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Biomedical subjects

K Thestrup-Pedersen

Publications and source records attributed to K Thestrup-Pedersen.

At least 55 records · Page 3Linked to original sources
PubMed1997

Monocyte chemotactic and activating factor (MCAF/MCP-1) has an autoinductive effect in monocytes, a process regulated by IL-10.

MCAF (MCP-1) a member of the chemokine-beta-family known to be chemotactic for monocytes is believed to play a significant role in several inflammatory processes, both immuno-pathological disorders, such as atherosclerosis, psoriasis, chronic inflammatory diseases of the liver and lungs, and during the normal immune response against microorganisms. This chemokine is produced spontaneously by monocytes, and in the present article we also demonstrate that MCAF induces its own production in monocytes. The methods used are two dimensional SDS-PAGE gel electrophoresis. Western-blotting and ELISA quantification of supernatant from monocyte cultures stimulated with MCAF (1, 10, 100 ng ml). Also, we found that this process is regulated by IL-10 (100 ng ml). Our results suggest that monocytes migrating to a site of inflammation due to the local production of the chemokine MCAF/MCP-1 further enhance the focal accumulation of monocytes by producing and releasing bioactive MCAF MCP-1.

Blotting, Western↗
PubMed1997

Atopic dermatitis may be a genetically determined dysmaturation of ectodermal tissue, resulting in disturbed T-lymphocyte maturation. A hypothesis.

Although atopic dermatitis is a skin disorder, it includes immune deviations such as T-cell accumulation and activation in the skin, resulting in chronic, relapsing eczema. The T-lymphocyte activation in the skin is not accompanied by specific allergies in up to two thirds of the patients. It has been shown that T-cell lines and clones can be established from skin biopsies of patients with atopic dermatitis showing cytokine-dependent, but antigen-independent, continuous growth in vitro. This indicates the existence of skin-homing T-lymphocytes with growth requirements different from those of mature T-lymphocytes in the blood. We suggest that atopic dermatitis is a genetically determined change of ectodermal tissue. The thymic epithelium is derived from the ectoderm, and because of that we hypothesize that the maturation of the T-cell immune system of persons who develop atopic dermatitis is disturbed due to a faulty selection of T-lymphocytes in the thymus. "Dys"-matured T-cells leave the thymus as a consequence of faulty selection and continue their growth in the skin. The cells are eventually eradicated by the immune surveillance conducted by the normal part of the patients' immune system and as a consequence of diminished output of faulty selected T-lymphocytes during maturation. Because of the increased proliferation capacity of the aberrant T-cells, a cytokine imbalance occurs and in some patients this leads to the development of type I allergies due to a skewing of the humoral immune system towards IgE production.

Dermatitis, Atopic↗
PubMed1996

IL-8 induces T cell chemotaxis, suppresses IL-4, and up-regulates IL-8 production by CD4+ T cells.

Interleukin-8 (IL-8), a neutrophil-activating cytokine, also activates certain T cell functions such as chemotaxis. We additionally find (n = 6) that recombinant (rIL-8; 1-100 ng/ml), when added to 24 h culture of human CD4+ T cells, suppressed the spontaneous production of IL-4 (50-85%). Steady state production of Il-4 was typically around 30 pg/ml, determined by use of a solid- phase immunoabsorbant assay. De novo synthesis of IL-4 from CD4+ T cells cultured for 3 days was also evaluated by use of detection of [35S]methionine incorporation, as visualized by autoradiography of 2-D gels, and showed that IL-8 suppressed IL-4 production. This suppression of IL-4 production was confirmed in the cytosol fraction by use of Western blotting. The effect of IL-8 (100 ng/ml) was comparable to that of 10 ng/ml recombinant interferon-gamma, both strongly suppressing IL-4 production. The regulatory effect of IL-8 on IL-4 production was also indicated by the fact that addition of a neutralizing monoclonal anti-IL-8 antibody (WS.4) enhanced the spontaneous IL-4 production when added to the culture of CD4+ T cells, thereby probably inactivating the effect of IL-8 originating from the cultured T cells. Also, we observed that IL-4 mRNA expression was down-regulated when the CD4+ T cells were cultured for 12 h in the presence of 100 ng/ml IL-8. The suppression of IL-4 mRNA expression could be prevented by adding anti-IL-8 (20 microgram/ml) or IL-10 (100 ng/ml) l h before adding rIL-8. Thus, IL-8 may be an important regulator of CD4+ T cell-derived IL-4, thereby possibly regulating the balance between humoral and cellular T cell-dependent responses.

