhancing factor Thr-Lys-Pro-Arg, and histamine at concentrations greater than 400 ng/ml; and nonchemotactic enhancing principles represented by ascorbate and by histamine at concentrations of 30 ng/ml or less. Local concentrations of eosinophils called to and immobilized at the site of a hypersenitivity reaction may express their regulatory functions by degrading the chemical mediators elaborated including histamine, slow-reacting substance of anaphylaxis (SRS-A), and platelet-activating factor (PAF) by way of their content of histaminase, arylsulfatase B, and phospholipase D, respectively. Immunologic pathways may thus provide the capability for early and specific host defense reactions with a later influx of eosinophils preventing irreversible local tissue alterations or distant organ effects.

Anaphylaxis↗
PubMed1993

Neutrophil adhesion molecule expression during cardiopulmonary bypass with bubble and membrane oxygenators.

The neutrophil-mediated tissue injury associated with cardiopulmonary bypass (CPB) is thought to require the interaction of specific neutrophil and endothelial adhesion molecules. In this study, the effects of CPB on the expression of neutrophil CD11b and CD18 (the components of the Mac-1 adhesion molecule) were examined; the effects of membrane versus bubble oxygenators on the expression of neutrophil CD11b and CD18 were compared; and the plasma levels of the intercellular adhesion molecule-1 (cICAM-1), an inducible endothelial adhesion molecule, were measured. In addition, the time courses of complement activation and neutrophil granule release were measured to determine their temporal relationship to the expression of the neutrophil adhesion molecule. Fifteen adult patients underwent procedures requiring cardiopulmonary bypass; hollow-fiber membrane oxygenators were used in 8 (group M) and bubble oxygenators were used in 7 (group B). Blood samples were drawn before, during, and after CPB for determination of the expression of neutrophil CD11b and CD18 (immunofluorescent flow cytometry), and the plasma cICAM-1, elastase, lactoferrin (enzyme-linked immunoabsorbent assay), and plasma C3a (radioimmunoassay) levels. CPB caused an immediate and sustained increase in the neutrophil CD11b and CD18 expression in both groups; after 60 minutes of CPB, CD11b expression had increased by 116.9% +/- 19.1% in group B and by 79.3% +/- 8.5% in group M (p = 0.78). Over the same period, CD18 expression increased by 97.2% +/- 17.9% in group B and by 72.4% +/- 16.8% in group M (p = 0.67).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1998

Complement and contact activation during cardiovascular operations in infants.

BACKGROUND: By comparing the results of cardiac operations with or without cardiopulmonary bypass (CPB) in infants in a prospective study, we sought to determine which part of the postoperative systemic inflammatory response was caused by CPB. METHODS: Thirty-five patients were divided into two groups: 11 infants operated on without CPB and 24 infants operated on with CPB. Blood samples were drawn before, during, and after the operation. We assessed complement function and the concentrations or activities of C1q, C3, C4, C1 inhibitor, factor B, the activated split product C3a, and prekallikrein and factor XIIa of the contact system. RESULTS: All of the patients exhibited a decrease of complement proteins. This was greater in infants who underwent CPB. A increase in C3a and factor XIIa and changes in prekallikrein activity occurred only in infants during CPB. CONCLUSIONS: Complement activation occurs in all infants, but is significantly higher in the group with CPB. Contact activation only occurs in patients who undergo CPB. Thus, the inflammatory response is caused by the use of a CPB circuit and to a lesser degree by surgical procedures and anesthesia.

Cardiac Surgical Procedures↗
PubMed1997

A flow cytometric immunoassay to quantify adsorption of complement activation products (iC3b, C3d, SC5b-9) on artificial surfaces.

