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T E Mollnes

Publications and source records attributed to T E Mollnes.

At least 37 records · Page 2Linked to original sources
PubMed2001

Increased systemic activation of neutrophils but not complement in preeclampsia.

OBJECTIVE: To investigate whether neutrophils and systemic complement are activated in pregnancies complicated by preeclampsia more than in normal pregnancies. METHODS: We measured native complement components and activation products in plasma by enzyme immunoassays in 19 women with uncomplicated pregnancies, 15 with preeclampsia before cesarean deliveries, and 16 nonpregnant women. Neutrophil activation was measured by specific enzyme immunoassays for myeloperoxidase and lactoferrin. RESULTS: Myeloperoxidase was significantly higher in women with preeclampsia (197 microg/L, 95% confidence interval [CI] 94, 646) than in women with uncomplicated pregnancies (124 microg/L, 95% CI 70, 289; P =.009), whereas lactoferrin did not differ between groups. C4 was decreased in preeclamptic women (0.16 g/L, 95% CI 0.07, 0.48) compared with women with uncomplicated pregnancies (0.21, 95% CI 0.10, 0.30, P <.001). There were no differences for the other native complement components. There was a significant decrease in C1rs-C1 inhibitor, 13 AU/mL (95% CI 9, 34) versus 19 (95% CI 13, 38) (P < or =.001) in normal pregnant women compared with nonpregnant women. There also was an increase in C3, C4, C9 (data not shown), C4bp, 132% (95% CI 94%, 161%) versus 91% (95% CI 57%, 128%); C3bc (7.4 AU/mL, 95% CI 4.2, 10.7) versus 4.8 AU/mL (95% CI 3.2, 7.3) and C4bc (8.6 AU/mL, 95% CI 5.7, 14.0) versus 3.5 AU/mL (95% CI 2.2, 6.7) in normal pregnant women compared with nonpregnant women (P < or =.001). CONCLUSION: Neutrophil activation in preeclampsia was shown by systemic increases in myeloperoxidase. Except for a decrease in C4, systemic complement activation could not be detected in preeclampsia.

Adult↗
PubMed2001

Veno-venous bypass in liver transplantation: heparin-coated perfusion circuits reduce the activation of humoral defense systems in an in vitro model.

We studied the effects of bypass circuit surface heparinization on kallikrein-kinin, coagulation, fibrinolytic and complement activation in a closed model system for simulating veno-venous bypass (WBP) in orthotopic liver transplantation (OLT). The circuits were identical to those in routine use during clinical OLT in our institution. Fresh whole human blood diluted 1:2 with Ringer's acetate was circulated at a non-pulsatile flow (2 l/min) and at a constant temperature (37.5 degrees C) for 12 h. In 10 experiments, the entire inner surface of the circuits was coated with end-point attached heparin (HC). In the remaining 10, non-treated PVC tubing was used (NC). Components of the plasma kallikrein-kinin, coagulation, fibrinolytic and complement systems were analyzed using functional techniques (chromogenic peptide substrate assays) and enzyme immunoassays at baseline, 3 and 12 h. Significant activation of the initial (C3bc) and terminal (TCC) components of the complement system were found in both the NC and HC groups after 3 and 12 h: C3bc: NC: baseline = 4 (3.5-7.7), 3 h = 17.3* (12.5-27), 12h = 31* (17.7-63.6), HC: baseline = 4.9 (3.2-6.8), 3h = 9* (6-14.4), 12h = 13.7* (7.4-18.1). TCC: NC: baseline = 0.4 (0.2-0.6), 3h = 5*(0.8-11.9), 12 h: 13.1* (4.2-25.7). HC: baseline = 0.5 (0.1-0.6), 3 h = 0.6* (0.1-0.8), 12 h = 1.2* (0.3-2) AU/ml; median and range (*: p < 0.05). The C3bc and TCC concentrations were significantly higher in the NC group at 3 and 12 h, compared to the HC group: C3bc (NC vs. HC group): 3 h, p < 0.001; 12 h, p < 0.001. TCC (NC vs. HC group): 3h, p < 0.001; 12 h, p < 0.001. Significant increases in the values of thrombin-antithrombin complexes (p = 0.003), prothrombin fragment 1 + 2 (p = 0.006) and plasmin-alpha2-antiplasmin complexes (p = 0.016) were found in the non-coated group, but not in the heparin-coated group during the observation period, showing that the coagulation and fibrinolytic systems were activated in the non-coated circuits. We conclude that heparin-coating of the internal surface of the extracorporeal perfusion circuit used for WBP reduces activation of the plasma cascade systems in a closed venous system in vitro.

