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Peter Schmid-Grendelmeier

Publications and source records attributed to Peter Schmid-Grendelmeier.

At least 19 recordsLinked to original sources
PubMed2007

Cross-reactivity and 1.4-A crystal structure of Malassezia sympodialis thioredoxin (Mala s 13), a member of a new pan-allergen family.

We have identified thioredoxins (Trx) of Malassezia sympodialis, a yeast involved in the pathogenesis of atopic eczema, and of Aspergillus fumigatus, a fungus involved in pulmonary complications, as novel IgE-binding proteins. We show that these Trx, including the human enzyme, represent cross-reactive structures recognized by serum IgE from individuals sensitized to M. sympodialis Trx. Moreover, all three proteins were able to elicit immediate-type allergic skin reactions in sensitized individuals, indicating a humoral immune response based on molecular mimicry. To analyze structural elements involved in these reactions, the three-dimensional structure of M. sympodialis Trx (Mala s 13) has been determined at 1.4-A resolution by x-ray diffraction analysis. The structure was solved by molecular replacement and refined to a crystallographic R factor of 14.0% and a free R factor of 16.8% and shows the typical Trx fold. Mala s 13 shares 45% sequence identity with human Trx and superposition of the solved Mala s 13 structure with those of human Trx reveals a high similarity with a root mean square deviation of 1.11 A for all Calpha atoms. In a detailed analysis of the molecular surface in combination with sequence alignment, we identified conserved solvent-exposed amino acids scattered over the surface in both structures which cluster to patches, thus forming putative conformational B cell epitopes potentially involved in IgE-mediated cross- and autoreactivity.

Adult↗
PubMed2006

Tolerance to celecoxib in patients with a history of adverse reactions to nonsteroidal anti-inflammatory drugs.

BACKGROUND: Adverse reactions to nonsteroidal antiinflammatory drugs (NSAIDs) are frequently reported, particularly among asthmatic patients. To date, there is no causal treatment available apart from tolerance induction. Therefore, the search for safe alternative drugs is of pivotal importance in clinical practice. OBJECTIVE: The aim of our prospective study was to investigate the tolerance to celecoxib, a selective cyclooxygenase-2 inhibitor, in a large group of patients with positive case history of NSAID intolerance in comparison to paracetamol and nimesulide. METHODS: 106 NSAID-sensitive patients, 46 (43.4%) of whom had experienced reactions only to one NSAID (single hypersensitivity), 60 (56.6%) to several NSAIDs (multiple hypersensitivity), were included in a single-blinded drug challenge protocol with cumulative doses of 175 mg of celecoxib, 875 mg of paracetamol and 175 mg of nimesulide. Objective and subjective symptoms during challenge were documented. RESULTS: Of 261 challenges in 106 patients, 31 challenges were positive: 5 of 106 (4.7%) for celecoxib, 10 of 64 (15.6%) for paracetamol and 16 of 91 for nimesulide (17.6%). Adverse reactions to celecoxib were mainly mild in character: three patients reported subjective symptoms including generalised pruritus and thoracic oppression, whereas two patients reacted with angio-oedema. CONCLUSIONS: Our results demonstrate that celecoxib is well tolerated by the majority of patients with NSAID intolerance. However, since adverse reactions to celecoxib cannot be ruled out completely, a controlled oral challenge test is still mandatory for proper management of patients with NSAID intolerance.

Acetaminophen↗
PubMed2006

Sensitization to the yeast Malassezia sympodialis is specific for extrinsic and intrinsic atopic eczema.

The opportunistic yeast Malassezia sympodialis belongs to the normal cutaneous flora but can also cause IgE-mediated sensitization in patients suffering from atopic eczema (AE). We investigated 706 individuals by ImmunoCAPm70 and skin-prick tests with a crude M. sympodialis extract. In AE patients, we further performed skin prick tests, atopy patch tests, ELISA, and peripheral blood mononuclear cells proliferation assays with recombinant M. sympodialis allergens (rMala s 1 and 5-9). In 52/97 patients with AE-specific IgE against M. sympodialis was detectable. Almost no reactivity to M. sympodialis was seen in patients suffering from other allergic diseases (4/571) and no reactivity at all was seen in healthy controls (0/38). Skin tests showed variable recognition patterns against the different molecular structures with a predominant sensitization to rMala s 1, 5, 6, and 9, confirmed also by specific serum IgE to these allergens. Interestingly, IgE- and T-cell-mediated reactivity against M. sympodialis was also found in patients with the intrinsic form of AE. Thus, sensitization to M. sympodialis is specific for AE patients and occurs in both the extrinsic and intrinsic variant of eczema. Recombinant yeast allergens represent a useful tool to study molecular structures and differential sensitization patterns in the pathogenesis of AE.

