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Biomedical subjects

G J Wolbink

Publications and source records attributed to G J Wolbink.

At least 19 recordsLinked to original sources
PubMed2005

Rituximab treatment in patients with primary Sjögren's syndrome: an open-label phase II study.

OBJECTIVE: To investigate the safety and efficacy of B cell depletion treatment of patients with active primary Sjögren's syndrome of short duration (early primary SS) and patients with primary SS and mucosa-associated lymphoid tissue (MALT)-type lymphoma (MALT/primary SS). METHODS: Fifteen patients with primary SS were included in this phase II trial. Inclusion criteria for the early primary SS group were B cell hyperactivity (IgG >15 gm/liter), presence of autoantibodies (IgM rheumatoid factor, anti-SSA/SSB), and short disease duration (<4 years). Inclusion criteria for the MALT/primary SS group were primary SS and an associated MALT-type lymphoma (Ann Arbor stage IE) localized in the parotid gland. Patients were treated with 4 infusions of rituximab (375 mg/m2) given weekly after pretreatment with prednisone (25 mg) and clemastine. Patients were evaluated, using immunologic, salivary/lacrimal function, and subjective parameters, at baseline and at 5 and 12 weeks after the first infusion. RESULTS: Significant improvement of subjective symptoms and an increase in salivary gland function was observed in patients with residual salivary gland function. Immunologic analysis showed a rapid decrease of peripheral B cells and stable levels of IgG. Human anti-chimeric antibodies (HACAs) developed in 4 of 15 patients (27%), all with early primary SS. Three of these patients developed a serum sickness-like disorder. Of the 7 patients with MALT/primary SS, complete remission was achieved in 3, and disease was stable in 3 and progressive in 1. CONCLUSION: Findings of this phase II study suggest that rituximab is effective in the treatment of primary SS. The high incidence of HACAs and associated side effects observed in this study needs further evaluation.

Adult↗
PubMed2004

Relationship between serum trough infliximab levels, pretreatment C reactive protein levels, and clinical response to infliximab treatment in patients with rheumatoid arthritis.

OBJECTIVE: To investigate the relationship between serum trough infliximab levels and clinical response to infliximab treatment in patients with rheumatoid arthritis (RA). METHODS: Disease activity and serum trough infliximab levels before and 2, 6, and 14 weeks after initiation of infliximab treatment at a dose of 3 mg/kg in a cohort of 105 patients with RA were assessed. Serum trough infliximab levels in responders and non-responders were compared. Additionally, the clinical responses of patients with high, intermediate, and low serum trough infliximab levels at 14 weeks were compared. RESULTS: After 14 weeks of treatment non-responders had lower serum trough levels of infliximab than responders (median (interquartile range) 0.5 (0.2-2.2) v 3.6 (1.4-8.2) mg/l; p<0.01)). Patients with low serum trough infliximab levels at 14 weeks had significantly less improvement in the 28 joint count Disease Activity Score (DAS28) score than patients with intermediate or high serum trough infliximab levels at 14 weeks. Pretreatment C reactive protein (CRP) levels correlated negatively with serum trough infliximab levels at 14 weeks after the start of treatment (Spearman rank correlation r(s) = -0.43, p<0.001). CONCLUSION: Serum trough levels of infliximab correlate with the clinical response to treatment with infliximab and pretreatment CRP levels. This study indicates that patients with high pretreatment CRP levels might benefit from higher dosages of infliximab or shorter dosing intervals.

Adult↗
PubMed2000

Complement activation induced by ischemia-reperfusion in humans: a study in patients undergoing partial hepatectomy.