Blood Coagulation Factors↗
PubMed2001

C1-inhibitor: an anti-inflammatory reagent with therapeutic potential.

Excessive activation of the protein cascade systems often leads to severe inflammatory tissue destruction with potential life-threatening outcome. These include clinical disorders, such as capillary leak syndrome, septic shock, myocardial infarction and other ischaemia/reperfusion injuries, trauma, burns, multiple organ failure, as well as graft rejection. A therapeutic substitution of appropriate regulators appears to be a reasonable approach to reduce undesirable inflammatory reactions. C1-inhibitor, a multifunctional regulator of the various kinin-generating cascade systems, is frequently reduced in patients suffering from severe inflammation. C1-inhibitor concentrate has been used for decades as a substitution therapy to treat acute attacks in patients with hereditary angioedema. Studies including pathophysiologically relevant animal models now provide sufficient evidence that C1-inhibitor may also serve as an effective means to protect against inflammatory tissue injury. Promising clinical results are emerging which support C1-inhibitor as a candidate for therapy in severe inflammatory disorders. Although treatment with C1-inhibitor is regarded as safe, recent reports on possible side effects in certain clinical situations emphasise the importance of controlled clinical studies. The following review will focus on the impact of C1-inhibitor treatment on diseases, where complement contributes to the pathogenesis.

Animals↗
PubMed2000

A novel enzyme immunoassay for plasma thrombospondin. Comparison with beta-thromboglobulin as platelet activation marker in vitro and in vivo.

A novel enzyme immunoassay for plasma thrombospondin (TSP) based on commercially available monoclonal antibodies was established. The following conditions for correct collection and preservation of blood samples were required: venipuncture directly into a vacutainer containing citrate, theophylline, adenosine and dipyridamole, storage on ice, and separation of plasma within 30 minutes. Thereafter, the plasma TSP concentration remained constant at room temperature and after five times of freezing and thawing. Both inter- and intraassay variation coefficients were 5%. The lower detection limit was 20 microg/L. Median TSP concentration among 40 healthy blood donors was 43 microg/L, slightly lower than previously published. The assay is valid, reliable, and has certain advantages compared with previously published methods. TSP and beta-thromboglobulin (BTG) were then compared as platelet activation and biocompatibility markers in vivo: 23 patients undergoing cardiopulmonary bypass (CPB); and in vitro: effect of coating polyvinyl chloride with heparin. The kinetic patterns of TSP and BTG were markedly different in vivo but virtually identical in vitro, explained by different in vivo clearance mechanisms during CPB. We conclude that BTG is superior to TSP for evaluation of platelet activation during in vivo CPB, whereas TSP and BTG are virtually identical as markers in vitro.

Antibodies, Monoclonal↗
PubMed2000

Pig endogenous retrovirus--a threat to clinical xenotransplantation?

Transplantation shows good results for patients with end-stage disease, but there is an increasing lack of organs. Xenotransplantation, the transfer of live animal cells, tissues, or organs to another species, offers a potential solution to this shortfall. Pig is regarded as the animal of choice for this purpose. Meanwhile demonstration of pig endogenous retrovirus (PERV) in all porcine herds has caused serious concern with respect to a possible transmission of the virus to humans with a transplanted organ. Transmission to human cells has been documented under certain in vitro conditions. However, no such transmission has been demonstrated in vivo. The possible consequences of introducing PERV into immunocompromised human organisms are not known and it is necessary to collect more information. Novel and sensitive genomic assays to detect PERV infection are now available in addition to established virological, immunoserological and molecular methods. In order to minimise the risk of PERV transmission rigorous procedures should be established. International guidelines to reduce the risk should be followed. Although a number of immunological, physiological and virological questions need to be answered before the introduction of xenotransplantation as an alternative clinical treatment, some problems can only be solved by judicious clinical trials.