Adolescent↗
PubMed2006

Atopic dermatitis.

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Antibodies, Anti-Idiotypic↗
PubMed2006

NADP-dependent mannitol dehydrogenase, a major allergen of Cladosporium herbarum.

Cladosporium herbarum is an important allergenic fungal species that has been reported to cause allergic diseases in nearly all climatic zones. 5-30% of the allergic population displays IgE antibodies against molds. Sensitization to Cladosporium has often been associated with severe asthma and less frequently with chronic urticaria and atopic eczema. However, no dominant major allergen of this species has been found so far. We present cloning, production, and characterization of NADP-dependent mannitol dehydrogenase of C. herbarum (Cla h 8) and show that this protein is a major allergen that is recognized by IgE antibodies of approximately 57% of all Cladosporium allergic patients. This is the highest percentage of patients reacting with any Cladosporium allergen characterized so far. Cla h 8 was purified to homogeneity by standard chromatographic methods, and both N-terminal and internal amino acid sequences of protein fragments were determined. Enzymatic analysis of the purified natural protein revealed that this allergen represents a NADP-dependent mannitol dehydrogenase that interconverts mannitol and d-fructose. It is a soluble, non-glycosylated cytoplasmic protein. Two-dimensional protein analysis indicated that mannitol dehydrogenase is present as a single isoform. The cDNA encoding Cla h 8 was cloned from a lambda-ZAP library constructed from hyphae and spores. The recombinant non-fusion protein was expressed in Escherichia coli and purified to homogeneity. Its immunological and biochemical identity with the natural protein was shown by enzyme activity tests, CD spectroscopy, IgE immunoblots with sera of patients, and by skin prick testing of Cladosporium allergic patients. This protein therefore is a new major allergen of C. herbarum.

Alcohol Oxidoreductases↗
PubMed2006

Wheat and maize thioredoxins: a novel cross-reactive cereal allergen family related to baker's asthma.

BACKGROUND: Baker's asthma is a serious problem for a significant proportion of workers in bakeries, confectionaries, and the food industry. Although several wheat allergens related to baker's asthma have been described, standardized reagents for a reliable diagnosis are not yet available. OBJECTIVE: To clone novel wheat allergens related to baker's asthma and investigate the cross-reactive potential of their maize and human homologues. METHODS: A wheat cDNA phage display library was screened with sera from bakers with occupational asthma for IgE-binding structures. Homologous sequences from maize and human thioredoxins were amplified from corresponding cDNA libraries. RESULTS: Within the enriched wheat cDNA repertoire we identified, among others, the sequence encoding wheat thioredoxin-hB (Triticum aestivum allergen 25 [Tri a 25]). The recombinant protein displayed enzymatic activity, and we observed a sensitization rate of 47% among bakers with occupational asthma and of 35% among patients with grass pollen allergy, but without a clinical history of cereal allergy. Furthermore, the previously characterized maize thioredoxin-h1 (Zea mays allergen 25 [Zea m 25]), sharing 74% identity with Tri a 25, exhibited distinct IgE cross-reactivity with its wheat homologue. Two bakers also showed sensitization to human thioredoxin, which shares 29% identity with Tri a 25. In a comparative study, we included recombinant alpha-amylase inhibitor 0.19, showing a sensitization rate of 65% in individuals with baker's asthma. CONCLUSION: Thioredoxins represent a novel family of cross-reactive allergens that might contribute to the symptoms of baker's asthma and might in addition be related to grass pollen allergy, as indicated by the reactivity of grass pollen allergic patients to cereal thioredoxins. CLINICAL IMPLICATIONS: The recombinant cereal thioredoxins will, together with the already reported wheat allergens, contribute to a more reliable diagnosis of baker's asthma and, perhaps, become a tool for the development of component-resolved immunotherapy.

