Klaus Bendtzen

• MD, DMSc
• Prof.em. DMSc. at Rigshospitalet

Objective: Infliximab, an anti-tumor necrosis factor alpha (anti-TNFalpha) antibody, is effective in the treatment of several immunoinflammatory diseases. However, many patients experience primary or secondary response failure, suggesting that individualization of treatment regimens may be beneficial. This study was undertaken to investigate wheth...

Activated mononuclear cells appear to be important effector cells in autoimmune beta cell destruction leading to insulin-dependent (type 1) diabetes mellitus. Conditioned medium from activated mononuclear cells (from human blood) is cytotoxic to isolated rat and human islets of Langerhans. This cytotoxic activity was eliminated from crude cytokine...

With the discovery of the central pathogenic role of tumor necrosis factor (TNF)-alpha in many immunoinflammatory diseases, specific inhibition of this pleiotropic cytokine has revolutionized the treatment of patients with several non-infectious inflammatory disorders. As a result, genetically engineered anti-TNF-alpha antibody constructs now const...

In the present study, we have explored the involvement of Toll-like Receptor 4 (TLR4) in atrial fibrillation (AF), by using a meta-analysis of publicly available human transcriptomic data. The meta-analysis revealed 565 upregulated and 267 downregulated differentially expressed genes associated with AF. Pathway enrichment analysis highlighted a sig...

Aim: To study the effect of sulfatide on gene expression and proliferation of human primary fibroblasts induced by insulin, insulin-like growth factor-1 and human growth hormone. Materials and methods: Human primary fibroblasts were exposed to 1, 3 and 30 μM of sulfatide or its precursor galactosylceramide (GalCer). Proliferation was determined...

This case report describes remarkably consistent improvements after administering an antibiotic, pivmecillinam (amdinocillin), to a patient suffering from a difficult-to-treat paroxysmal atrial fibrillation (AFib). Pivmecillinam is an orally active prodrug of mecillinam primarily used to treat urinary tract and renal infections caused by Gram-negat...

Background It remains unknown whether infliximab (IFX) successfully can be discontinued once Crohn's disease (CD) patients have attained sustained, complete clinical, biochemical, and endoscopic remission. No randomized, placebo (PBO) controlled trial has previously assessed this. Methods This double-blind, randomized, PBO-controlled multicenter t...

Background: Primary non-response to infliximab (IFX) inherits a poor prognosis in inflammatory bowel disease (IBD). We explored underlying mechanisms and therapeutic thresholds in an effort to provide basis for optimizing therapy. Methods: A prospectively followed cohort of 166 IBD patients having received standard IFX induction therapy (5 mg/kg at...

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) has posed a serious threat to global health. As no specific therapeutics are yet available to control disease evolution, more in-depth understanding of the pathogenic mechanisms induced by SARS-CoV-2 will help to characterize new targets for the man...

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) has posed a serious threat to global health. As no specific therapeutics are yet available to control disease evolution, more in-depth understanding of the pathogenic mechanisms induced by SARS-CoV-2 will help to characterize new targets for the man...

Major depressive disorder (MDD) is a common condition that afflicts the general population across a broad spectrum of ages and social backgrounds. MDD has been identified by the World Health Organization as a leading cause of disability worldwide. Approximately 30% of patients are poor responsive to standard of care (SOC) treatment and novel therap...

Background: Immunoinflammatory disorders are often accompanied by depression. Here, we review the available preclinical and clinical studies suggesting a role for the pro-inflammatory cytokine Macrophage migration inhibitory factor (MIF) and the second member of the MIF family, D-dopachrome tautomerase (D-DT; DDT), in the pathogenesis of Major Dep...

The AB0 blood group has been linked to ischaemic heart disease, stroke, and periodontal disease, while the Lewis blood group has been linked to ischaemic heart disease and obesity, all of which have been associated with periodontitis. AB0 or Lewis blood group phenotype may therefore constitute common hereditary components predisposing to these diso...

