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Biomedical subjects

M B Hansen

Publications and source records attributed to M B Hansen.

At least 19 recordsLinked to original sources
PubMed1995

Influence of interleukin-6 (IL-6) autoantibodies on IL-6 binding to cellular receptors.

Neutralizing autoantibodies to interleukin-6 (aAb-IL-6) have been reported in healthy individuals, in patients with autoimmune diseases, and in pharmaceutically prepared pooled IgG (IVIg). We investigated the ability of aAb-IL-6 derived from IVIg to interfere with IL-6 binding to the undifferentiated monocytic cell line U-937. High-affinity aAb-IL-6, primarily of the IgG1 subclass, constituted approximately 1:10(6) of the total IgG in IVIg preparations. IL-6 binding to cellular receptors was strongly inhibited by one class of aAb-IL-6. These antibodies recognized epitope(s) on IL-6 essential for the binding of IL-6 to the alpha subunit of the IL-6 receptor (IL-6R). Another class of aAb-IL-6 recognized epitope(s) on IL-6, which is not essential for the binding to IL-6R but nevertheless important for the formation of high-affinity cellular IL-6 binding. These antibodies presumably interfered with the association of IL-6 receptor beta chains (gp130) with IL-6/IL-6R complexes, implicating that small IL-6/aAb-IL-6 immune complexes bound saturably (low affinity/high capacity) to cellular IL-6 receptors. There was no detectable binding of IL-6 through aAb-IL-6 and Fc receptors on U-937, and IVIg had no direct IL-6 receptor antagonizing activity. Dissociation kinetics of IL-6/aAb-IL-6 complexes at 37 degrees C revealed that IL-6 was liberated from 75% of the aAb-IL-6 with a half-time (t/2) approximately 4 h but bound almost irreversibly to the remaining aAb-IL-6 (t/2 > 20 h). Cellular IL-6 uptake and degradation was suppressed by aAb-IL-6. Taken together, the data suggest that loss of immunologic tolerance against IL-6 might be a novel physiological mechanism by which IL-6 activities are effectively attenuated. Finally, binding of IL-6 in complex with IgG1 aAb-IL-6 on cells expressing IL-6 receptors implicates that such cells could be targets of antibody-dependent immunological reactions, including cytotoxic reactions.

Animals↗
PubMed1995

Cytokines and autoantibodies to cytokines.

Cytokines are essential components of our defense and repair systems but also potentially harmful mediators of infectious and immunoinflammatory reactions. Clinically important cytokines function systemically as pleiotropic hormones with overlapping effects on many cell types. All engage in a complex network of agonists and antagonists. Some immunoglobulin G (IgG) antibodies have been found to be potent and specific regulators of cytokines. These antibodies bind interleukin (IL-1)alpha, IL-6, IL-10, leukemia inhibitory factor (LIF), and interferon (IFN)-alpha/beta with exceptional force. They neutralize their corresponding cytokines ex vivo and perhaps in vivo, although they may also function as cytokine carriers. The biological role of autoantibodies to cytokines is not yet understood, but they may provide a level of regulation not appreciated at present. Inappropriate production/function of such antibodies could be pathogenetically involved in immunoinflammatory and other diseases. Cytokine antibodies may also contribute to the anti-inflammatory effects of human IgG therapy.

Adjuvants, Immunologic↗
PubMed1995

Interleukin-4 and interferon-gamma production by Leishmania stimulated peripheral blood mononuclear cells from nonexposed individuals.

Interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) production by Leishmania reactive peripheral blood mononuclear cells (PBMC) from non-exposed individuals was investigated. IFN-gamma was measured in culture supernatants after antigen stimulation. For the measurement of IL-4, antigen stimulated cells were pulsed with PMA and ionomycin before IL-4 release was measured. L. donovani and L. major antigens induced IL-4 production (105-1748 pg/ml) in 13 and seven cultures, and IFN-gamma production (1.7 - > 66 IU/ml) in 14 and 11 of 20 cultures, respectively. IL-4 production rose steeply after 6 days of antigen stimulation suggesting a response due to antigen recognition. Both IL-4 and IFN-gamma production was abrogated by depletion of CD2+ or CD4+ but not CD8+ cells. CD2+ or CD4+ but not CD8+ enriched cultures produced cytokines as unseparated PBMC. Thus, in non-exposed individuals circulating Leishmania reactive CD4+ T cells could be demonstrated. The cells from different individuals showed different patterns of IFN-gamma and/or IL-4 production upon antigenic stimulation. In experimental leishmaniasis the early balance between IFN-gamma and IL-4 is important for the clinical outcome. Our findings call for studies of the importance of cytokine production by cross-reactive T cells for the outcome of L. donovani infections in humans and show that the method for IL-4 detection is useful for this purpose.