Animals↗
PubMed2000

The inflammatory response following treatment of abdominal aortic aneurysms: a comparison between open surgery and endovascular repair.

OBJECTIVES: to compare the inflammatory response following endovascular and conventional AAA repair. DESIGN: prospective study. PATIENTS AND METHODS: ten patients were selected for open surgery (OPEN) and ten for endovascular (ENDO) AAA repair. Leukocytes, platelets, myeloperoxidase, lactoferrin, beta-thromboglobulin, C-reactive protein (CRP), interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-alpha) and complement activation products were measured before, during and after surgery. RESULTS: in the OPEN group the median hospital stay was longer (6 vs. 12 days, p=0.001) and more patients required transfusion (p=0.02). IL-6 and CRP increased postoperatively, most in OPEN (p<0.01). Platelet counts decreased after the first angiography in ENDO (p<0.01) and before aortic cross-clamping in OPEN (p<0.05). The decrease was larger in OPEN (p=0.02). Leukocyte counts decreased after the first angiography in ENDO, and thereafter increased (p=0.001). An equivalent increase was observed in OPEN after declamping (p=0.001). Leukocyte and platelet degranulation products increased after the first angiography in ENDO and after declamping in OPEN. Changes in complement activation products were small. TNF-alpha did not change significantly. CONCLUSION: endovascular AAA repair caused significant leukocyte and platelet activation. Based on the timing of activation this could be caused by radiographic contrast media.

Acute-Phase Reaction↗
PubMed2000

Interferon-alpha2a effects on complement activation and regulation in MS patients.

OBJECTIVES: To evaluate the treatment effect of recombinant interferon-alpha2a (rIFN-alpha2a) on complement activation and regulation in MS patients. MATERIAL AND METHODS: Plasma levels of the complement activation products C3bc and terminal complement complex (TCC) and serum levels of the complement regulatory proteins, complement receptor 1, CR1 (CD35) and the membrane inhibitor of reactive lysis, protectin (CD59), were determined by enzyme-linked immunosorbent assay (ELISA) in MS patients treated with IFN-alpha2a (14 patients) or placebo (7 patients). RESULTS: The level of soluble CD35 decreased while the level of TCC and to a lesser degree C3bc increased in the IFN-alpha2a treated patients during the initial part of the treatment. There was also a concomitant reduction of leukocytes in the same patients. CONCLUSIONS: The results indicate that complement is activated during the initial phase of rIFN-alpha2a treatment. This could partly be due to a concomitant reduction in soluble CD35.

Adult↗
PubMed1999

[Transplantation from animal to man].

Because of a severe shortage of donor organs, organ transplantation therapy can only be offered to a fraction of all patients needing it. This has sparked an increasing interest in xenotransplantation. Transgenic pigs could potentially provide tissue and organs to thousands of patients on waiting lists world-wide. Xenografts may be used as bridges or as permanent alternatives to organ allotransplants. Clinical trials of transplantation of pig cells and tissues to treat diabetes and neurodegenerative disorders are in progress. The most striking immunologic obstacle to xenotransplantation of solid organs, that of hyperacute rejection, is close to being overcome. Next steps in research are to refine immunosuppression, improve our knowledge of physiology and to allow for small and strictly regulated clinical studies. However, the risk for the recipients from infectious agents, particularly retroviruses, and potential dissemination of these in the human population cannot be ignored and must be thoroughly investigated. Ethical, safety, and monitoring guidelines are needed to control the development of xenotransplantation.

Animals↗
PubMed1999

Inhibition of platelet aggregation by the GPIIb/IIIa antagonist reopro does not significantly prolong xenograft survival in an ex vivo model.

Effects on hyperacute rejection were studied in a discordant model with the platelet GPIIb/IIIa antagonist Reopro. Pig kidneys perfused with human blood survived median 118 min in the Reopro group and 103 min in the controls (P = 0.22). Platelet and leukocyte counts decreased, whereas plasma thrombospondin and soluble as well as platelet membrane P-selectin increased significantly in both groups without significant intergroup differences. beta-Thromboglobulin and myeloperoxidase increased significantly more in the control group than in the Reopro group (P = 0.009 and P = 0.02, respectively). The classical complement pathway was substantially and similarly activated in both groups. Light and electron microscopy revealed arterial thrombi and numerous glomerular platelet aggregates in the control group in contrast to the Reopro group. In conclusion, Reopro reduced platelet aggregation, and platelet and leukocyte activation to some extent, but had no effect on complement activation and did not significantly prolong xenograft survival, even though better preservation of morphology was shown.

