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Biomedical subjects

K Bendtzen

Publications and source records attributed to K Bendtzen.

At least 19 recordsLinked to original sources
PubMed1992

Lymphokines and soluble interleukin-2 receptors in juvenile chronic arthritis. Clinical and laboratory correlations.

Serum levels of interleukin (IL)-2, interferon gamma (IFNg) and soluble IL-2 receptors (sIL-2R) were determined in sera from 34 patients with poly- or pauciarticular juvenile chronic arthritis (JCA) by use of enzyme-linked immunosorbent assays (ELISAs). Levels of sIL-2R were elevated in the group of patients compared with those of healthy children and correlated significantly with several parameters of clinical activity, including the functional capacity, joint score, visual-analogue score and erythrocyte sedimentation rate (ESR). Serum IL-2 levels were also elevated in the JCA patients, correlating with the patients functional capacity. Serum levels of IFNg were below the detection limit of the assay. Our data supported the notion that T-cell activation plays a role in the immunopathologic processes leading to clinical JCA.

Adolescent↗
PubMed1992

1,25-Dihydroxyvitamin D3-mediated suppression of T lymphocyte functions and failure of T cell-activating cytokines to restore proliferation.

1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) has been shown to be a potent inhibitor of lymphocyte proliferation in vitro. The present study was undertaken to determine if this is caused by a direct effect on the lymphocytes, and to evaluate to what degree this suppression may be restored by the addition of cytokines. 1,25-(OH)2D3, > or = 10(-10) M, significantly inhibited the proliferation of pokeweed mitogen (PWM)-driven human peripheral blood mononuclear cells (MNC). Depletion of monocytes did not alter the response to 1,25-(OH)2D3. The antiproliferative effect was preceded by decreased production of interleukin (IL)-1 alpha and lymphotoxin (LT), both of which are crucially involved in T cell activation. However, the suppressive effect of 1,25-(OH)2D3, seen in MNC cultures stimulated with PWM alone, was of the same magnitude as the effect seen in MNC cultures stimulated with a combination of PWM and recombinant (r)IL-1 alpha, rIL-6, recombinant tumour necrosis factor (rTNF) alpha, rIL-2 or rLT, as well as PWM plus conditioned medium. Although pretreatment of monocytes for 2 h with 1,25-(OH)2D3 caused significant reduction in the release of IL-1 alpha and TNF alpha, reconstitution of monocyte-depleted cultures with similarly treated monocytes had no inhibitory effect on the proliferative response. In conclusion, even though it cannot be excluded that a low but critical number of monocytes are essential for the suppressive effect of 1,25-(OH)2D3-mediated inhibition of MNC proliferation, the inhibition is most likely the result of a direct effect on the lymphocytes and independent of monocytes and exogenously added cytokines.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

1,25-Dihydroxyvitamin D3 inhibits cytokine production by human blood monocytes at the post-transcriptional level.

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] inhibits lymphocyte proliferation and production of antibodies and lymphokines such as interleukin (IL)-2 and interferon gamma. These lymphocyte functions are dependent upon cytokines, including IL-1 alpha, IL-1 beta, IL-6 and tumour necrosis factor alpha (TNF-alpha), produced by the antigen presenting cells. In the present study we examined the effect of 1,25-(OH)2D3 on the production of these cytokines, as well as superoxide generation by freshly isolated mononuclear cells and partially purified monocytes. The immediate precursor of 1,25(OH)2D3, 25-OH D3, and the synthetic analogue MC 903 ('Calcipotriol') were examined in parallel. 1,25-(OH)2D3 dose-dependently inhibited the production of IL-alpha, IL-6 and TNF-alpha by Escherichia coli lipopolysaccharide (LPS)-stimulated monocytes, without affecting superoxide production. MC 903 had comparable effects while 25-OH D3 was ineffective. The inhibition caused by 1,25-(OH)2D3 was not abolished by supraoptimal concentrations of LPS or indomethacin. 1,25-(OH)2D3 had similar effects on secreted and cell-associated IL-alpha. Nuclear run-off analysis indicated that inhibition of these cytokines was not caused by impaired production of mRNA. Taken together, the study demonstrates a vitamin D-induced inhibitory effect of LPS-driven monokine production, which is most likely a vitamin D-receptor mediated phenomenon exerted at a post-transcriptional, presecretory level. Impaired monokine production may be of importance in 1,25-(OH)2D3-mediated inhibition of lymphocyte functions in vitro.