Background Even though bacteria trigger inflammation, most of the tissue destruction in periodontitis is due to the host inflammatory response. In addition to immunological events that drive development of early periodontitis, numerous environmental factors like genetics and smoking play a role. We investigated whether the carriage of selected sing...

Gasotransmitters are a group of gaseous molecules, with pleiotropic biological functions. These molecules include nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO). Abnormal production and metabolism of these molecules have been observed in several pathological conditions. The understanding of the role of gasotransmitters in the i...

Introduction: Genetically engineered monoclonal antibodies and fusion proteins directed against cytokines or their receptors represent a breakthrough in the treatment of various chronic immune-inflammatory diseases. Areas Covered: Studies show high remission rates in several diseases, but clinical practice shows a significant percentage of individu...

Linked Content This article is linked to Ungar et al and Ben‐Horin et al papers. To view these articles visit https://doi.org/10.1111/apt.13862 and https://doi.org/10.1111/apt.13932 .

Cholesterol deposits and pro-inflammatory cytokines play an essential role in the pathogenesis of atherosclerosis, a predominant cause of cardiovascular disease (CVD). Epidemiological evidence has linked periodontal disease (PD) with atherosclerotic CVD. Accordingly, viable periodontal pathogens, including Porphyromonas gingivalis, have been found...

Dose titration of the pan-caspase inhibitor Z-VAD-FMK. (A) Isolated monocytes were cultured with no stimulation, P. gingivalis (P.g)-lipopolysaccharide (LPS) and cholesterol crystals (CHCs), and Pg-LPS and CHCs in combination with different concentrations of Z-VAD-FMK (5, 10 and 25μM). Concentrations of interleukin (IL)-1β in the supernatants after...

The role of toll-like receptors (TLR) 4 and TLR2 in cytokine responses upon stimulation with E. coli (Ec)-lipopolysaccharide (LPS) and P. gingivalis (Pg)-LPS. (A-E) Isolated monocytes were cultured with no stimulation, anti-TLR2, Pg-LPS) alone and Pg-LPS in combination with anti-TLR2 antibody. The content of IL-1β (n = 11), TNF-α (n = 11), IL-6 (n...

Dose-titration of cholesterol crystals (CHCs). Isolated monocytes were cultured with no stimulation and CHCs at different concentrations (0.1, 0.5, 1, 2 and 4 mg/mL as indicated by numbers after CHCs). The content of interleukin (IL)-1β in the supernatants after 20 hours is shown as means±SD for experiments using two healthy donors. (TIF)

Background: Primary non-response (PNR) to infliximab (IFX) has been reported in up to one third of patients with inflammatory bowel disease (IBD) and represents a major therapeutic challenge. This study aimed to asses if IFX trough levels during induction therapy differed between patients with and without PNR to IFX and to calculate therapeutic thr...

Background: Clinical use of therapeutic drug monitoring (TDM)-based strategies for infliximab (IFX) treatment is limited by lack of validated and well-defined cut-off points for IFX trough levels distinguishing between therapeutic and sub-therapeutic drug levels. This study aimed to identify serum IFX levels associated with clinical remission and b...

The possible use of HIV protease inhibitors (HIV-PI) as new therapeutic option for the treatment of cancer primarily originated from their success in treating HIV-related Kaposi's sarcoma (KS). While these findings were initially attributed to immune reconstitution and better control of oncogenic viral infections, the number of reports on solid tum...

Objectives: With the present study we wanted to explore the impact of treatment with a tumor necrosis factor-α -inhibitor (TNFi) on levels of soluble biomarkers in rheumatoid arthritis (RA) patients and to identify predictors of impaired drug levels and development of anti-TNFi antibodies (anti-TNFi Abs). Methods: Blood samples from 26 patients...

