EBV-induced post-transplant lymphoproliferative disorder (PTLD).
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Antibodies, Viral↗
Biomedical subjects
K Bendtzen
Publications and source records attributed to K Bendtzen.
[Chronic fatigue syndrome--a controlled cross-sectional study].
Twenty-one patients fulfilling the Center for Disease Control criteria for chronic fatigue syndrome (CFS) were examined in a controlled study. Viral antibodies and tests evaluating the immune system were investigated in the patients and in a control group of 21 sex- and age-matched individuals. Production in vitro of the predominantly T-cell-derived cytokines interleukin-2 and interferon-gamma was significantly higher in patients with CFS compared the control group. Furthermore, the serum concentrations of IgA and IgE were significantly lower in patients with CFS; however, the values were within the normal reference range. All other variables were similar in the two groups. This study does not suggest a clearly disordered immune system or a chronic viral infection as a major pathogenetic factor in CFS. Longitudinal studies of immunological and virological parameters in CFS are warranted as are studies on patients that are severely handicapped.
Adolescent↗
Stimulation of the B9 hybridoma cell line by soluble interleukin-6 receptors.
Interleukin-6 (IL-6) exerts its effects by binding to specific receptors on the cell surface. The IL-6 receptor consists of at least two components, a ligand binding 80 kDa low-affinity component (IL-6R) and a signal-transducing non-ligand binding 130 kDa component (gp130). The presence of soluble forms of these components has been described in both conditioned media and biological fluids. The soluble (s) IL-6R has been shown to enhance the IL-6 sensitivity of several both murine and human IL-6 sensitive cell types. A sensitive and commonly used method for measuring biological IL-6 activity is based on the IL-6 dependent proliferation of the murine hybridoma cell line B9. In this paper, we demonstrate that recombinant (r) human (h) sIL-6R enhances the sensitivity of B9 cells in a dose-dependent manner. The rhsIL-6R enhanced the binding of 125I-rhIL-6 to B9 cells. The rhsIL-6R induced stimulation of B9 proliferation was maximal at 100 ng/ml, even without addition of rhIL-6 and in the presence of anti-hIL-6 antibodies. This may be due to endogenous IL-6 production by the B9 cells, low levels of IL-6 in the fetal calf serum used, or perhaps an IL-6 independent effect by the rhsIL-6R. In conclusion, this and other reports point to the necessity of confirming measured biological activities through the use of neutralizing specific antibodies or parallel measurements in immunochemical assays.
Animals↗
Cytokines and natural regulators of cytokines.
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Cytokines↗
Effects of 1,25-dihydroxyvitamin D3 and the analogues MC903 and KH1060 on interleukin-1 beta-induced inhibition of rat pancreatic islet beta-cell function in vitro.
The cytokine interleukin-1 beta (IL-1 beta) has been proposed to be involved in pancreatic beta-cell destruction during the development of autoimmune insulin-dependent diabetes mellitus. It has been demonstrated that 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) inhibits T-lymphocyte and monocyte functions in vitro, probably through an effect on cytokine actions, and that in vivo treatment with vitamin D can prevent pancreatic insulitis in diabetes-prone NOD mice. In this study isolated rat pancreatic islets were exposed to human IL-1 beta (25 U/ml) in the absence or presence of 1,25-(OH)2D3 or the analogues MC903 and KH1060 for 48-72 h in tissue culture, whereupon medium insulin accumulation, islet DNA and insulin contents, glucose-stimulated insulin secretion and glucose oxidation rates were assessed. All three vitamin D derivatives counteracted the suppressive effect of IL-1 beta on medium insulin accumulation, 1,25-(OH)2D3 being active at concentrations down to 0.1 nM, i.e., 1-2 orders of magnitude more efficacious than the analogues. However, only KH1060 opposed the suppressive effect of IL-1 beta on islet glucose-stimulated insulin secretion and glucose oxidation rate despite the fact that KH1060 itself reduced the islet DNA and insulin content by approximately 10% and 30%, respectively. The protective effect observed against IL-1 beta-induced beta-cell dysfunction might be related to a beneficial action of vitamin D3 on the mitochondrial calcium metabolism of the beta-cells.