CD4-Positive T-Lymphocytes↗
PubMed1996

Psoriasin: a novel chemotactic protein.

Inflammatory skin disorders such as psoriasis show a preferential epidermal infiltration of neutrophils and T lymphocytes. This observation raises a question as to which factors determine the appearance and composition of leukocyte tissue infiltrations. Previously, we described a low molecular mass calcium-binding protein (psoriasin, molecular mass 11,457 Da, pI 6.77) belonging to the S1OO family that is highly upregulated in psoriatic keratinocytes and whose expression patterns implied a role in the inflammatory response. Here we report that human psoriasin is a potent and selective chemotactic inflammatory protein for CD4+ T lymphocytes and neutrophils at concentrations of about 10(-11) M. Psoriasin is not structurally related to the alpha or the beta chemokine subfamilies or to lymphotactin, a member of a newly described class of chemokines. Thus, we have observed a chemotactic protein outside the chemokine subfamilies that could be an important new inflammatory mediator.

CD4-Positive T-Lymphocytes↗
PubMed1996

Treatment of chronic idiopathic urticaria with topical steroids. An open trial.

Twenty-three patients with chronic idiopathic urticaria and 3 patients with urticaria pigmentosa received a 2-week treatment with daily application of potent topical steroid using plastic occlusion. Seventy per cent of the chronic urticaria patients had a statistically significant, immediate response, which, however, did not last until the final evaluation after 1.5 years. Relapse occurred after on average 3 weeks, but 39% reported less severity. The 3 patients with urticaria pigmentosa remained free from attacks for 6 to 9 months, after which they gradually relapsed. Two women were diagnosed during the follow-up period to have a carcinoma of the breast, and one patient developed systemic lupus erythematosus.

Administration, Topical↗
PubMed1996

Atopic dermatitis may be linked to whether a child is first- or second-born and/or the age of the mother.

Five hundred and thirty families with at least 1 child who had been referred to a dermatologist with atopic dermatitis were interviewed in an effort to determine whether factors such as the age of the mother when a child is born and/or birth rank can contribute to the development of atopic dermatitis. The families interviewed had a total of 1,084 children, or an average of 2 children per family. Sixty per cent of the children with atopic dermatitis were under 5 years of age. Ninety-one per cent of them had developed the disease before the age of 3; those most severely affected had developed the disease during the first year of life. In families with 2 children, but only 1 child with atopic dermatitis, the odds ratio for the second child to develop atopic dermatitis was 1.379 (0.025 < p < 0.05). The average maternal age was 24.8 to 25.2 years when giving birth to the first child and 28 years when giving birth to the second child, irrespective of the status of the child. Thus, atopic dermatitis can be related to birth rank or to the age of the mother.

Adult↗
PubMed1995

Recombinant human growth-regulated oncogene-alpha induces T lymphocyte chemotaxis. A process regulated via IL-8 receptors by IFN-gamma, TNF-alpha, IL-4, IL-10, and IL-13.