BACKGROUND/AIM: Activation of the complement system is induced by ischemia-reperfusion (I/R) in animal models. Whether I/R also induces complement activation in humans is not known. Here, we investigated complement activation in patients undergoing major liver resection. METHODS: In 11 of 17 patients, the hepatoduodenal ligament was clamped, making the liver transiently ischemic (HEMI+; mean ischemia time, 42 +/- 18 min); 6 patients were operated without clamping (HEMI-). Activation at plasma level (circulating activation products) was studied in blood samples collected prior to surgery and 5, 24 and 48 h thereafter. Parameters analyzed were C4b/c and C3b/c, C4d and C3d, C3a, as well as complexes between complement and C-reactive protein (CRP), which reflect CRP-induced complement activation. Activation at tissue level (C3 and C4 fixation) was studied in liver biopsies obtained before and after resection. RESULTS: In plasma, post-operative levels of C4b/c and C3b/c were not different from baseline levels in both groups. Mean plasma levels of C4b/c and C3b/c were significantly decreased at 24 h post-surgery in the HEMI+ group (p=0.02 and p=0.07). At the same time, levels of C4d-CRP and C3d-CRP were significantly increased (p<0.01 for both parameters). At tissue level, activated complement fragments were observed intracellularly in some pericentral hepatocytes. In I/R livers, large numbers of hepatocytes were positively stained for all complement activation products. CONCLUSIONS: Our data show that in situ complement activation via the classical route occurred during liver resection and that ischemia and/or reperfusion may have contributed to activation. Levels of complement activation products in the circulation were low, showing that transient ischemia had no severe influence on systemic complement activation, suggesting a locally contained response.

Adult↗
PubMed1999

C-reactive protein as a cardiovascular risk factor: more than an epiphenomenon?

BACKGROUND: Circulating levels of C-reactive protein (CRP) may constitute an independent risk factor for cardiovascular disease. How CRP as a risk factor is involved in cardiovascular disease is still unclear. METHODS AND RESULTS: By reviewing available studies, we discuss explanations for the associations between CRP and cardiovascular disease. CRP levels within the upper quartile/quintile of the normal range constitute an increased risk for cardiovascular events, both in apparently healthy persons and in persons with preexisting angina pectoris. High CRP responses after acute myocardial infarction indicate an unfavorable outcome, even after correction for other risk factors. This link between CRP and cardiovascular disease has been considered to reflect the response of the body to the inflammatory reactions in the atherosclerotic (coronary) vessels and adjacent myocardium. However, because CRP localizes in infarcted myocardium (with colocalization of activated complement), we hypothesize that CRP may directly interact with atherosclerotic vessels or ischemic myocardium by activation of the complement system, thereby promoting inflammation and thrombosis. CONCLUSIONS: CRP constitutes an independent cardiovascular risk factor. Unraveling the molecular background of this association may provide new directions for prevention of cardiovascular events.

Adult↗
PubMed1998

Human eosinophils express, relative to other circulating leukocytes, large amounts of secretory 14-kD phospholipase A2.

Human eosinophils perform several functions dependent on phospholipase A2 (PLA2) activity, most notably the synthesis of platelet-activating factor (PAF) and leukotriene C4 (LTC4). Several forms of PLA2 have been identified in mammalian cells. In the present study, the 14-kD, secretory form of PLA2 was detected in human eosinophils by immunocytochemical staining with the specific monoclonal antibody (MoAb) 4A1. In contrast, preparations of neutrophils, monocytes, lymphocytes, and basophils did not show detectable staining. With two MoAbs in a sandwich enzyme-linked immunosorbent assay (ELISA), large amounts of sPLA2 were detected in lysates of eosinophils, that were 20-fold to 100-fold higher than in the other circulating leukocytes (ie, neutrophils, basophils, monocytes, and lymphocytes). In addition, with a commercially available sPLA2 activity assay kit, we were able to show high activity of sPLA2 in human eosinophils relative to neutrophils. Investigations at the ultrastructural level showed that sPLA2 in eosinophils is mainly located in specific granules. Immunoelectron microscopy also visualized sPLA2 within phagosomes after addition of opsonized particles to the eosinophils. However, sPLA2 was not detected in the cell-free supernatants of activated eosinophils, in contrast to eosinophil-cationic protein (ECP), which colocalizes with sPLA2 in resting eosinophils. These findings warrant further studies into the role of sPLA2 in eosinophil function.

Basophils↗
PubMed1998

Reduction of circulating secretory phospholipase A2 levels by anti-tumor necrosis factor chimeric monoclonal antibody in patients with severe Crohn's disease. Relation between tumor necrosis factor and secretory phospholipase A2 in healthy humans and in active Crohn's disease.