Allergens↗
PubMed2006

Absence of T-regulatory cell expression and function in atopic dermatitis skin.

BACKGROUND: The role of regulatory T cells has been widely reported in the suppression of T-cell activation. A dysfunction in CD4(+)CD25(+) T-regulatory cell-specific transcription factor FoxP3 leads to immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome, often associated with atopic dermatitis. Increasing the number and activity of regulatory T cells in affected organs has been suggested as a remedy in various inflammatory diseases, including allergy. OBJECTIVE: To determine the presence and function of regulatory T cells in atopic dermatitis. METHODS: Immunohistochemistry of lesional atopic dermatitis skin and control skin conditions was used to demonstrate regulatory cells and cytokines in situ. The role of effector and regulatory T cells as well as their specific cytokines in apoptosis in human keratinocyte cultures and artificial skin equivalents was investigated. RESULTS: Human T-regulatory type 1 cells, their suppressive cytokines, IL-10 and TGF-beta, as well as receptors for these cytokines were significantly expressed, whereas CD4(+)CD25(+)FoxP3(+) T-regulatory cells were not found in lesional and atopy patch test atopic dermatitis or psoriasis skin. Both subsets of regulatory T cells suppress the allergen-specific activation of T(H)1 and T(H)2 cells. In coculture and artificial skin equivalent experiments, subsets of T-regulatory cells neither induced keratinocyte death nor suppressed apoptosis induced by skin T cells, T(H)1 cells, IFN-gamma, or TNF-alpha. CONCLUSION: A dysregulation of disease-causing effector T cells is observed in atopic dermatitis lesions, in association with an impaired CD4(+)CD25(+)FoxP3(+) T-cell infiltration, despite the expression of type 1 regulatory cells in the dermis.

Adult↗
PubMed2006

The role of sensitization to Malassezia sympodialis in atopic eczema.

Atopic eczema (AE) is a chronic relapsing, highly pruritic inflammation of the skin with a worldwide prevalence of 10-20% in children and of 1-3% in adults. Malassezia sympodialis has been reported as the most frequent skin-colonizing yeast in both AE patients and healthy individuals. Approximately 50% of the AE patients show immediate-type skin reactions or have specific serum IgE against M. sympodialis. Sensitization to the yeast occurs almost exclusively in AE patients. The main cause for this specific sensitization may be the disrupted skin barrier facilitating allergen uptake. So far thirteen allergens of Malassezia have been cloned produced, characterized and partly studied in vitro and in vivo. Phylogenetically conserved allergen structures, such as manganese superoxide dismutase, may play a role as cross-reactive allergens in a subset of AE patients as a result of molecular mimicry and cross-reactivity with structurally related human proteins and might contribute to the perpetuation of the inflammatory skin reactions. The use of recombinant Malassezia allergens will contribute to elucidate the pathways of sensitization occurring in AE, the underlying immunological mechanisms governing IgE- and T-cell-mediated responses and may provide new therapeutic options to alleviate Malassezia-related symptoms in AE.

Allergens↗
PubMed2006

Benefits from the use of a pimecrolimus-based treatment in the management of atopic dermatitis in clinical practice. Analysis of a Swiss cohort.

BACKGROUND: Controlled studies established the efficacy and good tolerability of pimecrolimus cream 1% for the treatment of atopic dermatitis but they may not reflect real-life use. OBJECTIVE: To evaluate the efficacy, tolerability and cosmetic acceptance of a pimecrolimus-based regimen in daily practice in Switzerland. METHODS: This was a 6-month, open-label, multicentre study in 109 patients (55% > or = 18 years) with atopic dermatitis. Pimecrolimus cream 1% was incorporated into patients' standard treatment protocols. RESULTS: The pimecrolimus-based treatment was well tolerated and produced disease improvement in 65.7% of patients. It was particularly effective on the face (improvement rate: 75.0%). Mean pimecrolimus consumption decreased from 6.4 g/day (months 1-3) to 4.0 g/day (months 3-6) as disease improved. Most patients (74.1%) rated their disease control as 'complete' or 'good' and 90% were highly satisfied with the cream formulation. CONCLUSION: The use of a pimecrolimus-based regimen in everyday practice was effective, well tolerated and well accepted by patients.

