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T Zuberbier

Publications and source records attributed to T Zuberbier.

At least 55 records · Page 3Linked to original sources
PubMed2001

Expression of mast cell growth modulating and chemotactic factors and their receptors in human cutaneous scars.

In order to explore possible mechanisms involved in the previously documented turnover of mast cell subpopulations in human cutaneous scars, we have examined selected factors known to stimulate and/or modulate mast cell hyperplasia (SCF, NGF, TGFbeta1, GM-CSF) and their receptors in human cutaneous scar tissue. On immunohistochemistry, numbers of SCF- and TGFbeta1-positive cells were significantly increased in the epidermis and throughout the dermis in scars (n = 27) of varying ages (4-369 d old), compared with normal skin (n = 12). Furthermore, TRbetaRI, II, and the NGF-p75 receptors were significantly increased in the epidermis, TRbetaRI and NGF-TrkA throughout the dermis, and TRbetaRII, NGF-p75, and GM-CSFR only in the mid- and lower dermis of scars. NGF and GM-CSF expression was in contrast scarce and weak, with no differences between normal skin and scars. In tissue extracts, mRNA levels of SCF, TGFbeta1, TRbetaI and II, and both NGF-receptors, but not GM-CSFR, were significantly increased as well. TRbetaI and II were identified in up to 90% and 83%, respectively, of isolated normal skin mast cells on flow cytometry, and GM-CSFR and NGFR-p75 were identified on 70% and 73%, respectively, of avidin-positive normal mast cells on double immunofluorescence microscopy. As described before for the SCF receptor KIT, GM-CSFR and NGFR-p75 were partly or entirely downregulated on avidin-positive mast cells in scars. The marked upregulation of TGFbeta1, its type I and II receptors, and SCF suggest that these factors play a major role in the orchestration of mast cell increase in human cutaneous scars whereas the role of NGF and GM-CSF is less clear, despite the significant upregulation of their receptors.

Cell Division↗
PubMed2001

The ascomycin macrolactam pimecrolimus (Elidel, SDZ ASM 981) is a potent inhibitor of mediator release from human dermal mast cells and peripheral blood basophils.

BACKGROUND: The ascomycin macrolactam pimecrolimus (Elidel, SDZ ASM 981) has recently been developed as a novel and cell-selective inhibitor of inflammatory cytokine secretion; it has fewer adverse effects than currently available drugs. OBJECTIVE: In this study, we investigated the capacity of pimecrolimus to directly inhibit in vitro mediator release from human skin mast cells and basophils. METHODS: Purified cutaneous mast cells or basophil-containing peripheral blood leukocytes were obtained from healthy human donors and preincubated with pimecrolimus (0.1 nmol/L to 1 micromol/L) in the absence or presence of its specific antagonist (rapamycin), cyclosporin A (100 nmol/L to 1 micromol/L), or dexamethasone (1 micromol/L) and then stimulated with anti-IgE or with calcium ionophore A23187 plus phorbol myristate acetate. Cell supernatants were kept for analysis of histamine, tryptase, LTC4, and TNF-alpha. RESULTS: Pimecrolimus caused a strong and dose-dependent inhibition of anti-IgE--induced release of histamine from mast cells and basophils (maximally 73% and 82%, respectively, at 500 nmol/L pimecrolimus) and of mast cell tryptase (maximally 75%) and a less pronounced inhibition of LTC4 (maximally 32%) and of calcium ionophore plus phorbol myristate acetate--induced mast cell TNF-alpha release (90% maximum at 100 nmol/L pimecrolimus). In contrast, inhibition achieved during mast cell histamine release was maximally 60% with cyclosporin A and only 28% with dexamethasone. CONCLUSION: These data demonstrate a marked inhibitory capacity of pimecrolimus on mediator release from human mast cells and basophils with a potency exceeding that of cyclosporin A and dexamethasone. Pimecrolimus might thus be expected to be effective in the treatment of mast cell-- and basophil-dependent diseases.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

[Urticaria. New developments and perspectives].