Calcifediol↗
PubMed1992

Effects of human anti-IL-1 alpha autoantibodies on receptor binding and biological activities of IL-1.

Immunoglobulin G (IgG) antibodies to interleukin 1 alpha (IL-1 alpha) are frequently found in the sera of healthy human individuals. The effects of these autoantibodies on receptor binding and biological activities of human IL-1 were tested. Using the murine T-lymphocyte line NOB-1, human thyrocytes and human foreskin fibroblasts, the antibodies competitively inhibited the biological activity of human recombinant IL-1 alpha (rIL-1 alpha). The degree of inhibition correlated with 125I-rIL-1 alpha binding to IgG in different immunoglobulin preparations and in individual sera. These antibodies also neutralized the IL-1 activity of isolated membrane fragments and lysates of human blood monocytes activated by lipopolysaccharide. In contrast, the supernatant IL-1 activity was not affected. Stronger inhibition of biological activity and cell binding of 125I-rIL-1 alpha was obtained with NOB-1 cells than with human thyrocytes. The antibodies failed to interfere with the biological activity of rIL-1 beta. It is concluded that IgG autoantibodies of IL-1 alpha in the sera of healthy humans selectively inhibit the biological activity of the soluble and membrane-associated forms of IL-1 alpha in vitro, and that the degree of biological inhibition afforded by these antibodies depends upon the target cell.

Animals↗
PubMed1992

Treatment of Crohn's disease with fusidic acid: an antibiotic with immunosuppressive properties similar to cyclosporin.

Fusidic acid is an antibiotic with T-cell specific immunosuppressive effects similar to those of cyclosporin. Because of the need for the development of new treatments for Crohn's disease, a pilot study was undertaken to estimate the pharmacodynamics and tolerability of fusidic acid treatment in chronic active, therapy-resistant patients. Eight Crohn's disease patients were included. Fusidic acid was administered orally in a dose of 500 mg t.d.s. and the treatment was planned to last 8 weeks. The disease activity was primarily measured by a modified individual grading score. Five of 8 patients (63%) improved during fusidic acid treatment: 3 at two weeks and 2 after four weeks. There were no serious clinical side effects, but dose reduction was required in two patients because of nausea. Biochemically, an increase in alkaline phosphatases was noted in 5 of 8 cases (63%), and the greatest increases were seen in those who had elevated levels prior to treatment. All reversed to pre-treatment levels after cessation of treatment. The results of this pilot study suggest that fusidic acid may be of benefit in selected chronic active Crohn's disease patients in whom conventional treatment is ineffective. Because there seems to exist a scientific rationale for the use of fusidic acid at the cytokine level in inflammatory bowel disease, we suggest that the role of this treatment should be further investigated.

Adolescent↗
PubMed1992

Serum-induced suppression of interferon (IFN) activity. Lack of evidence for the presence of specific autoantibodies to IFN-alpha in normal human sera.

IgG antibodies binding to different IFN species have been described in sera of healthy and diseased individuals. Human serum immunoglobulins have also been shown to interfere with IFN bioactivity. To characterize these antibodies, human recombinant IFN-alpha 2A (rIFN-alpha) was radioiodinated, and ligand binding studies were performed in human sera as well as on the human cell line A-549 in the presence of human serum. 125I-rIFN-alpha bound to serum factors of healthy individuals. However, less than 3% of the binding was to IgG and the binding was non-saturable and therefore most likely non-specific. 125I-rIFN-alpha bound to receptors on A-549 cells, and the ligand-receptor complexes appeared to internalize. However, both cell binding and internalization of 125I-rIFN-alpha were independent of the presence of human serum. We conclude that normal human sera do not contain detectable autoantibodies to rIFN-alpha.

Animals↗
PubMed1992

Effects of immunomodulators on ecto-5'-nucleotidase activity on blood mononuclear cells in vitro.