Administration, Cutaneous↗
PubMed2006

A comparison of the skin irritation potential of transdermal fentanyl versus transdermal buprenorphine in middle-aged to elderly healthy volunteers.

OBJECTIVE: Establishing local tolerability of transdermal opioid systems is important as more systems become available for use in a range of indications. We compared the skin irritation potential of a single application of transdermal fentanyl (Durogesic D-trans; DDTDF) and transdermal buprenorphine (Transtec; TDB) patches in healthy volunteers. METHODS: 46 healthy males and females (mean age [range]: 59.6 [50-69] years) with healthy skin received a single dose of both the DDTDF 25 mug/h patch and the TDB 35 mug/h patch in a randomised order under naltrexone cover. The incidence and severity of erythema was assessed at various timepoints after patch removal. RESULTS: There was a non-significant trend towards a higher incidence of erythema 60 min after patch removal with TDB compared with DDTDF. The severity of erythema at 60 min and the incidence of erythema at 72 h after patch removal were significantly higher with TDB than with DDTDF (p = 0.01 and 22% versus 4.9%, p = 0.04, respectively). In general, the results from the chromametric assessment of treated skin were in agreement. The incidence of topical adverse events (AEs) was lower with DDTDF than with TDB (one versus six events) and subjects preferred the DDTDF patch and felt it was less noticeable on the skin. The DDTDF patch was considered less painful to remove, and, consistent with that, the TDB patch was judged to have better adhesion. Twenty-one subjects reported systemic AEs with DDTDF plus naltrexone and 22 with TDB plus naltrexone, most of which were considered treatment-related, 34 and 60 AEs, respectively. CONCLUSIONS: Local tolerability of transdermal opioid systems should be considered when making a therapeutic choice. Even after a single application in healthy volunteers, differences in local tolerability, assessed both clinically and by chromametry, and patch comfort were shown between DDTDF and TDB, in favour of DDTDF.

Administration, Cutaneous↗
PubMed2005

Prevention of allergy by a recombinant multi-allergen vaccine with reduced IgE binding and preserved T cell epitopes.

Novel approaches for the prevention of allergy are required, because of the inevitably increasing prevalence of allergic diseases during the last 30 years. Here, a recombinant chimeric protein, which comprises the whole amino acid sequences of three bee venom major allergens has been engineered and used in prevention of bee venom sensitization in mice. Phospholipase A2 (Api m 1), hyaluronidase (Api m 2) and melittin (Api m 3) fragments with overlapping amino acids were assembled in a different order in the Api m (1/2/3) chimeric protein, which preserved entire T cell epitopes, whereas B cell epitopes of all three allergens were abrogated. Accordingly, IgE cross-linking leading to mast cell and basophil mediator release was profoundly reduced in humans. Supporting these findings, the Api m (1/2/3) induced 100 to 1000 times less type-1 skin test reactivity in allergic patients. Treatment of mice with Api m (1/2/3) led to a significant reduction of specific IgE development towards native allergen, representing a protective vaccine effect in vivo. These results demonstrate a novel prototype of a preventive allergy vaccine, which preserves the entire T cell epitope repertoire, but bypasses induction of IgE against native allergen, and side effects related to mast cell/basophil IgE FcepsilonRI cross-linking in sensitized individuals.

Allergens↗
PubMed2005

A major allergen gene-fusion protein for potential usage in allergen-specific immunotherapy.

BACKGROUND: Specific immunotherapy is a common treatment of allergic diseases and could potentially be applied to other immunologic disorders. Despite its use in clinical practice, more defined and safer allergy vaccine preparations are required. Differences between epitopes of IgE that recognize the 3-dimensional structure of allergens and T cells that recognize linear amino acid sequences provide a suitable tool for novel vaccine development for specific immunotherapy. OBJECTIVE: The aim of the study was to delete B-cell epitopes and prevent IgE crosslinking, but to preserve T-cell epitopes by fusion of 2 major allergens of bee venom because of a change in the conformation. METHODS: By genetic engineering, we produced a fusion protein composed of the 2 major bee venom allergens: phospholipase A 2 (Api m 1) and hyaluronidase (Api m 2). RESULTS: The Api m [1/2] fusion protein induced T-cell proliferation and both T H 1-type and T H 2-type cytokine responses. In contrast, IgE reactivity was abolished, and profoundly reduced basophil degranulation and type 1 skin test reactivity was observed. Pretreatment of mice with Api m [1/2] fusion protein significantly suppressed the development of specific IgE as well as other antibody isotypes after immunization with the native allergen. CONCLUSION: The novel fusion protein of 2 major allergens bypasses IgE binding and mast cell/basophil IgE FcepsilonRI crosslinking and protects from IgE development.