Although the etiology of urticaria is mostly unclear, there are a number of recent new insights into the underlying pathomechanisms and causes. Dermal mast cell numbers and endothelial cell adhesion molecule and cytokine expression are also increased in uninvolved skin, while serum P-selectin levels are elevated, suggesting a systemic activation of the cutaneous inflammatory system in urticaria. In all adults, but not children with indolent mastocytosis, we found activating point mutations of c-kit, the mast cell growth factor receptor, in lesional cutaneous mast cells. In acute urticaria, IgE-dependent mechanisms are only rarely involved (0.9%), in contrast to generally held beliefs, whereas acute upper respiratory infections (39.3%) and drug intolerance (9.2%) are more frequent. In chronic urticaria, pseudoallergies to food (73%) and more rarely chronic inflammatory gastrointestinal diseases (11%) play a major role, with avoidance or elimination of the eliciting factors leading to long term remission. On the basis of recent findings, autoantibodies must be viewed mostly as secondary rather than causative in chronic urticaria.

Adult↗
PubMed2000

Anti-FcepsilonRIalpha serum autoantibodies in different subtypes of urticaria.

BACKGROUND: In recent years, a histamine-releasing anti-FcepsilonRIalpha autoantibody has been demonstrated in about one-third of patients with chronic urticaria. However, its clinical significance is still unclear. The objective was to detect a possible correlation between the occurrence of the anti-FcepsilonRIalpha autoantibody and the clinical type or cause of urticaria. METHODS: Sera from 66 consecutively seen in- and outpatients with various types of urticaria and five healthy controls were examined for the presence of anti-FcepsilonRIalpha autoantibodies with a sandwich ELISA technique. In addition, basophil histamine release was studied in 13 autoantibody-positive sera. RESULTS: Anti-FcepsilonRIalpha autoantibodies were found in 17/48 patients with chronic urticaria, in 2/4 with angioedema, in 1/2 with urticarial vasculitis, and in 2/11 with dermographic urticaria. However, no anti-FcepsilonRIalpha autoantibodies were detected in acute, cold, or delayed-pressure urticaria; in urticaria pigmentosa; or in normal controls. Of all chronic urticaria patients, 22 were classified as idiopathic since no underlying cause could be found. Of this group, seven were seropositive for anti-FcepsilonRIalpha. However, anti-FcepsilonRIalpha was also found in patients who went into remission after treatment of identified causes; namely, in one with type I allergy, one with drug intolerance, one with Helicobacter infection, and six with food intolerance. The autoantibody was also detected in 2/4 patients with associated autoimmune diseases. Functional activity was shown in basophil histamine release in 3/4 autoantibody-positive sera of patients with chronic idiopathic urticaria and in 4/6 autoantibody-positive sera of patients who went into remission after the treatment of underlying causes. CONCLUSIONS: These data confirm that anti-FcepsilonRIalpha autoantibodies in urticaria are mostly found in chronic urticaria. Furthermore, their detection independently of the apparent cause of the urticaria suggests that as yet unidentified mechanisms must be operative, possibly related to the chronic inflammatory process and/or individual predispositions that favor their induction.

Autoantibodies↗
PubMed2000

Clinical relevance of food additives in adult patients with atopic dermatitis.