Abciximab↗
PubMed1999

Heparin-coated cardiopulmonary bypass equipment. I. Biocompatibility markers and development of complications in a high-risk population.

OBJECTIVES: 1. To study possible clinical benefits of heparin-coated cardiopulmonary bypass in patients with a broad range of preoperative risk factors. 2. To evaluate the correlation between the terminal complement complex and clinical outcome. 3. To identify clinical predictors of complement activation and correlates of granulocyte activation during cardiac surgery. METHODS: Blood samples from adults undergoing elective cardiac surgery with Duraflo II heparin-coated (n = 81) or uncoated (n = 75) cardiopulmonary bypass sets (Duraflo coating surface; Baxter International, Inc, Deerfield, Ill) were analyzed for activation of complement (C3 activation products, terminal complement complex), granulocytes (myeloperoxidase, lactoferrin), and platelets (beta-thromboglobulin) by enzyme immunoassays. Preoperative risk was assessed by means of the "Higgins' score." Complications (cardiac, renal, pulmonary, gastrointestinal, and central nervous system dysfunction, infections, death) were registered prospectively. Data were analyzed by analysis of variance, logistic regression, and linear regression. RESULTS AND CONCLUSIONS: Sixty-seven percent of the patients had predefined risk factors. Complications developed in 53 patients (34%), equivalently with and without heparin-coated bypass sets (P =. 44-.82), despite a significant reduction in complement and granulocyte activation by heparin coating. No clear-cut relationship between the terminal complement complex and outcome was found, even if it was significant in the models for renal and central nervous system dysfunction and infections (P =.006). The Higgins' score was significantly related to complement activation (P <.05). Approximately 50% of the variation in granulocyte activation was explained by complement (P </=.01) and platelet activation (P <.05), heparin/protamine dose ratio (P =.02), duration of cardiopulmonary bypass (P <.01), and gender (P <.05). Therefore measures reducing complement activation alone will not necessarily reduce granulocyte activation sufficiently for clinical significance.

Aged↗
PubMed1999

Heparin-coated cardiopulmonary bypass equipment. II. Mechanisms for reduced complement activation in vivo.

OBJECTIVE: Our objective was to study mechanisms for reduced complement activation by heparin coating of cardiopulmonary bypass equipment in clinical heart surgery. METHODS: Adults undergoing elective coronary artery bypass grafting were randomized to cardiopulmonary bypass with Duraflo II heparin-coated (n = 15) or uncoated (n = 14) sets (Duraflo coating surface; Baxter International, Inc, Deerfield, Ill). Blood samples were analyzed with the use of enzyme immunoassays for C1rs-C1 inhibitor complexes and the activation products Bb, C4bc, C3bc, C5a-desArg, and the terminal complement complex. Data were compared by repeated-measures analysis of variance. RESULTS: C1 was activated during bypass, and increases in C1rs-C1 inhibitor complexes were larger with heparin coating (P =.03). C4bc increased after administration of protamine, without intergroup differences (P =.69). Bb (P =.22) and C5a-desArg (P =.13) tended to increase less with heparin coating. Formation of C3bc (P =.03) and the terminal complement complex (P <.01) was significantly reduced with heparin coating. C5a-desArg increased 2-fold during bypass, whereas the terminal complement complex increased 10- to 20-fold. Maximal terminal complement complex concentrations were significantly correlated to maximal Bb and C3bc (R = 0.6, P <.001), but not to C1rs-C1 inhibitor complexes or C4bc (R < 0.05, P >.8). CONCLUSIONS: C1 activation during bypass was increased by heparin coating, but further classical pathway activation was held in check until administration of protamine. Heparin coating significantly inhibited C3bc and terminal complement complex formation. Terminal complement complex concentrations were related to alternative pathway activation and may be useful for evaluation of differences in bypass circuitry. Increases and intergroup differences in terminal complement complex concentrations were much larger than those in C5a-desArg.