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The inflammatory response at infliximab (IFX) treatment failure due to tumor necrosis factor (TNF)-α-independent Crohn disease activity is unknown. This is an exploratory, hypothesis-generating study based on samples collected in a clinical trial among patients failing conventional IFX dosages and treated with an intensified IFX regimen for 12 week...

Background: Biological tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of inflammatory bowel disease and redefined treatment goals to include mucosal healing. Clinicians are faced with challenges such as inadequate responses, treatment failures, side effects, and high drug costs. The objective is to review optimization of...

Phthalates are plasticisers added to a wide variety of products, resulting in measurable exposure of humans. They are suspected to disrupt the thyroid axis as epidemiological studies suggest an influence on the peripheral thyroid hormone concentration. The mechanism is still unknown as only few in vitro studies within this area exist. The aim of th...

LDH-contents (y-axis) in supernatants from TSH-stimulated thyroid cell cultures. Cells were exposed to DEHP and MEHP, as well as positive cytotoxicity- (i.e. cell cultures exposed to Triton X-100) and negative culture- (i.e. cell cultures not exposed to phthalates) controls for 72 h. N = one culture in single determination except for the negative c...

Overview of 2 way ANOVA and post-hoc Tukey results from phthalate-exposed (72 h) thyroid cell cultures, in TSH- and unstimulated controls. If log10 of data was used, the estimated differences between groups are expressed as ratios, e.g. the mean cAMP-secretion from 10 μM DEHP-exposed cells was 21% lower than the mean cAMP-secretion from 0.001 μM DE...

cAMP secretion from individual cell cultures (culture 1–7) exposed to DnBP (0.001 to 100 μM) for 72 hours. The dashed line indicates the level of the ethanol controls (ratio = 1). DnBP: di-n-butyl phthalate. (TIF)

Function of TSH-stimulated human thyroid cell cultures exposed to IL-1β. Cell cultures were exposed to IL-1β (100 to 105 U/l) for 72 hours (n = one culture in single determination). The dashed line indicates the level of the ethanol controls (ratio = 1). Tg- and cAMP-secretion was assessed in supernatants and mRNA in cells. cAMP: 3'-5'-cyclic adeno...

Sequences of the primers used in RT-qPCR. (PDF)

The impact of TSH-starvation (A) and addition of FBS (B) during experiments. Results of the outcome variables were analysed by paired T-test and experiment duration was 72 h. A: outcome from experiments with thyroid stimulation hormone (TSH) -starvation are compared to those without TSH-starvation. B: outcome from experiments without foetal bovine...

ANOVA and Tukey post-hoc results from the study of the culture duration. TSH-stimulated primary thyroid cells were cultured for 6, 24, 48 or 72 h, before supernatants and cells were harvested and outcome variables were analysed. All experiments were conducted in triplicates. cAMP: 3'-5'-cyclic adenosine monophosphate. IL: interleukin. NIS: sodium i...

Background Treatment of Philadelphia chromosome negative chronic myeloproliferative neoplasms (MPNs) with recombinant pegylated interferon alpha2a/b (rIFN-alpha) has proven effective. It is well known that prolonged therapy with recombinant type 1 interferons (IFN-alpha and IFN-beta) may induce neutralizing antibodies (nAbs) against the drug leadin...

Antibodies (Abs) against adalimumab (ADL) have been associated with low ADL levels and treatment failure. To characterize the temporal characteristics of anti-ADL Ab appearance and possible disappearance, and determine the clinical significance on drug efficacy and disease course. Cohort study including inflammatory bowel disease patients in whom a...

The introduction of biological tumor necrosis factor (TNF)-α inhibitors has transformed the paradigm for the treatment of inflammatory bowel disease (IBD), i.e. Crohn's disease and ulcerative colitis. The specific TNF inhibitors currently approved for patients with IBD are infliximab, adalimumab and certolizumab pegol for Crohn's disease refractory...

Phthalates are a group of endocrine disrupting chemicals, suspected to influence the immune system. The aim of this study was to investigate the influence of phthalates on cytokine secretion from human peripheral blood mononuclear cells. Escherichia coli lipopolysaccharide and phytohemagglutinin-P were used for stimulation of monocytes/macrophages...