Adult↗
PubMed2005

IgE-mediated and T cell-mediated autoimmunity against manganese superoxide dismutase in atopic dermatitis.

BACKGROUND: Autoreactivity of patients with atopic dermatitis (AD) to human proteins has been postulated as a decisive pathogenetic factor for AD. OBJECTIVE: In this study, it was investigated whether the stress-inducible enzyme manganese superoxide dismutase (MnSOD) of human and fungal origin might act as an autoallergen in atopic dermatitis. METHODS: Patients with AD (n = 69; mean SCORAD [SCORing Atopic Dermatitis], 27) and other inflammatory skin diseases as well as with inhalant allergies were investigated. The presence of specific IgE against recombinant MnSOD of fungal and human origin and the fungal extracts of Aspergillus fumigatus and Malassezia sympodialis was measured by CAP, ELISA, skin prick test, and in subset of patients also by atopy patch tests (APTs) and PBMC proliferation assays. Cross-reactivity between allergens was determined by CAP inhibition. The presence of MnSOD in human skin in various inflammatory skin conditions was investigated by immunohistochemistry. RESULTS: Specific IgE antibodies against human MnSOD correlating with the disease activity were found in 29 out of 67 patients with AD. The human protein was able to induce in vitro T-cell reactivity and eczematous reactions in APT in MnSOD-sensitized patients with AD. MnSOD was upregulated in various inflammatory skin reactions and APT skin specimens. Cosensitization to structurally related and cross-reacting fungal MnSOD and the skin-colonizing yeast M sympodialis was observed in all patients sensitized against human MnSOD. CONCLUSION: Human MnSOD may play a role as an autoallergen in a subset of patients with AD, including nonatopic eczema. By molecular mimicry leading to cross-reactivity such sensitization might be induced primarily by exposure to environmental fungal MnSOD of M sympodialis .

Adult↗
PubMed2005

Chemokines and their receptors in the pathogenesis of allergic asthma: progress and perspective.

PURPOSE OF REVIEW: The importance of chemokines and their receptors to development and maintenance of allergic asthma is reflected in the burgeoning amount of literature currently devoted to this topic. Based on a series of selected references published during the last year, this review now summarizes recent advances and discusses the likely implications of these findings. RECENT FINDINGS: Of particular interest are reports describing novel interactions between chemokines and both eosinophils and mast cells, including a role for CXCL5 (epithelial cell-derived neutrophil-activating peptide-78) and intracellular CCR3. New insights into TH2-cell dominance are presented in reports dealing with a range of chemokines, including CCL3 (MIP-1alpha), CCL4 (MIP-1beta), CCL5 (RANTES), CXCL9 (Mig), and CXCL10 (IP-10). The increasing importance of structural cell participation is emphasized by reports focusing on the eotaxin family (CCL11, CCL24, and CCL26), as well as CCL17 (TARC), CCL22 (MDC), CXCL9 (Mig), and CX3CL1 (Fractalkine). A developing role for nonreceptor regulatory mechanisms is also emphasized by seminal work relating to metalloproteinases, as well as reports focusing on proteoglycans and beta-Arrestin-2. Finally, significant progress in the field of asthma heritability is featured in reports relating to both known and novel genes, including those encoding CCR5 and DPP-10. SUMMARY: The critical influence of chemokine biology on the outcome of allergic asthma continues to be highlighted in recent reports describing novel mechanisms by which eosinophils are recruited into the lung and local TH2-cell dominance is maintained. Also of considerable interest is the increasing emphasis currently being realized for structural cell participation, nonreceptor regulatory mechanisms, and the influence of susceptibility genes.

Asthma↗
PubMed2004

Topical photodynamic therapy in the treatment of actinic keratoses and Bowen's disease in transplant recipients.