Animals↗
Naturally occurring autoantibodies to interleukin-1 alpha, interleukin-6, interleukin-10, and interferon-alpha.
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Adult↗
Specific autoantibodies directed against interferon-alpha in pharmaceutically prepared human immunoglobulin preparations.
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Antibody Specificity↗
Increased plasma levels of soluble IL-2R are associated with severe Plasmodium falciparum malaria.
Plasma samples from children with mild and severe Plasmodium falciparum malaria and from children with unrelated diseases were collected to investigate whether the clinical outcome of infection was associated with plasma factors which reflected the activity of different cells of the immune system. Children with severe P. falciparum malaria had significantly higher plasma levels of soluble IL-2R than children with mild malaria. Plasma levels of IL-2R and levels of parasitaemia were significantly correlated. Neither parasitaemia nor plasma levels of tumour necrosis factor-alpha (TNF-alpha), IL-6, lymphotoxin (LT), interferon-gamma (IFN-gamma), IL-4, soluble IL-4R or soluble CD8 differed significantly between the two groups of children with malaria. High plasma levels of soluble CD8 were associated with failure of lymphocytes to produce IFN-gamma in vitro following stimulation with P. falciparum antigen. We conclude that soluble IL-2R is a useful marker of disease severity independently of the association with levels of parasitaemia, and that functional regulation of different lymphocyte subsets occurs during acute malaria episodes.
CD8 Antigens↗
Sex- and age-dependency of IgG auto-antibodies against IL-1 alpha in healthy humans.
Naturally occurring anti-interleukin (IL)-1 alpha IgG antibodies (Ab-IL-1 alpha) were measured in sera of 466 healthy Danish blood donors. Ab-IL-1 alpha bound IL-1 alpha with exceptionally high affinity (Kd: 10(-11) M) and neutralized both cell-associated and extracellular IL-1 alpha but not IL-1 beta or IL-1 receptor antagonist. More than 80% of the saturable binding of rIL-1 alpha to serum was to Ab-IL-1 alpha, suggesting that these antibodies are the quantitatively most important IL-1 alpha-binding components in serum. Judged by second antibody precipitation assay, the prevalence of Ab-IL-1 alpha varied between 30% and 75% and correlated positively with age (P = 0.037). The binding capacity of serum also increased with age. Although men were more frequently positive than women (P < 0.001), there were no sex- or age-dependent alterations in the average affinities of the antibodies. Free IL-1 alpha-like molecules were generally not detected in these sera. However, acid treatment showed that 25% of Ab-IL-1 alpha-positive sera contained low amounts of IL-1 alpha-Ab-IL-1 alpha immune complexes. IgG4 represented the main IgG isotype, whereas IgG3 Ab-IL-1 alpha were undetectable. The relative amounts of IgG4 Ab-IL-1 alpha increased while IgG2-and IgG1 Ab-IL-1 alpha decreased in elderly individuals. The presence in normal individuals and the lack of affinity maturation with age suggest that Ab-IL-1 alpha may be regulatory natural auto-antibodies perhaps coded by germline genes.
Adolescent↗
Th1-like human T-cell clones recognizing Leishmania gp63 inhibit Leishmania major in human macrophages.
The major surface protease of Leishmania major, gp63, has been suggested as a vaccine candidate for cutaneous leishmaniasis. In this study gp63 was purified from L. major promastigotes. A panel of human T-cell clones recognizing this protein were generated from individuals who had previously had self-healing cutaneous leishmaniasis. The T-cell clones expressed CD4, and the alpha chain of the T-cell antigen receptor. GP63 reactive T-cell clones activated by antigen or by immobilized anti-CD3 antibody released relative large amounts of interferon-gamma and no or little interleukin-4, thereby resembling Th1 cells. Autologous mononuclear cells and Epstein-Barr virus-transformed B cell lines were equally efficient in presenting the antigen to the T cells. The gp63 reactive T cells induced resistance to infection in cultured human macrophages by L. major. The data confirm that human CD4+ T cells recognizing gp63 can take part in the host defence against L. major infections.