In this study the effects of immunomodulators on the ecto-5'-nucleotidase (ecto-5'-NT) activity on blood mononuclear cells (BMC) were examined in vitro. Interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) decreased the level of ecto-5'-NT activity on BMC whereas prostaglandin E2 (PGE2) increased the ecto-5'-NT level. All three immunomodulators influenced the ecto-5'-NT activity of isolated monocytes whereas only IL-4 and PGE2 had an effect on the enzyme level on isolated lymphocytes. The effect was dependent upon protein synthesis. The effect was dose dependent: IL-4 was effective at concentrations down to 0.5 U/ml, IFN-gamma down to 40 U/ml and PGE2 at nanomolar concentrations. These data indicate that immunomodulators may also take part in the regulation of ecto-5'-NT activity on BMC in vivo. BMC from 7 patients with different immunodeficiency syndromes showed decreased ecto-5'-NT activity on freshly isolated cells. However, following culture ecto-5'-NT activity was increased above the level found on freshly isolated BMC from healthy persons. On BMC from 3 patients with hypogammaglobulinaemia, the effect of IL-4 on the level of ecto-5'-NT activity was identical to that found on BMC from healthy donors, whereas PGE2 increased ecto-5'-NT activity on BMC from only 1 of the 3 patients investigated. The decreased ecto-5'-NT activity of BMC from patients with immunodeficiency may thus be due to a defective regulation of ecto-5'-NT activity in vivo.

5'-Nucleotidase↗
PubMed1992

Biomolecular regulation of the IgE immune response. I. Cell-associated IgE and in vitro IgE synthesis.

Several cell types, including mast cells, basophils, macrophages/monocytes, lymphocytes, platelets and eosinophils, may bind or contain IgE. To investigate the source of cell-associated IgE and its relation to spontaneous IgE synthesis, peripheral blood mononuclear cells from allergic and non-allergic donors were examined. Using a combination of different cell fractionation techniques and varying methods for extraction of cell-associated IgE, data were obtained indicating that monocytes constitute a major source of cell-associated IgE in human blood. The amount of cell-associated IgE in peripheral blood mononuclear cells from allergic and non-allergic donors varied more than 100-fold but correlated closely to the level of serum IgE (r = 0.84, p < 0.001, n = 38). Spontaneous and mitogen-induced in vitro syntheses of IgA, IgE and IgG were compared for allergic and non-allergic donors. Only one donor with very high serum IgE demonstrated spontaneous or mitogen-induced in vitro IgE synthesis despite synthesis of IgA and IgG.

Asthma↗
PubMed1992

Interleukins increase surface ganglioside expression of pancreatic islet cells in vitro.

This experiment was conducted in order to investigate whether expression of gangliosides on islet cell surface in vitro is influenced by cytokines, especially interleukin 1. Islets from adult Lewis rats were incubated with different concentrations of recombinant-derived human cytokines. Following dispase treatment, the single cells were labeled with monoclonal antiganglioside antibodies A2B5 or R2D6, and conjugate. Both are directed against beta cells; A2B5 is recognized to bind specifically to pancreatic islet cells, while R2D6 is shown to bind no other pancreatic cells than beta cells. Surface labeling was evaluated in blind trials using a fluorescence microscope and a fluorescence-activated cell sorter (FACS). A2B5 staining demonstrated a significantly higher number of labeled cells after incubation with interleukin 1 alpha (14.9% +/- 2.8; p less than 0.005), interleukin 1 beta (23.2% +/- 4.2; p less than 0.0005) or TNF alpha (16.1% +/- 4.0; p = 0.005) compared to endotoxin controls (4.1% +/- 1.1). Interleukin 1 beta (9.5% +/- 1.5; p less than 0.005) showed a significantly increased number of R2D6-stained cells (control: 2.3% +/- 1.3). A similar but not significant effect was seen with interleukin 1 alpha and TNF alpha. Interleukin 6 had no effect on the antigen expression. The intensity of labeling was elevated among interleukin 1 beta-incubated cells compared to control samples. Thus, treatment of islets with different cytokines, especially interleukin 1 beta, increases surface antigen expression. We suggest that this mechanism of action in vitro may be of importance for the putative diabetogenic effect of interleukin 1.

Animals↗
PubMed1992

Effect of fusidic acid on interleukin-1 (IL-1)- and IL-6-induced pancreatic beta-cell functions in rats.