BACKGROUND: Transplant recipients (TR) have a dramatically increased risk for widespread epithelial neoplasms of the skin. Thus, there is a need to treat initial stages of these neoplasms such as actinic keratoses (AK) and Bowen's disease (BD) to prevent progression to invasive and potentially fatal squamous cell carcinoma. Topical photodynamic therapy (PDT) has been proven to be an effective treatment for AK and BD in immunocompetent patients, but no prospective trials in immunocompromised TR have been performed so far. METHODS: Twenty TR and 20 controls with histologically confirmed AK or BD underwent either a single or two consecutive treatments of topical PDT in an open trial. The application of 20% 5-aminolevulinic acid (ALA) for 5 hours was followed by illumination with 75 J/cm2 of visible light delivered at 80 mW/cm2 by an incoherent light source. RESULTS: The overall complete response rates in TR at 4, 12, and 48 weeks were 0.86, 0.68, and 0.48, respectively. The cure rates in both patient groups were comparable at 4 weeks but were significantly lower in TR than in controls at 12 and 48 weeks (P<0.05). Side effects included erythema, edema, and crust formation after illumination. Cosmetic results were excellent without scar formation or alterations in pigmentation. CONCLUSIONS: Topical PDT with 20% 5-ALA is an effective and safe treatment for AK and BD in immunosuppressed TR, with initial response rates comparable with those in immunocompetent patients. It is particularly useful in TR because of the possibility for repeated treatment of large lesional areas.

Administration, Topical↗
PubMed2004

Microbial colonization and atopic dermatitis.

PURPOSE OF REVIEW: Atopic dermatitis is a chronic relapsing, pruritic inflammation of the skin, affecting 10-20% of children and 1-3% adults worldwide, with increasing prevalence in highly industrialized countries. Here we review relevant studies, published since June 2002, about immunological triggers in atopic dermatitis, with emphasis on the role of microbial colonization. RECENT FINDINGS: During the past 2 years there has been considerable interest in the mechanisms and trigger factors underlying the increased microbial colonization of atopic skin. Staphylococcus aureus appears to play a significant role as it leads to a worsening of disease severity by producing superantigens that induce a strong proliferation of T cells and favour a T helper type 2-like cytokine profile. In addition, different Malassezia species seem to elicit and maintain skin inflammation after sensitization, but the precise immunological pathway has not yet been described. All these microorganisms are not only perceived as aetiological factors but also as agents responsible either for sustained disease activity or resistance to therapy by modulation of the immune response. SUMMARY: New insights into the important role of microorganisms and their key immunomodulatory pathways in atopic dermatitis may have important implications from a therapeutic point of view because patients with atopic dermatitis may benefit from more than just anti-inflammatory treatment in the future.

Adolescent↗
PubMed2003

A second step of chemotaxis after transendothelial migration: keratinocytes undergoing apoptosis release IFN-gamma-inducible protein 10, monokine induced by IFN-gamma, and IFN-gamma-inducible alpha-chemoattractant for T cell chemotaxis toward epidermis in atopic dermatitis.

Activation and skin-selective homing of T cells and their effector functions in the skin represent sequential immunological events in the pathogenesis of atopic dermatitis (AD). Apoptosis of keratinocytes, induced mainly by T cells and mediated by IFN-gamma and Fas, is the essential pathogenetic event in eczema formation. Keratinocyte apoptosis appears as activation-induced cell death in AD. By IFN-gamma stimulation, chemokines such as IFN-gamma-inducible protein 10, monokine induced by IFN-gamma, and IFN-gamma-inducible alpha-chemoattractant are strongly up-regulated in keratinocytes. These chemokines attract T cells bearing the specific receptor CXCR3, which is highly expressed on T cells isolated from skin biopsies of AD patients. Accordingly, an increased T cell chemotaxis was observed toward IFN-gamma-treated keratinocytes. Supporting these findings, enhanced IFN-gamma-inducible protein 10, monokine induced by IFN-gamma, and IFN-gamma-inducible alpha-chemoattractant expression was observed in lesional AD skin by immunohistochemical staining. These results indicate a second step of chemotaxis inside the skin after transendothelial migration of the inflammatory cells. Keratinocytes undergoing apoptosis in acute eczematous lesions release chemokines that attract more T cells toward the epidermis, which may further augment the inflammation and keratinocyte apoptosis.

Adult↗