BACKGROUND: Secretory phospholipase A2 group II (sPLA2-II) has pro-inflammatory effects. The importance of tumor necrosis factor (TNF) for induction of plasma sPLA2-II in humans was studied in two groups of subjects. SUBJECTS: Six healthy volunteers received a single intravenous injection of recombinant human TNF or isotonic saline at random. Ten patients with active Crohn's disease received a single intravenous infusion of an anti-TNF chimeric monoclonal antibody, cA2. RESULTS: TNF infusion in healthy volunteers resulted in an increase of sPLA2-II at 3 h, with a maximal plasma level at 6 h (20.8+/-8.9 ng/ml; P < 0.05). In Crohn's disease base-line sPLA2-II levels were 33.9+/-13.4 ng/ml 24 h after infusion of cA2, 11.0+/-2.9 ng/ml (P < 0.005). Further decrease occurred in all except two patients at 2 weeks. The decrease in plasma sPLA2-II preceded all clinical signs of remission. CONCLUSION: TNF infusion in healthy humans can induce a rapid increase of circulating sPLA2-II, and selective blocking of TNF-alpha with cA2 results in a rapid decrease in sPLA2-II in peripheral blood. These data confirm that TNF has an important role in regulating the release of sPLA2-II in systemic and local inflammatory reactions.

Adult↗
PubMed1998

Complement activation in patients with sepsis is in part mediated by C-reactive protein.

The involvement of C-reactive protein (CRP) in the activation of complement in patients with sepsis was investigated. In 104 patients with infections of varying severity, circulating levels of CRP-complement complexes, which are specific indicators for CRP-mediated complement activation, were assessed. Complement-CRP complexes were increased in almost all patients and correlated significantly with levels of C3a (r = .59; P < .001) and C-reactive protein (r = .76; P < .001). In addition, they correlated with levels of secretory phospholipase A2 (r = .59; P < .001). Levels of complement-CRP complexes in patients with a pneumococcal type of infection were similar to those in patients with other types of infections. Complement-CRP complexes were significantly higher in patients with shock (P = .01) and in patients who died (P = .03). These results demonstrate that part of the complement activation in patients with sepsis is independent from a direct interaction with microorganisms but rather results from an endogenous mechanism involving CRP.

C-Reactive Protein↗
PubMed1997

C-reactive protein colocalizes with complement in human hearts during acute myocardial infarction.

BACKGROUND: Rises in circulating C-reactive protein (CRP), the prototypical acute-phase protein in humans, correlate with clinical outcome in patients with myocardial ischemia and infarction. We hypothesized that these correlations might reflect active participation of CRP in the local inflammatory response ensuing in the jeopardized myocardium because on binding to a ligand, CRP is able to activate the classic pathway of complement, and in addition, complement activation has been shown to occur locally in infarcted myocardium. METHODS AND RESULTS: To verify our hypothesis, we investigated localization of CRP in relation to deposition of complement in tissue specimens of infarcted and healthy heart tissue obtained from 17 patients who had died after acute myocardial infarction. CRP was found to be deposited only in infarcted regions and not in normal-appearing areas of the myocardium, being colocalized with depositions of C4 and C3 activation fragments of the complement system. Deposition of CRP and complement in infarcted myocardium appeared to be time dependent, because it was found in all infarctions except for one of young age (< 12 hours old) and two of greater age (> 1 year old), whereas another tissue specimen of an infarct < 12 hours old showed only moderate but positive staining for both CRP and complement in comparison with older infarctions. CONCLUSIONS: We conclude that in humans, CRP may localize in infarcted heart tissue and suggest that this acute-phase protein promotes local complement activation, and hence tissue damage, in acute myocardial infarction.

Aged↗
PubMed1997

A role for secretory phospholipase A2 and C-reactive protein in the removal of injured cells.

The acute phase response is initiated in response to infection or physical trauma and is characterized by an increase in the levels of some plasma proteins. Here, Erik Hack and colleagues suggest that the combined actions of two of these acute phase proteins, secretory phospholipase A2 and C-reactive protein, may serve to promote phagocytosis of injured cells and tissue debris, thereby enhancing inflammation and tissue damage.

Acute-Phase Reaction↗
PubMed1997

Inhibition of human complement by beta-glycyrrhetinic acid.

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

Administration, Topical↗
PubMed1996

CRP-mediated activation of complement in vivo: assessment by measuring circulating complement-C-reactive protein complexes.