A recent review by Hendy et al1 discusses the use of anti-tumour necrosis factor (TNF) drug and anti-drug antibody (ADAb) measurements to achieve a personalised approach to treating patients with inflammatory bowel disease with loss of response (LOR) to protein-based TNF-antagonist therapy. While highly appreciated and filling an important gap in t...

Specific inhibition of the cytokine, tumor necrosis factor-α (TNF), has revolutionized the treatment of patients with several autoimmune diseases, and genetically engineered anti-TNF antibody constructs now constitute a heavy medicinal expenditure in many countries. Unfortunately, up to 30% of patients do not respond and about 50% of those who do l...

Immunogenicity of biopharmaceuticals is complex and influenced by both structural and pharmacological factors, and by patient-related conditions such as disease being treated, previous and concomitant therapies, and individual immune responsiveness. Essential for tailored therapeutic strategies based on immunopharmacological evidence from individua...

Background: Phthalates are a group of endocrine disrupting chemicals suspected to influence the immune system. The aim of this systematic review is to summarise the present knowledge on the influence of phthalates on monocyte and macrophage production and secretion of cytokines, an influence which could affect both pro- and anti-inflammatory abili...

In Crohn's disease patients failing infliximab therapy, interventions defined by an algorithm based on infliximab and anti-infliximab antibody measurements have proven more cost-effective than intensifying the infliximab regimen. This study investigated long-term economic outcomes at the week 20 follow-up study visit and after 1 year. Clinical outc...

Objective. To investigate if antibodies towards biological TNF-α inhibitors (anti-TNFi Abs) are present in patients with rheumatoid arthritis (RA) in clinical remission and to relate any anti-TNFi Abs to circulating level of TNF-α inhibitor (TNFi). Methods. Patients with RA, treated with infliximab or adalimumab, and in clinical remission (DAS28(CR...

It is recommended to intensify the infliximab (IFX) regimen in case of inadequate treatment effect. However, the rationale is not well defined as underlying mechanisms varies. To explore the association between changes in serum IFX and anti-IFX antibodies (Abs) after IFX intensification and clinical outcomes. Post hoc analysis of randomized clinica...

Biologic drugs, including genetically engineered anti-tumor-necrosis factor-α (TNF-α) immunoglobulin constructs, have markedly improved treatment of chronic immunoinflammatory diseases. These agents selectively modulate TNF-mediated disease pathways leading to reduced inflammatory activity. The results have dramatically improved outcomes for patien...

Increasing evidence supports the role of epigenetics in the development of autoimmune disorders and the possibility of using epigenetic modifying drugs in the context of MS has not yet been investigated. We have explored the effect of the hypomethylating agent 5-aza-2′-deoxycytidine (DAC) in two murine models of experimental allergic encephalomyeli...

Infliximab (IFX), a monoclonal chimeric antibody against tumour necrosis factor (TNF) α, is effective for induction and maintenance of remission in moderate to severe Crohn's disease. Discontinuation of IFX maintenance therapy in patients in remission should be considered in order to reduce the potential long-term side effects and lower costs. This...

Background: Endotoxaemia is widely used as an experimental model to study sepsis under controlled conditions. Nighttime endotoxaemia induces a more pronounced inflammatory stress response compared to daytime. Previously, we have shown that melatonin has antioxidative and anti-inflammatory effects in inflammatory response to daytime endotoxaemia. H...

Background: A notable proportion of patients with inflammatory bowel disease (IBD) are switched from infliximab (IFX) to adalimumab (ADL). We investigated if immunogenicity of IFX influenced immunogenicity and clinical outcomes of later ADL therapy. Methods: Single-center cohort study including all patients with IBD assessed for antibodies (Abs)...