Crosslinked agarose microspheres and various polystyrene microspheres were analyzed for complement components after incubation with serum at 37 degrees C for times up to 2 h. Quantification involved direct flow cytometric analysis of the beads after the bound complement proteins were indirectly fluorescently tagged by use of a monoclonal antibody against a complement protein: C5b-9, iC3b, C3d, C4d, Bb, C3a, and C1q. Calibration with fluorescein microbead standards demonstrated that the membrane attack complex (SC5b-9) was surface bound on all surfaces and that the surface concentration gradually increased to levels as high as 0.5 micrograms/cm2. Further, the surface bound represented a substantial percentage of the total generated. The iC3b level on polystyrene beads rapidly reached 0.09 micrograms/cm2 and the C3d levels were an order of magnitude less. On agarose beads the iC3b levels continually rose to 0.17 micrograms/cm2 and, as before, the C3d levels were substantially lower. The surface concentration of C4d and Bb on both surfaces were significant but less than 1.0 ng/cm2. There was minimal evidence of C3a and C1q adsorption for any surface. Use of amino-polystyrene beads moderately reduced the level of bound iC3b, C3d, and SC5b-9, whereas carboxylated beads reduced the levels by almost a factor of two. The appreciable amounts of iC3b and SC5b-9 consistently noted on the artificial surfaces tested in this paper suggests that for these two activation products in vitro analysis of material induced complement activation should also include surface analysis.

Adsorption↗
PubMed2004

C1-inhibitor reduces hepatic leukocyte-endothelial interaction and the expression of VCAM-1 in LPS-induced sepsis in the rat.

INTRODUCTION: Increased leukocyte-endothelial interaction (LEI) leading to hepatic microperfusion disorders is proposed as major contributor for hepatic failure during sepsis. Recently it has been demonstrated that complement inhibition by C1-inhibitor (C1-INH) is an effective treatment against microcirculatory disturbances in various diseases. The purpose of this study was to investigate the influence of C1-INH on microcirculation and LEI in the liver in a rat model of sepsis. MATERIALS AND METHODS: Rats received lipopolysaccharides (LPS) from Escherichia coli intravenously. Controls received Ringer solution only. Ninety minutes after LPS infusion some animals were treated with C1-INH intravenously (LPS + C1-INH). Others (LPS + SC) and controls (Ringer + SC) received sodium chloride (SC). Hepatic LEI and mean erythrocyte velocity (MEV) were quantified by intravital microscopy (IVM) 90 min after LPS or Ringer infusion (0) and 30, 60, 90 and 120 min following treatment. VCAM-1 m-RNA in hepatic tissue, C3a, TNF-alpha and hepatic enzyme liberation in blood was analysed. RESULTS: Leukocyte sticking to the endothelial wall in postsinusoidal venules was significantly reduced in the LPS + C1-INH vs. the LPS + SC group 30, 60, 90 and 120 min after treatment. VCAM-1 m-RNA expression in the hepatic tissue was markedly and C3a levels in plasma were significantly reduced in the LPS + C1-INH vs. the LPS + SC group. No differences in TNF-alpha levels were detected between these two groups. MEV was improved in the LPS + C1-INH vs. the LPS + SC group. CONCLUSIONS: Our results indicate that even upon delayed treatment hepatic adhesion molecule expression and LEI can be reduced by C1-INH. The multifunctional regulator may reduce hepatic microcirculatory disturbances during sepsis under clinical conditions.

Animals↗
PubMed1994

Complement activation on solid surfaces as determined by C3 deposition and hemolytic consumption.