Fusidic acid and its sodium salt (fusidin) are anti-staphylococcal drugs with a steroidal primary structure. Both compounds have been shown to prevent the lymphocyte co-stimulatory activities of the cytokines, interleukin (IL)-1 and IL-6, in a manner similar to that of cyclosporin A. As shown in this paper, fusidin also prevents the inhibitory effect of human recombinant IL-1 beta (rIL-1 beta) and the stimulatory effect of human rIL-6, on glucose-induced insulin production in vitro by normal rat pancreatic islets. The drug also inhibited rIL-1 beta-induced IL-6 production by the islets. Fusidin showed a dose-related effect at pharmacologically relevant concentrations from 3 to 30 micrograms/ml, and the drug was progressively less active when added 1, 4 and 24 h after rIL-1 beta. Electron microscopical studies showed that beta cells cultured for 72 h with rIL-1 beta accumulated less lipid in the presence of fusidin, most probably reflecting the functionally protective effect of the drug. Other characteristic ultrastructural changes induced in beta cells by rIL-1 beta were, however, not altered. It is suggested that fusidin may prove clinically effective as a modulator of IL-1- and IL-6-induced changes in beta-cell functions.

Animals↗
PubMed1992

Anti-diabetogenic effect of fusidic acid in diabetes prone BB rats.

Fusidic acid and its sodium salt (fusidin) are anti-staphylococcal drugs. In vitro studies have shown that they prevent the lymphocyte co-stimulatory activities of the cytokines IL-1 and IL-6 in a manner similar to that of cyclosporin A, and prevent the inhibitory effect of IL-1 on glucose-induced insulin production. As IL-1 and IL-6 are thought to play a role in the pathogenesis of Type 1 diabetes, the aim of this study was to investigate whether fusidin could influence the disease incidence of the spontaneously diabetic BB rat model. Accordingly, a group of 50 BB rats receiving fusidin dissolved in their drinking water were compared to a control group of 55 rats over a period of 200 days. The incidence of diabetes was found to be 52% in the experimental group and 71% in the control group (P < 0.05). The degree of insulitis and the number of islets at histological examination were similar among the non-diabetic animals whereas the diabetic fusidin-treated animals showed a higher degree of islet preservation than the diabetic control rats. The results are highly indicative of an anti-diabetogenic effect of fusidin.

Administration, Oral↗
PubMed1992

Cytokine expression in labial salivary glands from patients with primary Sjögren's syndrome.

The presence and distribution of 7 cytokines was examined immunohistologically in labial salivary gland (LSG) specimens from patients with primary Sjögren's syndrome (SS) and control subjects. The cytokines interleukin (IL)-1 beta IL-6, tumor necrosis factor (TNF) alpha and interferon (IFN) gamma were identified in defined parts of LSG from patients but not in the corresponding parts of control glands: (a) LSG acinar epithelium expressed IL-1 beta, (b) blood vessels located in both normal LSG stroma and within lymphocytic infiltrates expressed IL-1 beta, IL-6 and IFN gamma, and (c) lymphocytic infiltrates expressed IL-1 beta, IL-6 and TNF alpha. All four cytokines were expressed by salivary ducts within both patient and control specimens, but with generally greater intensity in patients. IL-1 alpha, IL-4 and TNF beta (lymphotoxin) could not be detected in any of the specimens from patients or controls. The locations of cytokines in LSG suggests possible mechanisms of immunologically mediated parenchymal damage in primary SS.

Adult↗
PubMed1992

Role of receptor binding and gene transcription for both the stimulatory and inhibitory effects of interleukin-1 in pancreatic beta-cells.