Animals↗
PubMed1995

Tropisetron and octreotide reduce serotonin-induced fluid hypersecretion in pig jejunum.

In vitro data suggest that the serotonin receptor subtype 4 (5-HT4) mediate part of the serotonin (5-HT)-induced intestinal secretion. This study elucidates the involvement of the intestinal 5-HT4 receptor subtype and the anti-diarrhoeal therapeutic potentials of tropisetron and octreotide in 5-HT-induced intestinal hypersecretion in vivo. The effects of intraluminal 5-HT, 5-methoxytryptamine, and tropisetron (ICS 205-930), and subcutaneous octreotide (SMS 201-995) on fluid hypersecretion (accumulation) was studied in tied-off loops in pig jejunum. 5-HT, 5-methoxytryptamine (5-HT4 agonist), and tropisetron (5-HT3/5-HT4 antagonist) all induced a dose-dependent hypersecretion. Low doses of tropisetron reduced, while high doses of tropisetron enhanced the 5-HT and 5-methoxytryptamine responses. Taking into account the hypersecretory effect by itself, tropisetron seemed to completely block the hypersecretory effects of 5-HT and 5-methoxytryptamine. Finally, octreotide reduced the hypersecretory effect of 5-HT, maximally by 30%. These results suggest the involvement of the intestinal 5-HT4 receptor subtype in 5-HT-induced hypersecretion in pig jejunum in vivo. Furthermore, this study demonstrates a potential therapeutic value for octreotide in 5-HT-related diarrhoeagenic disorders in the pig.

Animals↗
PubMed1995

Bacterial colonization of the larynx and trachea in healthy children.

Fifty healthy children were included in the study; tracheal and laryngeal aspirations were performed after oral endotracheal intubation during minor surgery. The aspirates were evaluated and examined in the same way as aspirates from children suspected of pneumonia; 31 samples were accepted for the final analysis. After culturing, specimens from 30 children exhibited growth of potential pathogenic bacteria either from the larynx, the trachea or both. Prior to culture, bacteria were seen by microscopy in 24 samples from 30 children. These results indicate that the majority of healthy children carry potential pathogenic bacteria, not only in the larynx but also to a certain extent in the trachea. We conclude that aspirates from the larynx and the trachea are of limited value in the diagnosis of bacterial pneumonia in children.

Adolescent↗
PubMed1995

Biomolecular regulation of the IgE immune response. II. In vitro IgE synthesis and spontaneous production of cytokines.

Distinct subtypes of T-helper cells have been incriminated as sources of a common regulatory mechanism behind IgE synthesis and eosinophil activation in IgE-mediated diseases. To investigate whether IgE-producing cells are in fact stimulated in vivo or have an increased susceptibility to certain stimuli, the in vitro IgE synthesis was compared for different patient groups. Peripheral blood mononuclear cells (PBMC) were isolated from three groups of donors: (1) patients with atopic dermatitis and high levels of serum IgE (> 5000 IU/ml, n = 11); (2) patients with diagnosed inhalant allergy and serum IgE in the range of 200-2,000 IU/ml (n = 10), and (3) nonallergic donors with serum IgE below 100 IU/ml (n = 10). PBMC were tested for the spontaneous and IL-4-induced IgE synthesis in 11-day cultures during which adhering cells were removed on day 2 by transferring the suspended cells and the medium to new wells. The three groups differed markedly in their capacity to synthesize IgE. The atopic dermatitis group demonstrated high spontaneous IgE synthesis (median 11.8 ng/ml), which was doubled (24.3 ng/ml, p < 0.05) by stimulation by IL-4. The two other groups had low spontaneous synthesis (0.7 and 0.3 ng/ml) but this increased (1.7 and 0.7 ng/ml, p < 0.01) upon IL-4 stimulation. The spontaneous production of IFN-gamma in the cultures did not differ between the groups, but upon stimulation with phorbol myristate acetate, the atopic dermatitis group demonstrated significantly lower IFN-gamma levels compared to the two other groups. The IL-4 production in the cultures were generally below the detection limit (100 pg/ml), and whereas plasma levels of 1-2 ng/ml of soluble IL-4 receptor could be detected in all donors, no differences could be detected between the groups. These data suggest that reduced ability in atopic dermatitis of mounting an IFN-gamma response may account for the high levels of plasma IgE and IgE synthesis found in these patients.