Complement activation was investigated on hydrophilic and hydrophobic glass beads incubated in serum. Very little complement activation was detected with these surfaces, as indicated by a hemolytic assay and by measurement of the amount of iC3b appearing in the solution. However, preadsorption with IgG at the hydrophobic and hydrophilic beads resulted in complement activation on both surfaces. We also investigated dependent deposition of C3 at hydrophobic and hydrophilic silicon surfaces when the complement was activated. The chemistry of those surfaces is similar to the hydrophobic and hydrophilic beads. Ellipsometry, an optical method, was used for determination of the amounts of organic material deposited at the surface. C3 deposition was observed at the IgG precoated hydrophobic surface but not at the IgG-coated hydrophilic surface. The absence of C3 deposition at the hydrophilic surface was probably due to reversible binding of IgG. However, precoating of the hydrophilic surface with a double layer of IgG and anti-IgG resulted in C3 deposition also at the hydrophilic surface. The results illustrate that methods based on measuring deposition of C3 at surfaces, such as immunofluorescence or ellipsometry, cannot exclude surface-associated complement activation that is probably due to reversible binding of the complement components of the activated molecule. On the other hand, it has previously been shown that determination of complement activation in solution with the use of a C3a assay cannot exclude surface-associated activation due to immobilization of C3a at the surface. This methodologic question is an important issue because factors such as C3a and C5a act as soluble anaphylatoxins, whereas deposited factors such as C3 act as cellular receptors.

Adsorption↗
PubMed1998

Complement activation by cellulose: investigation of the effects of time, area, flow rate, shear rate and temperature on C3a generation in vitro, using a parallel plate flow cell.

The development and utilization of a parallel plate flow system to study the blood response to flat sheet biomaterials, is described. Unlike most other parallel plate flow systems, which have been used to study cellular interactions with biomaterials, the controlled flow test cell described below employs the test materials on both sides of the channel through which the blood flows. The flow cell is used to conduct an investigation into the in vitro generation of C3a by a regenerated cellulose membrane, Cuprophan. The effects of experimental variables such as temperature, blood flow rate, contact area and wall shear rate on C3a generation by Cuprophan were studied. The results show that C3a generation by Cuprophan is lower at 12 degrees C than at 22 degrees C, which is in turn lower than C3a generation at 37 degrees C. Furthermore, a decrease in contact area, and increase in wall shear rate and blood flow rate, can produce a decrease in C3a concentration.

Journal Article↗
PubMed2003

Structure-function studies of the C3a-receptor: C-terminal serine and threonine residues which influence receptor internalization and signaling.

The anaphylatoxic peptide C3a is a pro-inflammatory mediator generated during complement activation, whose specific G protein coupled receptor is expressed on granulocytes, monocytes, mast cells, activated lymphocytes, and in the nervous tissue. We have generated RBL-2H3 cell clones stably expressing mutants of the human C3a-receptor (C3aR) with combined alanine (Ala) substitutions of ten C-terminal serine (Ser) or threonine (Thr) residues, which may represent putative phosphorylation sites to characterize their role in ligand-induced C3aR internalization and signaling. Ser475/479 and Thr480/481 as well as Ser449 seemed not to be involved in ligand-induced receptor internalization. Either directly or by a conformational change they even "inhibit" C3aR internalization. In contrast, mutants with Ala substitutions at Ser465/470 and Thr463/466 were poorly internalized, and Thr463 seemed to be the most important C-terminal Thr or Ser residue directly effecting receptor internalization. However, it is likely that other C3aR regions additionally participate in this negative feed-back mechanism since even mutants with multiple Ala substitutions still internalized to a limited degree. Interestingly, in a mutant with a single exchange of Ser449 to Ala, the signal transduction assessed by a Ca(2+) assay and [(35)S]GTP gamma S-binding on HEK cells transiently co-transfected with G-alpha 16 or G-alpha O, respectively, was severely impaired, indicating that this residue of C3aR is involved in G protein coupling.

Animals↗
PubMed1994

Effect of thrombosis on complement activation and neutrophil degranulation during in vitro hemodialysis.