Anticoagulants↗
PubMed1999

C1-inhibitor attenuates hyperacute rejection and inhibits complement, leukocyte and platelet activation in an ex vivo pig-to-human perfusion model.

Xenotransplantation may be a future alternative due to increased shortage of organs. Classical complement activation is central in hyperacute rejection in pig-to-human combinations. We investigated the effects of C1-inhibitor (C1-INH), a regulator of the complement and contact systems, on hyperacute rejection. Pig kidneys were perfused with fresh human blood to which either C1-INH (n = 6) or human serum albumin (n = 6) was added. The survival of the C1-INH perfused kidneys (mean 327 min) was significantly longer (p < 0.00001) than the controls (79 min). C1-INH substantially inhibited complement activation (C1rs-C1-INH complexes, C4bc, C3bc and terminal complement complex) (p < 0.001 for all) compared with the marked complement activation in the controls. No contact activation was found. Leukocytes and platelets were substantially activated (counts, myeloperoxidase, beta-thromboglobulin, thrombospondin, soluble P-selectin) in the control group, and this activation was markedly reduced by C1-INH (p < 0.02 for all). Immunohistochemistry showed less C1q, C3, TCC, IgG and fibrin deposition in the C1-INH group. C1-INH may be useful to attenuate hyperacute rejection, probably through inhibition of complement. The reduced activation of neutrophils and platelets may mainly be secondary to inhibition of complement.

Animals↗
PubMed1999

Compstatin, a peptide inhibitor of C3, prolongs survival of ex vivo perfused pig xenografts.

Compstatin, a newly described C3-binding peptide, inhibits complement activation by blocking C3 convertase-mediated cleavage of C3. As the complement activation is an essential part of the rejection reaction, we evaluated the ability of Compstatin to delay or prevent hyperacute rejection in an ex vivo xenograft model. Pig kidneys were perfused with fresh human blood containing either Compstatin (n=6) or a control agent (n=6). Graft survival and activation of complement, leukocytes and platelets both in the fluid-phase and in the tissue were examined. The survival of the Compstatin-perfused kidneys (median, 380 min) was significantly (P=0.0036) longer than that of the controls (median, 90 min). The classical complement pathway (C1rs-C1inhibitor and C4bc) was significantly and equally activated in both groups during the first 60 min. C3 activation products increased fivefold and terminal complement complex eightfold in the control group, but no increase occurred in the Compstatin group during this period. Immunohistochemistry showed less C3 and fibrin deposition and immune electron microscopy showed less terminal SC5b-9 complement complex deposition in the Compstatin group. A significant change in total white cells, neutrophils, myeloperoxidase, and expression of the surface activation markers CD11b (CR3) and CD35 (CR1) and CD62L (L-selectin) was observed in both groups. Leukocyte activation was lower in the Compstatin group but the difference was not statistically significant. There were no differences in platelet counts, thrombospondin, soluble P-selectin or beta-thromboglobulin between the groups. We conclude that Compstatin prolongs graft survival and suggest that it may be a useful agent for attenuating hyperacute rejection by inhibiting C3 and thus terminal complement pathway activation.

Animals↗
PubMed1999

Complement activation and increased systemic and pulmonary vascular resistance indices during infusion of postoperatively drained untreated blood.