Adult↗
PubMed1995

High avidity IFN-neutralizing antibodies in pharmaceutically prepared human IgG.

This paper demonstrates and characterizes naturally occurring antibodies to interferon (IFN) in human IgG preparations. In vitro neutralization of the antiviral effect of IFN alpha and IFN beta, but not IFN gamma, was observed in 12 of 15 normal IgG preparations. The neutralizing capacity was higher against rIFN alpha 2A and rIFN alpha 2C than against lymphoblastoid IFN alpha and IFN beta. Frühsommer meningoencephalitis hyperimmune IgG and hepatitis-B hyperimmune IgG showed potent neutralization, whereas anti-rhesus D-, anti-rabies-, and anti-tetanus IgG showed weak neutralization. Saturable binding of 125I-rIFN alpha 2A was demonstrated only in those IgG preparations found to neutralize the antiviral effect of IFN. Significant correlation between IFN binding and neutralization capacity was observed. The antibodies bound with Fab to rIFN alpha 2A with an avidity of approximately 30 pM; the majority was of the IgG1 subclass. Maximum binding capacity was 490 pg rIFN alpha 2A/mg IgG. Cross-binding of rIFN alpha 2C, lyIFN alpha N1 and IFN beta occurred with 10 and 100-200 times lower activities than that of rIFN alpha 2A. There was no cross-binding with rIFN gamma or rIL-6. IgG preparations containing anti-IFN antibodies blocked the binding of 125I-rIFN alpha 2A to A549 cells. In conclusion, pharmaceutically prepared human IgG preparations contain variable but significant levels of high-avidity IFN alpha and IFN beta neutralizing antibodies.

Antibodies, Monoclonal↗
PubMed1995

Cytokine autoantibodies in rheumatoid arthritis.

Sera from 42 patients with rheumatoid arthritis (RA) and 40 healthy controls (HC) were examined for cytokine autoantibodies (CK-aAb) by accurate and sensitive radioimmunoassays. The prevalences of detectable CK-aAb in RA (HC) were: aAb-IL-1 alpha = 36% (38%); aAb-IL-6 = 29% (13%), p = 0.06; aAb-IL-8 = 0% (0%); aAb-IFN alpha = 12% (3%), p = 0.11. The levels of the individual CK-aAb did not correlate, and there were no correlations between CK-aAb levels and clinical or laboratory variables. CK-aAb levels remained constant in 8 RA patients tested over a period of 6 months. With regard to alterations in aAb-IL-1 alpha levels, 4/11 HC were consistently positive over 18-36 months; 2/11 converted and became highly positive. The levels of aAb-IFN alpha and aAb-IL-6, but not aAb-IL-1 alpha, tended to be increased in RA patients; aAb-IL-8 were undetectable in both RA and HC.

Adult↗
PubMed1995

Tumour necrosis factor alpha in uncomplicated malaria in young adults.

The purpose of this study was: 1) to measure tumour necrosis factor alpha (TNF) in the plasma of Plasmodium falciparum infected subjects; and 2) to correlate the presence of TNF to symptomatology. Plasma from 77 malaria infected individuals (with malaria parasites) were assayed for TNF by ELISA. The mean age of the subjects under study was 16.36 +/- 0.80 (mean +/- SEM) years. Thirty-nine (51%) subjects had measurable plasma TNF. Taking symptomatology into account, 10 (59%) of the 17 asymptomatics and 29 (48%) of the 60 symptomatics had measurable plasma TNF. A risk ratio of 0.9 was obtained for the association between the detection of plasma TNF and the presence of symptoms. In plasma from 13 healthy controls no TNF was detected. The results suggest that if TNF plays a negative role in the pathogenesis of malaria, it must be in the presence of other predisposing factors.