Coagulation proteins are known to affect the complement system and neutrophils. To assess the influence of thrombosis on complement and neutrophils during hemodialysis, whole human blood obtained from normal donors and anticoagulated with either 0.8 or 2.0 U/mL of heparin was recirculated for 4 h through cellulose acetate hollow fibers in vitro. Plasma fibrinopeptide A (FPA) levels were measured to assess thrombosis, whereas the activation of the complement system was evaluated at various stages by determining plasma C3a(desArg), C5a(desArg), and SC5b-9 concentrations. The activation of circulating neutrophils was assessed by quantitation of the extracellular release of the intragranular proteins elastase and lactoferrin. Thrombosis was observed when 0.8 U/mL of heparin was used, as indicated by a 36-fold increase in (FPA) levels at 240 min of recirculation and occasional grossly visible blood clots. In contrast, no increase in FPA or clot formation was observed with 2.0 U/mL of heparin. The higher dose of heparin was also associated with a lesser increase in plasma C3a(desArg) and C5a(desArg) concentrations, an observation that is compatible with either an inhibitory effect of heparin or a stimulatory effect of coagulation on the complement system. Plasma elastase or lactoferrin concentrations increased during hemodialysis but were not dependent on heparin dosage at any time. It was concluded that anticoagulation with higher heparin concentration inhibits complement activation in the hemodialysis circuit, but it does not affect neutrophil degranulation.

Anticoagulants↗
PubMed2005

New insights into the role of the complement pathway in allergy and asthma.

Despite extensive inquiry, the mechanisms underlying the pathophysiology of allergic diseases remain unknown. Recently, there has been a resurgence of interest in the role of the innate immune mediators of the complement pathway in asthma pathogenesis, particularly the anaphylatoxins (C3a, C5a). The emerging paradigm is that C3a production at the airway surface serves as a common pathway for the induction of airway hyperresponsiveness to a variety of asthma triggers (ie, allergens, viral infections, particulate matter, ozone, smoke), whereas C5/C5a plays a dual immunoregulatory role by protecting against Th2-mediated immune responses during initiation of responses and a proinflammatory role once immune responses are established. Support for a causal role for altered anaphylatoxin production in human disease comes from reports of exaggerated complement production in the lungs of asthmatics as well as the association of asthma with polymorphisms in C3/C3aR genes. Herein, we explore our current understanding of the role of complement activation in asthma pathogenesis and highlight the potential of targeting complement pathways for therapeutic drug development.

Animals↗
PubMed1996

A phase II study of interferon-alpha, interleukin-2 and 5-fluorouracil in advanced renal carcinoma: clinical data and laboratory evidence of protease activation.

OBJECTIVE: To confirm the activity and evaluate the toxicity of the combination of subcutaneous interferon-alpha (IFN-alpha) and interleukin-2 (IL-2) with intravenous 5-fluorouracil (5-FU) in patients with advanced and recurrent renal carcinoma and of performance status 0-2. Additionally, to examine protease, complement and neutrophil activation as potential mediators of IL-2 toxicity. PATIENTS AND METHODS: Fifty-five patients were treated in an 8-week cycle with IFN-alpha (6 MU/m2 on day 1 in weeks 1 and 4 and thrice weekly in weeks 2-3, and 9 MU/m2 thrice weekly in weeks 5-8) IL-2 (20 MU/m2 on days 3-5 in weeks 1 and 4 and 5 MU/m2 thrice weekly in weeks 2-3) and 5-FU (750 mg/m2 on day 1 of weeks 5-8). Patients responding to the first cycle were eligible to continue with further cycles. Toxicity and effects on quality of life were assessed using World Health Organization criteria and the Rotterdam Symptom Checklist and Hospital Anxiety and Depression Scale. Serum levels of C3a, prekallikrein and elastase-alpha 1 proteinase inhibitor (elastase-alpha 1-antitrypsin) were assayed in a subset of patients before, during and after the administration of high-dose IL-2 in week 1. RESULTS: There were partial remissions in nine patients, with responses in 24% (95% CI 10-38%) of evaluable patients and 16% of all patients. Amongst 25 evaluable patients who had undergone nephrectomy, the response rate was 32% (95% CI 14-50%), whereas there was only one response amongst 22 patients who had not undergone nephrectomy. The median survival for patients with stable disease or partial remission exceeded 22 months. Outcome and survival were related to performance status, number of sites of metastases and nephrectomy. This group of patients was of relatively poor performance status and 18 patients (36%) failed to complete one 8-week treatment cycle. Cardiovascular and renal toxicities were less than those seen with intravenous IL-2 schedules but 44% of patients experienced at least one grade III toxicity and only 14% reported less than two grade II toxicities. Plasma levels of elastase-alpha 1 proteinase inhibitor exceeded the normal range in three of seven patients tested before treatment and increased in all seven patients after treatment with IL-2. The same three patients had raised levels of C3a before treatment and in all patients examined, C3a increased after treatment with IL-2. In contrast, plasma prekallikrein concentrations were below normal before treatment and decreased further afterwards. CONCLUSIONS: This study confirms the activity of this regimen in patients of good performance status, with limited sites of disease and in those who are fit for nephrectomy, but also showed that treatment was associated with considerable toxicity. The administration of IL-2 is associated with protease activation which may be a suitable target for pharmacological intervention in attempts to ameliorate toxicity.