In nine healthy young patients, operated on for thoracic scoliosis, a pulmonary artery catheter was inserted for the study of haemodynamic variables and blood sampling during autologous transfusion of postoperatively drained blood. At 1-3 h after wound closure, 10 ml kg/body weight of drained untreated blood from the wound was collected and recirculated over a l-h period. The concentration of the complement activation product, C3bc, increased from a mean of 5.4 (SD 1.5) AU ml-1 before infusion to 11.1 (3.9) AU ml-1 during infusion and then returned to 7.8 (2.8) AU ml-1 after infusion. The concentration of the terminal complement complex (TCC) increased from 0.5 (0.2) to 1.3 (0.5) AU ml-1 and was reduced to 0.7 (0.3) AU ml-1 after infusion. Only TCC exceeded the reference values which are 14 AU ml-1 for C3bc and 1.0 AU ml-1 for TCC. Pulmonary vascular resistance index concomitantly increased from a mean of 130 (SD 52) to 195 (88) dyn s cm-5 m-2 and was reduced to 170 (86) dyn s cm-5 m-2 after infusion. Systemic vascular resistance index increased from a mean of 1238 (SD 403) to 1349 (473) dyn s cm-5 m-2 and returned to 1196 (401) dyn s cm-5 m-2 after infusion. White blood cell count (WCC) increased from 14.4 (4.3) x 10(9) litre-1 before infusion to 17.8 (7.2) x 10(9) litre-1 during and after infusion. No change in platelet count during infusion was observed. There were no differences in WCC or platelet count between mixed venous or peripheral arterial blood. Pulmonary and systemic vascular resistance indices may be influenced by activated complement in drained untreated blood when it is recirculated.

Adolescent↗
PubMed1999

Complement activation in patients with systemic lupus erythematosus without nephritis.

OBJECTIVE: To study the association between disease activity and complement activation prospectively in patients with systemic lupus erythematosus (SLE). PATIENTS AND METHODS: Twenty-one SLE patients were examined monthly for 1 yr. Disease activity, autoantibodies, conventional complement tests and the following complement activation products were investigated: C1rs-C1inh complexes, C4bc, Bb, C3a, C3bc, C5a and the terminal SC5b-9 complement complex (TCC). RESULTS: Modest variation in disease activity was noted. None of the patients had nephritis. Flare was observed at 27 visits. Four patients had anti-C1q antibodies in conjunction with modestly low C1q concentrations. The complement parameters were rather constant during the observation period. Slightly to moderately decreased C4 (0.05-0.10 g/l) was found in 10 patients and severely decreased C4 (<0.05 g/l) in seven patients. Decreased C4 was not associated with increased complement activation. Complement activation products were either normal or slightly elevated. TCC was the only activation product correlating significantly with score for disease activity at flare. None of the variables tested predicted flares. CONCLUSION: Complement tests are of limited importance in routine examination of SLE without nephritis, although TCC is suggested to be one of the most sensitive markers for disease activity.

Adult↗
PubMed1999

Resistance to both complement activation and phagocytosis in type 3 pneumococci is mediated by the binding of complement regulatory protein factor H.

To study the role of surface-associated proteins in the virulence of Streptococcus pneumoniae, we used two serotype 3 strains, ATCC 6303 and WU2, and two PspA-negative mutants of WU2, an encapsulated one, JY1123 (Caps(+)/PspA(-)), and an unencapsulated one, DW3.8 (Caps(-)/PspA(-)). ATCC 6303 and WU2 were highly virulent in mice, while the virulence of JY1123 was slightly decreased (50% lethal doses [LD(50)s], 24, 6, and 147 CFU/mouse, respectively); DW3.8 was avirulent (LD(50), 2 x 10(8) CFU). In vitro, ATCC 6303, WU2, and JY1123 (Caps(+)/PspA(-)) strongly resisted complement activation and complement-dependent opsonophagocytosis, whereas DW3.8 (Caps(-)/PspA(-)) was easily phagocytized in fresh serum. Trypsin treatment of ATCC 6303, WU2, and JY1123 (Caps(+)/PspA(-)) resulted in enhanced complement activation and complement-dependent opsonophagocytosis. Trypsin had no deleterious effect on the polysaccharide capsule. In addition, trypsin pretreatment of ATCC 6303 strongly reduced virulence upon intraperitoneal challenge in mice. This indicated that surface proteins play a role in the resistance to complement activation and opsonophagocytosis and contribute to the virulence of type 3 pneumococci. In subsequent experiments, we could show that the modulation of complement activation was associated with surface components that bind complement regulator factor H; binding is trypsin sensitive and independent of prior complement activation. Immunoblotting of cell wall proteins of the virulent strain ATCC 6303 with anti-human factor H antibody revealed three factor H-binding proteins of 88, 150, and 196 kDa. Immunogold electron microscopy showed a close association of factor H-binding components with the outer surface of the cell wall. The role of these factor H-binding surface proteins in the virulence of pneumococci is interesting and warrants further investigation.

Animals↗