A brief exposure of pancreatic islets to the cytokine interleukin-1 beta (IL-1 beta) induces an initial stimulatory phase, which is followed by inhibition of islet function and eventually beta-cell damage. In the present study we have investigated the effects of IRAP, a blocker of type I IL-1 receptor and actinomycin D, an inhibitor of DNA transcription, on both the stimulatory and inhibitory effects of IL-1 beta on rat pancreatic islets in vitro. The two test agents counteracted the initial stimulatory actions of IL-1 beta on both islet glucose-induced insulin release and glucose oxidation rates. Furthermore, cycloheximide, an inhibitor of protein synthesis, could also prevent the early IL-1 beta-induced stimulation of insulin release. When islets were exposed for 1 hr to IL-1 beta and studied after 12 hr, there was a 75% inhibition of glucose induced insulin release, a 50% decrease in glucose oxidation rates and a 30% decrease in (pro)insulin biosynthesis. These effects were completely counteracted by coincubation with IRAP or actinomycin D, but were not affected by coincubation with pertussis toxin. Islet exposure to IL-1 alpha also induced a 60-80% inhibition of glucose-induced insulin release after 12 hr. As observed with rIL-1 beta, IRAP was also able to block the suppressive effects of IL-1 alpha on islet function. Mouse islets exposed for 2 hr to IL-1 beta and studied after 12 hr presented a 50% decrease in the glucose-induced insulin release. This effect was completely blocked by coincubation with a rat monoclonal antibody generated against the type I mouse IL-1 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Inhibition of human T lymphocyte proliferation and cytokine production by 1,25-dihydroxyvitamin D3. Differential effects on CD45RA+ and CD45R0+ cells.

1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3), the biologically active form of vitamin D3, has been shown to modulate lymphocyte functions in vitro. These effects are exerted through binding to specific receptors that are expressed in activated, but not in resting lymphocytes. 1,25-(OH)2 D3 inhibits lymphocyte proliferation, immunoglobulin production and the release of cytokines including interleukin-2 (IL-2) and interferon gamma (IFN gamma) by mitogen driven blood mononuclear cells (MNC). A distinction between CD45RA+ and CD45R0+ subsets of T cells has, however, proven extremely relevant in terms of immunoactivation and immunopathology. The present study was undertaken to evaluate effects of 1,25-(OH)2 D3 on proliferation and cytokine production by purified CD45RA+ and CD45R0+ T cells. 1,25-(OH)2 D3 caused a dose- and time-dependent reduction in phytohemagglutinin-(PHA) and poke-weed mitogen (PWM)-driven proliferation of purified CD45R0+ T cells. In contrast, proliferation of the CD45RA+ subset was unaffected by this treatment. Comparable levels of lymphotoxin (LT), IFN gamma and IL-2 were obtained in cultures of both subsets. 1,25-(OH)2 D3 reduced these levels, but the suppressive effect of the hormone was delayed in cultures of CD45RA+ T cells. The results suggest that the CD45R0+ subset is relatively more sensitive than CD45RA+ subset to the inhibitory effects of 1,25-(OH)2 D3. This finding may be of pharmacological interest, because the CD45R0+ subset plays a key role in immune activation and because these cells have been associated with the pathogenesis of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.

Adult↗
PubMed1991

Eosinophil protein X/eosinophil derived neurotoxin (EPX/EDN). Detection by enzyme-linked immunosorbent assay and purification from normal human urine.

Eosinophil protein X/eosinophil derived neurotoxin (EPX/EDN) is one of the cationic proteins found in the granules of the human eosinophilic granulocytes. EPX was purified from extracts of granules isolated from blood buffy coat cells of healthy donors. Polyclonal anti-EPX antibodies were subsequently raised in rabbits. The anti-EPX-antibodies raised in rabbits showed no reactivity with other proteins in the granule extract. The sandwich ELISA utilized the biotin/avidin amplification system and measured EPX over the range of 60-2000 pg/ml. The intra- and interassay coefficients of variation were 6.5% and 8.2%, respectively, and the mean recoveries of 25 and 50 pg of purified EPX added to diluted serum samples were 106 +/- 16% (mean +/- SD; n = 12) and 112 +/- 14%, respectively. Using this assay we found high amounts of EPX in normal human urine (U-EPX). U-EPX was purified by a two step procedure involving affinity chromatography on heparin Sepharose and size exclusion chromatography on Sephadex G-50 superfine. Extracted EPX and U-EPX had ribonuclease activity and comigrated on agarose electrophoresis. They also showed immunological identity when evaluated with rabbit anti-EPX antibodies, but they differed slightly on SDS-PAGE probably due to differences in glycosylation. Our results support the findings that EPX/EDN is identical to a nonsecretory ribonuclease isolated from urine.

Blood Proteins↗