Adult↗
Increased concentrations of interleukin-6 and interleukin-1 receptor antagonist and decreased concentrations of beta-2-glycoprotein I in Gambian children with cerebral malaria.
To investigate the pathogenic versus the protective role of cytokines and toxin-binding factors in Plasmodium falciparum infections, we measured the concentrations of tumor necrosis factor alpha, interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-1 receptor antagonist, and IL-6, as well as soluble receptors of tumor necrosis factor and IL-6 (sIL-6R) in serum of Gambian children with cerebral malaria, mild or asymptomatic malaria, or other illnesses unrelated to malaria. Because cytokine secretion may be triggered by toxic structures containing phosphatidylinositol (PI), we also measured concentrations of anti-PI antibodies and the PI-binding serum protein beta-2-glycoprotein I. We found increased concentrations of IL-6, sIL-6R, IL-1ra, and some immunoglobulin M antibodies against PI in children with cerebral malaria, but those who died had decreased concentrations of beta-2-glycoprotein I. We conclude that increased concentrations of cytokines and soluble cytokine receptors represent a normal host response to P. falciparum infections but that excessive secretion of cytokines like IL-6 may predispose to cerebral malaria and a fatal outcome while beta-2-glycoprotein I may protect against a fatal outcome of cerebral malaria.
Antibodies, Protozoan↗
Tumor necrosis factor-alpha increases myocardial microvascular transport in vivo.
Tumor necrosis factor-alpha (TNF-alpha) is a primary mediator in the pathogenesis of tissue injury, and high circulating levels of TNF-alpha are found in a variety of pathological conditions. In open-chest anesthetized dogs, the effects of intracoronary recombinant human TNF-alpha (rTNF-alpha; 100 ng/kg for 60 min) on myocardial microvascular transport of a small hydrophilic indicator was examined by the single-injection, residue-detection method. Intracoronary infusion of rTNF-alpha increased myocardial microvascular transport after 120 min. This increase was preceded by a sustained decline in cardiac output and was associated with the appearance of areas with myocardial necrosis in the regional left ventricular wall. The myocardial plasma flow rate and maximum plasma flow rate in response to a 30-s coronary occlusion were not influenced by rTNF-alpha, although a decrease in the myocardial plasma flow rate was observed after 180 min. Circulating neutrophil counts were increased by rTNF-alpha, but the increase in myocardial capillary permeability could not be ascribed to regional neutrophil infiltration. We conclude that picomolar levels of rTNF-alpha can influence the movement of small hydrophilic molecules across the myocardial microvascular barrier in vivo and induce a prolonged decrease in cardiac performance. These effects may be important elements in myocardial pathophysiology.
Animals↗
Cytokines suppress human islet function irrespective of their effects on nitric oxide generation.
Cytokines have been proposed as inducers of beta-cell damage in human insulin-dependent diabetes mellitus via the generation of nitric oxide (NO). This concept is mostly based on data obtained in rodent pancreatic islets using heterologous cytokine preparations. The present study examined whether exposure of human pancreatic islets to different cytokines induces NO and impairs beta-cell function. Islets from 30 human pancreata were exposed for 6-144 h to the following human recombinant cytokines, alone or in combination: IFN-gamma (1,000 U/ml), TNF-alpha (1,000 U/ml), IL-6 (25 U/ml), and IL-1 beta (50 U/ml). After 48 h, none of the cytokines alone increased islet nitrite production, but IFN-gamma induced a 20% decrease in glucose-induced insulin release. Combinations of cytokines, notably IL-1 beta plus IFN-gamma plus TNF-alpha, induced increased expression of inducible NO synthase mRNA after 6 h and resulted in a fivefold increase in medium nitrite accumulation after 48 h. These cytokines did not impair glucose metabolism or insulin release in response to 16.7 mM glucose, but there was an 80% decrease in islet insulin content. An exposure of 144 h to IL-1 beta plus IFN-gamma plus TNF-alpha increased NO production and decreased both glucose-induced insulin release and insulin content. Inhibitors of NO generation, aminoguanidine or NG-nitro-L-arginine, blocked this cytokine-induced NO generation, but did not prevent the suppressive effect of IL-1 beta plus IFN-gamma plus TNF-alpha on insulin release and content. In conclusion, isolated human islets are more resistant to the suppressive effects of cytokines and NO than isolated rodent islets. Moreover, the present study suggests that NO is not the major mediator of cytokine effects on human islets.