BACKGROUND: Adverse reactions to food play an important role in the pathogenesis of atopic dermatitis (AD). In infancy and childhood, food allergies are observed in up to 30%, whereas nonallergic hypersensitivity reactions (pseudoallergic reactions) towards food additives have been reported to occur between 2 and 7%. By contrast, sensitizations towards food allergens are rarely of clinical relevance in adults and little data is available on nonallergic hypersensitivity reactions. To date the role of pseudoallergic reactions as an aggravating factor in AD of adult patients remains controversial. However, many adult patients report on food-related aggravation of the disease and nonallergic hypersensitivity reactions have been incriminated repeatedly. OBJECTIVE: To elucidate the relevance of food additives in adult patients suffering from AD. METHODS: Fifty patients were monitored over 4 weeks under regular diet followed by 6 weeks of a diet omitting known pseudoallergens. Skin status of patients was assessed every 2 weeks by a standardized scoring, and serum eosinophilic cationic protein (ECP) was determined before and after diet. RESULTS: Nine of fifty patients dropped out, 26 showed a significant improvement of the Costa-score by 57%. In 23/26 patients a corresponding reduction of serum ECP level by 52% on average was determined. Responder patients (24/26) were orally challenged with food rich in pseudoallergens followed by double-blind exposure to food additives (n = 15). A worsening of the eczema was seen in 19/24 patients after intake of pseudoallergen-rich food and in 6/15 patients after exposure to food additives. CONCLUSION: These results indicate that a subgroup of adult patients with AD clinically improve on low-pseudoallergen diet but only a small subgroup respond to oral provocation with food additives.

Adolescent↗
PubMed2000

Nerve growth factor-beta induces mast-cell marker expression during in vitro culture of human umbilical cord blood cells.

Nerve growth factor-beta (NGF) is known as a growth factor for human basophils and murine mast cells and has recently been shown to also up-regulate mast cell characteristics in human leukaemic mast cells. We have examined here the effect of NGF on the differentiation of normal human mast cells from cord blood progenitors during culture with stem cell factor (SCF), NGF alone or in combination, or fibroblast supernatants. All these supplements induced mast cell immunoreactivity against tryptase, c-Kit and FcepsilonRIalpha, but none of the cells reacted against the basophil specific antibody 2D7 before or during culture. Intracellular tryptase activity increased as well, with maximal levels on combined culture with SCF and NGF. On reverse transcription-polymerase chain reaction (RT-PCR), cells lacked tryptase and chymase and expressed low levels of FcepsilonRI and c-Kit mRNA prior to culture, with marked up-regulation of FcepsilonRI and c-Kit, and with de novo expression of mast-cell specific alpha- and beta-tryptase by week 3, and of chymase by week 5. Only the TrkA and not the p75 NGF receptor was detected at m-RNA and protein level, and only the TrkA NGF receptor was up-regulated during NGF-driven culture. These findings show therefore that, like SCF, NGF is another growth factor that can induce and regulate human mast-cell development and differentiation.

Biomarkers↗
PubMed2000

Mast cell and myeloid marker expression during early in vitro mast cell differentiation from human peripheral blood mononuclear cells.

UNLABELLED: In order to characterize the phenotype of human mast cell precursors in the peripheral blood mononuclear fraction and its alterations during in vivo mast cell differentiation, cells were studied before and during culture with stem cell factor or stem cell factor-containing cell supernatants. Prior to culture, 86% of cells were immunoreactive for the monocytic marker CD14, slightly fewer for CD11b and CD64, < 10% expressed FcepsilonRIalpha, rare cells were CD34 + ( < 0,1%), and none stained for CD1, CD33, c-Kit, and tryptase. After 2 wk of culture, there was de novo expression of c-Kit (14% - 43% positive cells), tryptase (26% - 79%), CD33 (57%), and CD64 (64%), an upregulation of FcepsilonRIalpha (23% - 52%), CD11b (93%), and CD68 (95%), but no expression of CD34. Levels of mRNA for FcepsilonRIalpha and c-Kit were detectable prior to culture and increased during culture, together with de novo expression of tryptase. Double staining after 2 wk of culture showed that FcepsilonRIalpha-positive cells were mostly CD14 + (90%), CD64 + (82%), and CD68 + (52%) on flow cytometry. Intracellular tryptase activity was first detectable after 1 wk of culture, increased FcepsilonRIalpha expression was only detectable by week 2. Cultured cells acquired the ability to release histamine during IgE-dependent stimulation, and culture with the c-Kit antibody YB5.B8 resulted in a downregulation of tryptase and FcepsilonRIalpha, but not of c-Kit. These data show that human mast cells develop from c-Kit- and tryptase-negative precursors in the myelomonocytic fraction of peripheral blood and that they upregulate, maintain, and share many phenotypic characteristics of cells from the monocyte/macrophage lineage during early phases of in vitro differentiation. KEYWORDS: c-kit/FcepsilonRI/SCF/tryptase.