The in vivo function of C-reactive protein (CRP) is unknown. Among the in vitro functions assigned to CRP is the ability to activate complement via the classical pathway. To date, there is no evidence supporting that CRP exerts this function in vivo. We here show a novel approach to assess CRP-mediated complement activation in vivo, which is based on the property that activated complement factors C3 and C4 fix to CRP during complement activation induced by this acute phase protein. We developed specific ELISAs for complexes between CRP and C4b, C4d, C3b, or C3d. We established that in vitro complement-CRP complexes were formed only during CRP-dependent activation, and not during activation by other activators, even in the presence of high CRP levels. Circulating levels of complement-CRP complexes were undetectable in normal donors, but significantly increased in nine patients following implantation of a renal allograft. Importantly, levels of complement-CRP complexes did not change in these patients upon a bolus infusion of mAb OKT3, which induces activation of the classical complement pathway, demonstrating in vivo that complement-CRP complexes are not formed during CRP-independent activation of complement, even when CRP is elevated. We conclude that measurement of complement-CRP complexes provides a suitable tool to study CRP-mediated activation of complement in vivo. Furthermore, increased levels of these complexes occur in clinical samples, indicating that CRP may induce activation of complement in vivo.

Adult↗
PubMed1996

OKT3-induced nephrotoxicity is associated with release of group II secretory phospholipase A2.

Administration of the murine IgG2a CD3 monoclonal antibody OKT3 exerts a transient nephrotoxic effect. Increased levels of group II secretory phospholipase A2 (sPLA2-II) might account for this nephrotoxicity as sPLA2-II induces the biosynthesis of prostaglandins, vasoactive lipid mediators that influence glomerular haemodynamics and renal function. Furthermore, extracellular phospholipases seem to be involved in proximal tubular cell injury. We studied plasma sPLA2-II levels in relation to circulating creatinine, tumour necrosis factor alpha, interleukin 6 and C-reactive protein levels in 15 renal allograft recipients receiving rejection treatment with OKT3. As a control group, we studied 15 renal allograft recipients receiving rejection treatment with methylprednisolone. A maximal fourfold increase in sPLA2-II levels was observed 48 h after the first OKT3 administration, preceded by increased tumour necrosis factor alpha and interleukin 6 levels and accompanied by increased C-reactive protein levels. Creatinine levels reached a maximal increase 72 h after initiation of treatment. During methylprednisolone treatment no increase in any of the studied parameters was observed. Thus, administration of OKT3 induces increased sPLA2-II levels, presumably via generation of cytokines. We hypothesize that sPLA2-II may contribute to the nephrotoxic effect of OKT3 by inducing vasoconstrictive prostaglandins and renal tubular cell injury.

Adolescent↗
PubMed1995

Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis.

OBJECTIVE: To define the influence of interleukin-1 activity on coagulation and fibrinolytic system activation and the release of proinflammatory mediators in the early human response to severe infection. STUDY DESIGN: All patients with severe sepsis syndrome who were enrolled from two surgical centers that were participating in a randomized, double-blind, placebo controlled, multicenter, multinational trial of recombinant human interleukin-1 receptor antagonist in the treatment of sepsis syndrome. POPULATION: Twenty-six patients with sepsis syndrome received an intravenous loading dose of recombinant human interleukin-1 receptor antagonist (100 mg) or placebo followed by a continuous 72-hour infusion of recombinant human interleukin-1 receptor antagonist (1.0 [n = 9] or 2.0 [n = 8] mg/kg per hour) or placebo (n = 9). OUTCOME MEASURE: Responses up to 72 hours after initiation of treatment. RESULTS: Plasma levels of the anaphylatoxin C3a and thrombin-antithrombin III complexes were reduced in the high-dose recombinant human interleukin-1 receptor antagonist treatment group after 72 hours (P < .05). Similarly, parameters of fibrinolysis, tissue-type plasminogen activator, and plasminogen activator inhibitor type 1 but not plasmin-alpha 2-antiplasmin complexes, were also significantly reduced (P < .05) after 72 hours of treatment with a high dose of recombinant human interleukin-1 receptor antagonist. Neutrophil elastase-alpha 1-antitrypsin complexes and phospholipase A2 levels were also significantly reduced in the high-dose recombinant human interleukin-1 receptor antagonist treatment group after 72 hours. CONCLUSIONS: The results confirm that activation of the coagulation and fibrinolytic systems and release of soluble inflammatory mediators are consistently observed in patients with severe sepsis syndrome. Interleukin-1 activity contributes to activation of these processes as documented by the reduction in surrogate activation markers during recombinant human interleukin-1 receptor antagonist treatment.

Adult↗