The human cytokine growth-regulated oncogene (GRO)-alpha is a small glycoprotein secreted by monocytes, endothelial cells, glycoprotein secreted by monocytes, endothelial cells, fibroblasts, synovial cells, and some tumor cells such as melanoma cells. It is structurally related to IL-8 and can activate neutrophils, whereas it induces chemotaxis, exocytosis, and a respiratory burst in neutrophils. To date, its functions on T lymphocytes have not been well established. We report here that recombinant human (rh)GRO-alpha is a potent chemoattractant for freshly isolated T lymphocytes, but not for anti-CD3 mAb-activated T lymphocytes. It attracts CD4+ and CD8+ T lymphocyte subsets to an equal extent. The migrating T lymphocytes toward rhGRO-alpha are predominantly CD45RO+ memory CD4+ and CD8+ subsets. The chemotactic migration of T lymphocytes toward rhGRO-alpha is stimulated via the IL-8 receptors on the cells. This process can be augmented by IFN-gamma and TNF-alpha, and inhibited by IL-4, IL-10, and IL-13. In addition, we also document that on T lymphocytes there exist IL-8 receptors that can be up-regulated by IFN-gamma, TNF-alpha, and IL-2. Our results demonstrate that rhGRO-alpha gene encodes for an inflammatory mediator that stimulates the directional migration of T lymphocytes. It may thus be another important mediator in the diseases in which T lymphocytes form the major constituent of the cellular infiltration.

Antigens, CD↗
PubMed1995

Peptide-induced anergy in allergen-specific human Th2 cells results in lack of cytokine production and B cell help for IgE synthesis. Reversal by IL-2, not by IL-4 or IL-13.

The induction of anergy in T cells is believed to be the result of triggering of the TCR in the absence of adequate costimulation mediated through the interaction of CD28 and its ligands, CD80 and CD86. Here, we demonstrate that stimulation of human group I allergen in Dermatophagoides pteronyssinus extract (Der p 1)-specific CD4+ Th2-like T cell clones with Der p 1-derived peptides in the absence of professional APC results in a state of nonresponsiveness. The induction of anergy occurred despite the expression of high levels of CD28, CD80, and CD86 on the surface of the T cell clones and was not prevented by the addition of anti-CD28 mAb. The anergic, Der p 1-specific, Th2 cells failed to mobilize calcium from intracellular stores, to proliferate, and to produce IL-2, IL-4, IL-13, GM-CSF, and TNF-alpha following optimal stimulation with Der p 1-derived peptide and autologous APC. However, they mobilized intracellular calcium following stimulation with Ca(2+)-ionophore and produced all of the above cytokines, including IFN-gamma, when stimulated with phorbol ester and Ca2+ ionophore. These results indicate that the anergic T cell clones are capable of responding to signals circumventing the TCR/CD3 complex activation pathway. In contrast to T cell clones optimally activated with peptide and APC, anergic T cells failed to induce IgG4 and IgE synthesis when cocultured with B cells, even in the presence of exogenous IL-4 or IL-13. Anergic T cells expressed normal levels of CD40L, suggesting that their inability to help in Ig production by B cells is due to conditions other than a lack of expression of this molecule. Finally, exogenous IL-2 restored the helper function of anergic Th2 T cells for IgE production by B cells, which was greatly enhanced by the addition of IL-4 or IL-13. These data suggest that induction of anergy in allergen-specific Th2 T cells by allergen-derived peptides may play an important role in the successful desensitization of allergic patients.

Allergens↗
PubMed1995

The delayed-type hypersensitivity reaction is dependent on IL-8. Inhibition of a tuberculin skin reaction by an anti-IL-8 monoclonal antibody.