Biomarkers↗
PubMed1999

Use of cetirizine in dermatologic disorders.

OBJECTIVE: This review is written to summarize the present state of knowledge on the use of cetirizine in dermatologic disorders, its efficiency, and concerns regarding the safety of the drug. DATA SOURCES AND STUDY SELECTION: A Medline search from 1980 until August 1997 was conducted. In addition, older literature especially concerning hydroxyzine was evaluated as well. The review considers all double-blind trials and in addition focuses on all information regarding the pharmacology and possible side effects of the drug. RESULTS: Peak plasma levels are reached within 1 hour after intake. Drug elimination occurs largely unchanged by renal excretion and drug interactions are not known. Cetirizine has no cardiac toxicity. No evidence for teratogenicity has been found. Possible adverse events include somnolence but are dose-dependent and mostly mild. At the dose of 10 mg no impairment of driving performance or response time was observed. In dermatology, cetirizine has proven to be effective in the treatment of various forms of urticaria and it reduces the pruritus of atopic eczema. For these conditions, frequently doses higher than 10 mg (up to 40 mg) are recommended to achieve the best benefit. In other pruritic dermatoses, cetirizine has been reported to be helpful but, with the exception of mosquito bites where 10 mg daily had a significant effect, controlled studies are missing. CONCLUSIONS: Cetirizine is a safe second generation antihistamine. It is effective especially in the treatment of urticaria and reduces significantly the pruritus of atopic dermatitis. An individual dosage should be chosen based on the severity of symptoms.

Adolescent↗
PubMed1999

Human mast cells produce and differentially express both soluble and membrane-bound stem cell factor.

Stem cell factor (SCF), characterized as mast cell growth factor, is known to be produced by fibroblasts, keratinocytes and endothelial cells. Two different splice variants encode for either a soluble (SCF-1) or a membrane-bound (SCF-2) form. In order to explore whether mast cells themselves can produce SCF, we examined cultured cord blood (CBMC) and peripheral-blood-derived mast cells (PBMC), mast/basophil cell lines (HMC-1 and KU-812), and skin mast cells for SCF expression. On immunocytochemistry, cytoplasmatic SCF-reactivity was observed in HMC-1 cells, with additional cell membrane staining in KU-812, skin and cultured mast cells. Low amounts of SCF could be detected by ELISA in lysates of isolated and unstimulated mast cells and in supernatants of skin cells stimulated with anti-IgE or Ca-ionophore A23187. SCF mRNA was detected in all cells, although marked quantitative differences were observed among the various cell types. SCF-2 mRNA expression was low in HMC-1 cells while it was marked in skin mast cells, KU-812 cells, CBMC and PBMC. A time-dependent, increasing induction of both SCF forms was seen in CBMC and PBMC during culture. After stimulation with A23187 and phorbol myristate acetate, an up-regulation of SCF mRNA was noted in HMC-1 and KU-812 cells, without changes in the relationship of the two splice variants. The differential expression of SCF-specific mRNA splice variants in immature and mature human mast cells and the secretion of this molecule by these cells may play a role in autocrine stimulation, maintenance of survival and the differentiation of tissue mast cells.

Cell Line↗
PubMed1999

Evaluation of systemic provocation tests in patients with suspected allergic and pseudoallergic drug reactions.