Adolescent↗
Tumour necrosis factor alpha during human pregnancy and labour: maternal plasma and amniotic fluid concentrations and release from intrauterine tissues.
The aims of this study were: to quantify immunoreactive tumour necrosis factor alpha (TNF-alpha) concentrations in maternal plasma and amniotic fluid obtained from women during pregnancy and labour, both at term and preterm; and to establish the effects of bacterial endotoxin and cytokines on the in vitro release of TNF-alpha from intrauterine tissues. Maternal plasma TNF-alpha concentrations did not change during pregnancy (457.2 +/- 102.9 ng/l, mean +/- SEM, N = 52) or at the time of labour (543.5 +/- 138.6 ng/l, N = 43). In contrast, amniotic fluid TNF-alpha concentrations increased significantly (p < 0.05) during pregnancy (early pregnancy, EP, 93.0 +/- 24.8 ng/l, N = 7; preterm not-in-labour, PNIL, 186.8 +/- 42.9 ng/l, N = 16; term not-in-labour. TNIL, 499.7 +/- 150.9 ng/l, N = 13) and in association with preterm labour (preterm in-labour, PIL, 958.7 +/- 575.6 ng/l, N = 5 vs PNIL, 186.8 +/- 42.9 ng/l, N = 16). Choriodecidual and placental explants (N = 3) maintained in in vitro culture released TNF-alpha. Furthermore, the release of TNF-alpha was increased significantly (p < 0.05) by bacterial endotoxin (lipopolysaccharide, 10 ng/l-10 mg/l) but was not affected by the following cytokines at the indicated doses: interleukin-1 alpha (0.28 nmol/l), interleukin-6 (12.5 nmol/l), granulocyte colony-stimulating factor (2.5 nmol/l), granulocyte-macrophage colony-stimulating factor (35 nmol/l), macrophage colony-stimulating factor (1.2 nmol/l), leukaemia inhibitory factor (0.45 nmol/l) and transforming growth factor-beta (0.4 nmol/l).(ABSTRACT TRUNCATED AT 250 WORDS)
Amnion↗
Liposomal delivery of antioxidant enzymes protects against hydrogen peroxide- but not interleukin-1 beta-induced inhibition of glucose metabolism in rat pancreatic islets.
The aim of the present investigation was to evaluate the putative involvement of oxygen free radicals in interleukin-1 beta (IL-1 beta)-induced suppression of islet glucose oxidation. Isolated adult rat pancreatic islets were exposed for 1 h to liposomally encapsulated superoxide dismutase (SOD; 10 mg/ml), catalase (CAT; 10 mg/ml) and glutathione peroxidase (GPX; 5 mg/ml), after which IL-1 beta (25 U/ml) or hydrogen peroxide (H2O2; 0.1 mM) was added, and the incubation was continued overnight. The following day, samples were taken from the incubation media for nitrite determinations, and islet glucose oxidation rates were measured. The CAT activity increased fourfold after addition of CAT-containing liposomes. It was found that IL-1 beta induced a marked increase in islet nitrite production, as an index of nitric oxide formation, and that this was paralleled by a decrease in islet glucose oxidation rates. H2O2-treated islets exhibited a modest decrease in glucose oxidation rates and a minor increase in the release of nitrite to the media. Treatment of islets with liposomes containing the antioxidant enzymes SOD, CAT and GPX, either alone or in combination, did not decrease the effect of IL-1 beta. However, the H2O2-induced decrease in glucose oxidation rates was counteracted by the combination of the antioxidants. It was concluded that, provided the intracellular delivery of the antioxidant enzymes to the islet cells was effective, oxygen free radicals probably do not play a decisive role in IL-1 beta suppression of islet glucose metabolism.