Several studies indicate a role for toll-like receptors (TLRs) in the pathogenesis of systemic lupus erythematosus (SLE). We aimed to investigate the risk of SLE and typical clinical and serological manifestations of SLE potentially conferred by selected single nucleotide polymorphisms (SNPs) of genes encoding TLR7, TLR8, and TLR9. Using a multiple...

When exposed to small amounts of bacterial endotoxin, matrices of cholesterol crystals, but not cholesterol itself, primed human monocytes/macrophages to a highly augmented (>10-fold) production of inflammatory tumor necrosis factor-α. Priming also sensitized the cells, as 10- to 100-fold lower levels of endotoxin were needed for TNF-α production e...

Objectives: Cost-effective guidance of therapeutic strategy in Crohn's disease patients with secondary infliximab (IFX) treatment failure may be achieved by serum IFX and anti-IFX antibody (Ab) measurements by radioimmunoassay (RIA). This study investigated implications of using other techniques for this purpose. Methods: This is a post hoc anal...

This study aimed to demonstrate possible associations between genetic polymorphisms in Toll-like receptor 3, interferon induced with helicase C domain 1 (IFIH1) and DEAD (Asp-Glu-Ala-Asp) box polypeptide 58 and systemic lupus erythematosus (SLE), including the phenotypes lupus nephritis and malar rash, as well as the presence of autoantibodies agai...

Objective Ischaemia-reperfusion (IR) injury is partly caused by the release of reactive oxygen species and cytokines and may result in remote organ injury. Surgical patients are exposed to surgical stress and anaesthesia, both of which can influence the IR response. An IR model without these interfering factors of surgery is, therefore, useful to t...

Circadian variation in bodily functions has been shown to impact health in acute and chronic medical conditions. Little is known about the relationship between circadian rhythm and sepsis in humans. We aimed to investigate circadian variations in the host response in a human endotoxaemia model. A cross-over study, where 12 healthy young men receive...

Background Upregulation of mRNA IFN-alpha activity (IFN signature) has been demonstrated in some patients with systemic lupus erythematosus (SLE). Based on this observation anti-IFN-alpha mAbs are currently being developed for the treatment of SLE. Interestingly naturally occurring antibodies towards IFN-alpha have previously been demonstrated in a...

Melatonin used as an exogenous drug has been documented to have potent antioxidant and anti-inflammatory effects in animal model. We aimed to examine the effect of melatonin in an experimental human sepsis model. Twelve healthy males were enrolled in a randomized, placebo-controlled, double-blinded cross-over trial. They received lipopolysaccharide...

Although the reasons for secondary loss of response to infliximab (IFX) maintenance therapy in Crohn's disease vary, dose intensification is usually recommended. This study investigated the cost-effectiveness of interventions defined by an algorithm designed to identify specific reasons for therapeutic failure. Randomised, controlled, single-blind,...

Background: Several techniques are used to measure infliximab (IFX) and anti-IFX antibodies (Abs) in Crohn's disease. The aim of this study was to compare different assays for this purpose. Methods: Fluid-phase radioimmunoassay (RIA), solid-phase enzyme-linked immunosorbent assay (ELISA), reporter gene assay (RGA), and enzyme immunoassay (EIA; a...

Background: Infliximab (IFX) is a chimeric murine/human anti-TNF antibody (Ab) used for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). Loss of response is common and associated with development of anti-IFX Abs during ongoing therapy. However, human anti-murine immunoglobulin Abs are common and may cross-react with the murine pa...

Background: The aim of the study was to investigate variations in anti-infliximab (IFX) antibody (Ab) levels and clinical implications thereof in patients with inflammatory bowel disease (IBD). Methods: A retrospective, explorative, single-center study of patients with IBD who developed anti-IFX Ab and in whom anti-IFX Ab were reassessed. Resul...

This article discusses the rationale behind recommending immunopharmacological guidance of long-term therapies with genetically engineered anti-TNF-α immunoglobulin constructs. Arguments why therapeutic decision-making should not rely on clinical outcome alone are presented. Central to this is that the use of theranostics (i.e., monitoring circulat...