Adult↗
PubMed1998

Removal of cytokines and activated complement components in an experimental model of continuous plasma filtration coupled with sorbent adsorption.

BACKGROUND: Sepsis is associated with enhanced cytokine production. Here, we examined the in vitro removal of plasma cytokines during continuous plasmafiltration coupled with sorbent adsorption. METHODS: Proinflammatory (tumour necrosis factor-alpha, interleukins-1, -8) and anti-inflammatory (interleukin 1 receptor antagonist, soluble tumour necrosis factor receptor type I and II) cytokines in whole blood spiked with Escherichia coli endotoxin were determined during 2-h recirculation in the ultrafiltrate (condition A), plasma filtrate (condition B), before and after different sorbents (of the Amberlite-, Amberchrome- Ambersorb -type and charcoal). We studied the maximal adsorbing capacity, the 1% leakage test for cytokines and C3a des Arg and the adsorption of complement-dependent leukocyte chemiluminescence. Plasma proteins eluted from the resins were examined by sodium dodecyl sulphate polyacrylamide gel electrophoresis and immunoblotting with an anti-human alpha2-macroglobulin. RESULTS: In condition B, we observed a 40- and 121-fold % increase (vs condition A) in the removed mass and clearance of tumour necrosis factor-alpha. For all other cytokines, the removed mass and the clearance increased from 2.3- up to 6-fold. The Amberchrome but not the Amberlite or Ambersorb resins could remove the highest amount of cytokines and could reduce complement-dependent chemiluminescence. Two protein bands of approximately 400,000 D and 200,000 D were eluted only from Amberchrome resins and immunoprecipitated by anti-human alpha2-macroglobulin and anti-human C3c antibodies, respectively. CONCLUSIONS: These studies suggest an efficient removal of cytokines in continuous plasmafiltration with sorbent adsorption. The binding of alpha2-macroglobulin, a carrier of cytokines in plasma, might be a additional mechanism in the removal of cytokines from plasma.

Adsorption↗
PubMedDate not supplied

Protein distribution across the human atherosclerotic wall with reference to immunoglobulins and complement components.

The concentrations of IgG, IgA, IgM, Clq, C3c, C4, C9, C3A, Albumin, Transferrin, Alpha-1-antitrypsin, Alpha-2-macroglobulin were determined in the serum, aortic atherosclerotic intima and media of 8 patients. The protein levels in the intima were dependent on their serum concentration. The passage of proteins from serum to media was investigated using the ratios between their intima/serum and media/intima concentrations. Immunoglobulins and complement components displayed higher intima/serum and lower media/intima ratios than the other proteins suggesting a preferential retention of the immune related proteins in the intima. This trapping into the intima seems to be related to their function too, suggesting a certain involvement in the progression of the atherosclerotic lesions.

Aged↗