Animals↗
Influence of tumour necrosis factor-alpha, tumour necrosis factor-beta and interferon-gamma, separately and added together with interleukin-1 beta, on the function of cultured human thyroid cells.
Interleukin (IL)-1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma have been demonstrated in thyroid tissue. We have previously shown that high concentrations of IL-1 inhibit and low concentrations stimulate human thyroid cell function in vitro. In the present study, TNF-alpha, TNF-beta and IFN-gamma all inhibited thyroglobulin (Tg) and cAMP production from cultured human thyroid cells. When TNF-alpha was added simultaneously with IL-1 beta, the highest concentration of TNF-alpha (10(6) U/l) enhanced the inhibition of Tg and cAMP induced by IL-1 beta (1-10(5) U/l). TNF-beta had no influence on IL-1 beta-induced inhibition. IFN-gamma (10(4) U/l) added together with IL-1 beta in lower concentrations (1-10(2) U/l) stimulated cAMP production, while at high concentrations of IL-1 beta (10(5) U/l), IFN-gamma enhanced the inhibitory influence of IL-1 beta on Tg production. The hormones of the immune system, IL-1, TNF and IFN-gamma, may thus contribute to the decreased thyroid function characteristic of some thyroid inflammatory diseases.
Cells, Cultured↗
Nicotinamide decreases nitric oxide production and partially protects human pancreatic islets against the suppressive effects of combinations of cytokines.
It has been recently reported that human pancreatic islets in tissue culture produce nitric oxide (NO) and show a decreased function when exposed for 6 days to combinations of cytokines (interleukin-1 beta (IL-1 beta) + tumor necrosis factor-alpha (TNF-alpha) + interferon-gamma (IFN-gamma). Here we study the effects of nicotinamide (Nic; 10 or 20 mmol/l) on these deleterious effects of cytokines (50 U/ml IL-1 beta + 1000 U/ml TNF-alpha + 1000 U/ml IFN-gamma). Islets were isolated from 8 human pancreata at the Central Unit of the beta-Cell Transplant, Brussels, sent to Uppsala and, after 3-5 days in culture, exposed for 6 additional days to the cytokines and/or Nic. The cytokines induced a 6-fold increase in islet NO production (P < 0.001), and this effect was partially counteracted by Nic (50-60% decrease in NO production; P < 0.001). The cytokines severely decreased the islet insulin content and glucose-induced insulin release (16.7 mmol/l glucose; 90% decrease; P < 0.001). Both these effects of cytokines were partially counteracted by Nic, especially at the highest concentration (20 mmol/l; 2-4-fold increase compared to islets exposed to cytokines alone; P < 0.01). Nic by itself did not affect the insulin content or insulin release by control islets. In conclusion, the present data indicate that Nic counteracts the deleterious effects of cytokines on human pancreatic islets. This effect of Nic may be relevant for the beneficial effects of the drug in early IDDM.
Adult↗
Nitric oxide production is not involved in the effects of interleukin-1 beta on cAMP, thyroglobulin and interleukin-6 in TSH-stimulated human thyroid cells.
Interleukin (IL)-1 inhibits the function of insulin-producing rat pancreatic beta-cells in vitro and in vivo, and it has been postulated that the IL-1 effect is mediated through the cytokine inducible nitric oxide (NO) synthase. IL-1 inhibits the function of cultured human thyroid cells too, and in this study human thyroid cell production of NO in response to the TSH-stimulated influence of IL-1 beta (10(5) U/l) and TNF-alpha (10(6) U/l), alone or in combination was measured. IL-1 beta, but not TNF-alpha, induced an increase in nitrite production, which was significantly reduced by the competitive inhibitor of nitric oxide synthase L-NG-monomethyl-arginine (L-NMMA) (0.1 mmol/L and 0.5 mmol/L). However, the nitrite production was unrelated to the IL-1 beta-induced inhibition of thyroglobulin (Tg) and cyclic AMP (cAMP) and the IL-1 beta-induced IL-6 production. Thus, it is unlikely that NO is a second mediator of the demonstrated effects of IL-1 beta and TNF-alpha on human thyroid cells in culture.
Cells, Cultured↗