Adolescent↗
PubMed1995

Interleukin-6 autoantibodies: possible biological and clinical significance.

The pleiotropic cytokines, interleukin (IL)-1 alpha, type I interferons and IL-6 also act on cells involved in antibody production. Somehow the immunologic tolerance to these cytokines is often spontaneously broken--even in healthy individuals. Thus, relatively high concentrations of high affinity IgG antibodies against IL-1 alpha and IL-6 frequently occur in the circulation of healthy adults. The autoantibodies specifically antagonize the respective cytokines in vitro. Thermodynamic estimations strongly suggest that autoimmunity can play a significant role in the regulation of certain cytokines. In the light of IL-6 autoantibodies the possible biological and clinical significance of cytokine autoimmunity is discussed.

Autoantibodies↗
PubMed1994

[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↗
PubMed1994

ICS 205-930 reduces 5-methoxytryptamine-induced short-circuit current in stripped pig jejunum.

The effect of ICS 205-930 on serotonin (5-hydroxytryptamine, 5-HT) and 5-methoxytryptamine (5-MeOT) induced short-circuit current (SCC) was studied in muscle-stripped pig jejunum in vitro. The selective 5-HT4 receptor agonist 5-MeOT and 5-HT both induced a concentration-dependent increase in SCC. The maximal efficacy of 5-HT was twice that of 5-MeOT. ICS 205-930 (Tropisetron) induced a small increase in SCC. Furthermore, ICS 205-930 reduced the 5-MeOT but not the 5-HT induced increase in SCC, except at the 100 microM ICS 205-930 concentration. Pretreatment with bumetanide reduced 5-HT, 5-MeOT, and ICS 205-930 induced peak increases in SCC by 64, 75, and 58%, respectively. Pretreatment with atropine reduced 5-HT, 5-MeOT, and ICS 205-930 induced peak increases in SCC by 38, 75, and 58%, respectively. Pretreatment with hexamethonium reduced 5-HT, 5-MeOT, and ICS 205-930 induced peak increases in SCC by 33, 50, and 36%, respectively. Pretreatment with tetrodotoxin reduced the peak increase in SCC elicited by 5-MeOT and ICS 205-930 by 41 and 50%, respectively. This study demonstrates involvement of a ICS 205-930, hexamethonium, atropine, bumetanide, and tetrodotoxin sensitive receptor in 5-MeOT induced SCC in muscle-stripped pig jejunum in vitro. These data suggest involvement of a neuronal 5-HT4 receptor subtype and acetylcholine in 5-HT elicited SCC and chloride secretion in the pig jejunum.

5-Methoxytryptamine↗
PubMed1994

Ketanserin and granisetron reduce cholera toxin-induced hypersecretion in pig jejunum.

BACKGROUND: Serotonin antagonists have been proven antisecretory in cholera toxin (CT)-induced hypersecretion in the small intestine of rodents. The pig small intestine is a good model for the human small intestine with regard to physiologic and pharmacologic processes. METHODS: The antisecretory effect of intraluminally administered methysergide, renzapride, ketanserin, granisetron, and tropisetron on CT-induced hypersecretion was tested in isolated pig jejunal loops in vivo. RESULTS: Methysergide, ketanserin, and granisetron reduced the hypersecretory effect of CT maximally by 25%, 80%, and 50%, respectively. Tropisetron enhanced whereas renzapride did not alter the CT response. Combination of ketanserin and granisetron gave a maximal inhibitory effect of about 85%. Surprisingly, renzapride, granisetron, and tropisetron each induced hypersecretion. Taking into account the hypersecretory effect of the antagonists, they all reduced this CT-elicited hypersecretion. CONCLUSIONS: Results suggest involvement of the 5-hydroxytryptamine-2 and 5-hydroxytryptamine-3 receptor subtypes as mediators in CT-induced hypersecretion in pig jejunum, and antidiarrheal therapeutic potentials of ketanserin and granisetron.

Animals↗