The role of naturally occurring autoantibodies (NAbs) in homeostasis and in disease manifestations is poorly understood. In the present chapter, we review how NAbs may interfere with the cytokine network and how NAbs, through formation of complement-activating immune complexes with soluble self-antigens, may promote the uptake and presentation of s...

Abstract is missing (Letter).

Single nucleotide polymorphisms (SNPs) in TNF receptor superfamily (TNFRSF) 1A and 1B, and Fas ligand (FASLG) genes, have been associated with responsiveness to infliximab (IFX) in Crohn's disease. To investigate if SNPs in TNFRSF1A and 1B, and FAS (TNFRSF6) and FASLG (TNFSF6), associated with short- or long-term clinical and biological efficacy an...

A 61 year old woman with active luminal Crohn's disease was successfully treated with infliximab induction therapy followed by 5 infusions every 8 weeks. However, symptoms returned in the weeks preceding the 7th and 8th infusions. The 9th infusion was therefore given only 4 weeks after the 8th infusion, but an acute severe anaphylactoid reaction oc...

Introduction: Variability in severity of Respira-tory Syncytial Virus (RSV) infection is reportedly due to differences in inflammatory response. Objective: To characterize the cytokine response in RSV+ infants aged 0 -36 months and to relate their responses to disease severity. Methods: Nasopharyngeal aspirations (NPAs) were ana-lyzed for RSV and I...

T and B lymphocytes of the acquired immune system are functionally superimposed on the evolutionary old innate immune system. The latter recognizes conserved microbial structures through pattern recognition receptors (PRR) which are coactivated by "danger" signals through cytoplasmic PRR termed NOD-like receptors (NLR). These signals include nuclea...

Cytoplasmic inflammasomes are formed through activation of pattern recognition receptors (PRR) of the innate immune system. Endogenous and exogenous danger signals, e.g. DNA- and RNA-fragments, urate- and cholesterol crystals, silica and asbestos, ß-amyloid, UV-light and skin irritants, may induce NOD-like receptor protein (NLRP)3 inflammasomes. Th...

A cell-based assay has been developed for the quantification of the activity of TNFα antagonists based on human erythroleukemic K562 cells transfected with a NFκB regulated firefly luciferase reporter-gene construct. Both drug activity and anti-drug neutralizing antibodies can be quantified with a high degree of precision within 2h, and without int...

Infliximab (IFX) elicits acute severe infusion reactions in about 5% of patients with inflammatory bowel disease (IBD). To investigate the role of anti-IFX antibodies (Ab) and other risk factors. The study included all IBD patients treated with IFX at a Danish university hospital until 2010 either continuously (IFX every 4-12 weeks) or episodically...

Introduction Anti-TNF Biopharmaceuticals Assays for Drug Bioavailability, Pharmacokinetics, and Immunogenicity Clinical Relevance of ADAS to TNF Inhibitors References

Pituitary adenomas cause morbidity and mortality due to their localization and influence on pituitary hormone secretion. Although the pathogenesis of pituitary adenomas is unclear, studies have indicated that cytokines are involved. We investigated the role of cytokines, in particular interleukin (IL)-8, in the pathogenesis of growth hormone (GH) p...

Patients undergoing long-term highly active antiretroviral therapy treatment are probably at a higher risk of various HIV-related complications. Hyperactivation of The mammalian target of rapamycin (mTOR) has been found to contribute to dysregulated apoptosis and autophagy which determine CD4(+)-T-cell loss, impaired function of innate immunity and...

Variations in the gene for the nucleotide-binding oligomerisation domain (NOD) 2 have been associated with Crohn's disease but not multiple sclerosis (MS). Here we investigate the effect of three polymorphisms in the NOD2 gene (rs5743277, rs2066842 and rs5743291) on cytokine production and CD4+ T cell proliferation elicited by human myelin basic pr...