In order to examine the diagnostic value of systemic provocation tests, we studied 56 inpatients hospitalized for identification of the agent eliciting previous severe allergic or pseudoallergic reactions to non-steroidal anti-inflammatory drugs, local anaesthetics or antibiotics. Skin tests were positive in only 4 patients reacting to antibiotics and propyphenazone and were always negative for local anaesthetics (n = 32). Only 4 of 26 patients reacted to oral or subcutaneous provocation, 3 times to penicillin and once each to mepivacain, propyphenazone and cyanocobalamine when the suspected drug was tested. In the remaining 30 patients, who for safety reasons were tested only with alternative drugs, none had positive reactions, but 11 patients reported non-specific symptoms, as did 9 of 21 patients given placebo. Systemic provocation tests for drug allergy thus gave few positive results. However, these tests should always be done together with placebo testing for validation of results, and they remain indispensable for identification of alternative, well-tolerated drugs.

Adult↗
PubMed1999

Alterations in ganglioside expression during the differentiation of human mast cells.

Gangliosides are physiological components of the outer cell membrane. In the present study, the role of ganglioside expression during differentiation of human mast cells was evaluated. After 11 days of culture in medium known to induce mast cell differentiation, 70% of peripheral blood mononuclear cells (PBMC) showed positive staining for the high affinity IgE receptor and tryptase on immunocytochemistry and an associated 20-fold increase of ganglioside GM3 expression. Furthermore, exogenous addition of GM3 during cultivation of PBMC in medium containing low levels of growth factors induced an increase of mast cell specific tryptase. The association of ganglioside expression with mast cell differentiation was confirmed by experiments with the human mast cell line HMC-1. FcepsilonRI-positive cultured cells enriched with immunobeads exhibited a 3-fold higher expression of GM3, compared to FcepsilonRI negative HMC-1 cells. Furthermore, measurable amounts of the gangliosides GM2, GM1 and GD1a were found only in the FcepsilonRI positive cells. A corresponding transient increase of mRNA for GalNAcT, the key enzyme in the production of these latter gangliosides, could be detected preceding the expression of these gangliosides and the FcepsilonRI by RT-PCR. Taken together, these data point to a functional role of gangliosides in the differentiation of human mast cells.

Basophils↗
PubMed1998

Expression and functional activity of the IL-8 receptor type CXCR1 and CXCR2 on human mast cells.

To further elucidate mechanisms involved in mast cell accumulation at sites of cutaneous inflammation, we have studied the ability of human leukemic mast cells (HMC-1 cells) to express functionally active IL-8 receptors. Expression of mRNA for both types of IL-8 receptors (CXCR1 and CXCR2) was demonstrated by PCR and of both proteins by flow cytometry. Binding and competition studies with 125I-labeled IL-8 and its homologue melanoma growth stimulating activity (125I-labeled MGSA) revealed two specific binding sites for IL-8, K1 = 1.1 x 10(11) M(-1) and K2 = 5 x 10(7) M(-1); and for MGSA, K1 = 2.8 x 10(10) M(-1) and K2 = 5 x 10(7) M(-1). This finding was supported by a dose-dependent rise of cytosolic free calcium concentration ([Ca2+]i) induced by both chemokines and to a lesser extent by the homologue neutrophil-activating peptide-2 (NAP-2). A significant migratory response of human leukemic mast cells (HMC-1) was observed with all three chemokines at a range from 10(-8) M to 10(-9) M. Moreover, the formation of cellular F-actin was induced in a rapid, dose-dependent fashion, with a maximally 1.7-fold increase at 10(-7) M. Using postembedding immunoelectron microscopy, we could show the expression of CXCRI on the cytoplasmatic membrane of isolated human skin mast cells whereas CXCR2 was located in mast cell-specific granules. These findings demonstrate for the first time the functional expression of both types of IL-8 receptors on human mast cells, suggesting a role for their ligands during mast cell activation and recruitment.

Actins↗
PubMed1998

The human mast cell line HMC-1 binds and responds to C3a but not C3a(desArg).