Cell-mediated immune reactions are essential to our immune response toward foreign organisms such as microorganisms, or in the response toward foreign tissue Ags, as seen in the rejection of allogeneic transplanted organs. Similar reactions form the basis for the development and the progression of delayed-type hypersensitivity (DTH) reactions. We found that the alpha-chemokine IL-8 plays an important pathophysiologic role for the development of a DTH reaction because infusion of a neutralizing anti-IL-8 mAb (WS-4) was able to suppress the development of a tuberculin skin reaction in rabbits, as judged by histologic, biochemical, and clinical examinations. Thus, the number of neutrophil granulocytes and lymphocytes at the site of tuberculin injection was decreased considerably, and the clinical signs of inflammation were suppressed almost completely at 24 h after intracutaneous injection of tuberculin, as judged by the size of the infiltrates. In contrast, we did not see any effect on the visible erythema of the skin. We found that the tissue content of myeloperoxidase (MPO), reflecting the number of infiltrating neutrophils, was lowered significantly. Furthermore, immunohistochemical analysis confirmed that IL-8 immunoreactivity is actually enhanced in the skin of positive tuberculin reactions. The results indicate that IL-8 plays an important role for the early accumulation of leukocytes in the skin and for the clinical signs of a DTH reaction.

Animals↗
PubMed1995

Interleukin-8 induces its own production in CD4+ T lymphocytes: a process regulated by interleukin 10.

The neutrophil and T cell chemotactic factor interleukin 8 (IL-8) is believed to play a pathophysiological role in the development of various inflammatory disorders. So far no other effects of IL-8 on T cells have been observed. We observed that purified CD4+ T cells in particular, but also CD8+ T cells, spontaneously synthesize IL-8 mRNA and secrete IL-8 protein. The culture supernatants of CD4+ T cells contained T cell chemotactic activity as well as IL-8 protein. In addition, we confirmed the ability of CD4+ T cells to produce IL-8 by double immunofluorescence staining and by the demonstration of IL-8 mRNA expression. Further, IL-8 induced its own production in CD4+ T cells, while its synthesis by CD8+ T cells was low and not always auto-stimulatory. Both the spontaneous, as well as the IL-8 induced IL-8 production, could be inhibited in the presence of human interleukin 10 (100 ng/ml). This observation suggests that IL-10 plays a homeostatic role in regulating the IL-8 circuit in CD4+ T cells.

Autoradiography↗
PubMed1995

Regulation of human T lymphocyte chemotaxis in vitro by T cell-derived cytokines IL-2, IFN-gamma, IL-4, IL-10, and IL-13.

There has been a number of conflicting reports regarding the T lymphocyte chemotactic activities of several cytokines. IL-2 and IFN-gamma are known to promote augmentation of immune inflammation, whereas IL-4, IL-10, and IL-13 display immunomodulatory effects on inflammatory cells including inhibition of cytokine production. Their effects on chemotaxis of inflammatory cells are unknown. We observed that IL-1 alpha could induce chemotaxis both in overnight cultured and anti-CD3 mAb-activated T lymphocytes and that overnight culture and anti-CD3 activation increase the number of IL-1R on T lymphocytes. In contrast, IL-8 selectively attracts freshly isolated T lymphocytes. Staurosporine inhibits freshly isolated T lymphocyte chemotaxis toward IL-8, whereas tyrphostin 23 inhibits chemotaxis of overnight cultured and anti-CD3-activated T lymphocytes toward IL-1 alpha. We have found that IL-2 and IL-13 inhibit the chemotactic migration of both CD4+ and CD8+ T lymphocytes toward IL-8, and RANTES. IL-4 inhibits only CD8+ T lymphocyte chemotaxis toward RANTES, IL-8 and IL-10. IL-10 inhibits only CD4+ T lymphocytes in their chemotactic response toward RANTES and IL-8. IFN-gamma does on the other hand augment the sensitivity of human T lymphocytes to chemotactic stimuli. Thus, our results demonstrate that different proinflammatory cytokines will induce chemotactic migration of T lymphocytes under different circumstances acting through different signaling pathways. The T cell-derived cytokines IL-2, IL-4, IL-10, and IL-13 are able to block further T lymphocyte chemotaxis, thus leading to a focusing of T lymphocytes in an area of T lymphocyte activation. These mechanisms seem relevant in our understanding of the specific and continuous localization of T lymphocytes in allergic and autoimmune disorders.