Controversial results have been published in the past regarding the functional reactivity of different cell types to the anaphylatoxin C3a and its degradation product C3a(desArg). To understand better the effects of C3a and C3a(desArg) on human mast cells, the authors performed binding experiments and calcium mobilization studies on the human mast cell line HMC-1 which has been shown previously to express C3a binding sites. For this purpose, functionally active, recombinant C3a (rC3a) was constructed with an 11 amino acid peptide attached to the N-terminus of the molecule. Using a monoclonal antibody (MoAb) against this tag, binding of rC3a to HMC-1 cells could be demonstrated by flow cytometry. Its binding was specific as it could be blocked with serum-derived C3a. In contrast, no binding of rC3a(desArg) to HMC-1 cells was detectable. Recombinant C3a led to a transient mobilization of intracellular calcium [Ca2+]i in HMC-1 which was inhibitable by the C3a-specific MoAb K13/16. No increase of [Ca2+]i was detected when the cells were treated with C3a(desArg). The authors found C3a receptor (C3aR)-specific mRNA in HMC-1 cells indicating that this receptor represents the binding site for C3a on these cells. These results demonstrate a specific binding for C3a but not for C3a(desArg) on cells of the human mast cell line HMC-1. As a consequence, functional activity was restricted to C3a with C3a(desArg) being completely inactive. Therefore, the data strongly suggest that the recently cloned high affinity C3aR which is assumed to represent the binding site for the anaphylatoxin on HMC-1 cells is unresponsive to C3a(desArg).

Animals↗
PubMed1998

Induction of human leukaemic mast cell differentiation by fibroblast supernatants, but not by stem cell factor.

In order to explore the potential existence of human mast cell growth factors other than stem cell factor (SCF), we have compared SCF to L-cell fibroblast supernatants (LCS) during in vitro mast cell differentiation, using human leukaemic mast cells (HMC-1 cells) which contain a gain-of-function mutated SCF receptor (c-Kit) as model. At baseline, cells exhibited an immature phenotype, with <25% being metachromatic or chloroacetate esterase, tryptase and FcepsilonRIalpha positive. Intracellular levels of histamine, tryptase, TNF-alpha and chymase were low, whereas 83% of cells were c-Kit positive. During a 10 day culture with 30% LCS, a significant, time-dependent increase of all mast cell markers, except for chymase and c-Kit, was observed at the protein and for tryptase and FcepsilonRIalpha also at the mRNA level. Cytoplasmatic granulation and stimulated histamine and leukotriene C4 release were increased as well. In contrast to LCS, rhSCF induced none of these changes in HMC-1 cells. On Sephadex G100 fractionation of LCS, HMC-1 cells increased tryptase activity with fractions between 40 and 60, and below 10 kDa, away from the SCF peak. These data show that HMC-1 cells fail to differentiate in response to SCF and that in addition to SCF, LCS contains other human mast cell growth factors.

Animals↗
PubMed1998

Role of nonallergic hypersensitivity reactions in children with chronic urticaria.

BACKGROUND: IgE-independent (pseudoallergic) reactions to food and food ingredients are common in a subgroup of adult patients with chronic urticaria, who have daily spontaneous occurrence of wheals. However, for children with chronic urticaria (duration longer than 6 weeks, no physical influence), no data on the importance of pseudoallergen-induced chronic urticaria are available. Therefore, we investigated the role of nonallergic hypersensitivity to food in all children seen with chronic continuous urticaria in our two clinics over the last 2 years (n = 16). METHODS: All patients were given a low-pseudoallergen diet for 3 weeks followed by provocation with food rich in pseudoallergens. To identify the main eliciting agents, a subgroup of responders was exposed to food additives by double-blind, placebo-controlled food challenges. RESULTS: Pseudoallergen-induced urticaria was diagnosed in 12 cases (75%). Reactions occurred mainly to coloring agents and preservatives, but also to monosodium glutamate and a sweetener (saccharin/cyclamate). CONCLUSIONS: These results confirm that nonallergic hypersensitivity reactions play a role in children with chronic urticaria, although the latter disease is rare at that age. In children, food additives, especially coloring agents and preservatives, appear to play a more important role in eliciting nonallergic hypersensitivity reactions than in adult patients, where naturally occurring pseudoallergens in fruits and vegetables are mainly responsible.

Adolescent↗