Chemokine CCL5↗
PubMed1995

Interleukin 13 suppresses cytokine production and stimulates the production of 15-HETE in PBMC. A comparison between IL-4 and IL-13.

We examined the ability of rIL-13 to regulate rIL-l alpha induced IL-1 beta, IL-1 receptor antagonist (IL-1ra) and IL-8 production in cultured peripheral blood mononuclear cells (PBMC), endothelial cells and fibroblasts. Furthermore we examined whether rIL-13 could influence the production of the arachidonic acid products LTB4, 12-HETE and 15-HETE by PBMC. rIL-1 alpha-stimulated PBMC cultures secreted high levels of IL-1 beta and IL-8; this could be inhibited to the level of unstimulated control cells by co-incubation with rIL-13 (10 ng/ml). IL-13 induced a 3-fold increase of the IL-1ra secretion which was inhibited by rIFN-gamma. In the presence of both rIL-1 alpha and rIL-13, endothelial cells increased IL-8 secretion, whereas dermal fibroblasts remained unchanged. Of the arachidonic acid metabolites examined, the greatest change was observed in the formation of 15-HETE. In unstimulated PBMC cultures the amount of 15-HETE was less than 4 ng/10(6) cells, whereas after addition of rIL-13 we measured a formation of 139 +/- 6.2 ng/10(6) cells. The effect of rIL-13 on the 15-HETE formation in PBMC was abolished by addition of 100 U/ml rIFN-gamma. rIL-13 only induced minor changes in the LTB4 and 12-HETE formation. Compared to IL-4, IL-13 induced a similar alteration of the cytokine cascade and arachidonic acid metabolism, supporting the hypothesis that the two cytokines use a common receptor complex or signal pathway.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1995

IL-4 and IL-13, but not IL-10, are chemotactic factors for human osteoblasts.

In this study we demonstrate that the cytokines IL-4 and IL-13, but not IL-10, can induce osteoblast chemotaxis. Recombinant IL-4 (rIL-4) and rIL-13 mediated cell migration was observed using a modified multi-well Boyden chamber system. Maximum chemotaxis was observed at concentrations of 100 ng/ml of both rIL-4 and rIL-13 with a chemotactic index of 2.0 +/- 0.1 and 2.3 +/- 0.4, respectively in this system, whereas IL-10 did not show chemotactic abilities for osteoblasts. Our results suggest that IL-4 and IL-13 could take part in the recruitment of osteoblasts and thereby be of importance in the cytokine regulation of bone resorption and healing.

Cells, Cultured↗
PubMed1995

Appearance of isochromosome 18q can be associated with in vitro immortalization of human T lymphocytes.

T lymphocytes cultured from a skin biopsy specimen of a patient with atopic dermatitis developed isochromosome 18q concomitant to escape from replicative senescence. Furthermore, two T-cell lines established from patients with cutaneous T-cell lymphoma also developed isochromosome 18q during continuous growth. The results indicate that a pathway leading to immortalization of human T lymphocytes could involve genes located at chromosome 18.

Cell Division↗
PubMed1995

Common clonal chromosome aberrations in cytokine-dependent continuous human T-lymphocyte cell lines.

Antigen-mediated T-cell proliferation is a transient phenomenon. Like other somatic cells, T lymphocytes generally show replicative senescence in vitro. However, we here show that cytokine-dependent continuous (immortal) T-cell lines can be established from skin biopsy specimens of inflammatory skin diseases. Continuous growth can be obtained by culturing T cells in medium supplemented with interleukin-2 and interleukin-4, but without antigen or antigen-presenting cells added. Loss of the T-cell antigen receptor complex is observed in some of the continuous T-cell lines. Most T-cell lines develop clonal chromosome aberrations during continuous growth. Aberrations for chromosomes 1, 2, 8, 16, and 18 are most commonly observed.

Cell Division↗