Publications by authors named "Gunter J Sturm"

29 Publications

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EAACI Allergen Immunotherapy User's Guide.

Pediatr Allergy Immunol 2020 05;31 Suppl 25:1-101

Department of Dermatology and Venerology, Medical University of Graz, Graz, Austria.

Allergen immunotherapy is a cornerstone in the treatment of allergic children. The clinical efficiency relies on a well-defined immunologic mechanism promoting regulatory T cells and downplaying the immune response induced by allergens. Clinical indications have been well documented for respiratory allergy in the presence of rhinitis and/or allergic asthma, to pollens and dust mites. Patients who have had an anaphylactic reaction to hymenoptera venom are also good candidates for allergen immunotherapy. Administration of allergen is currently mostly either by subcutaneous injections or by sublingual administration. Both methods have been extensively studied and have pros and cons. Specifically in children, the choice of the method of administration according to the patient's profile is important. Although allergen immunotherapy is widely used, there is a need for improvement. More particularly, biomarkers for prediction of the success of the treatments are needed. The strength and efficiency of the immune response may also be boosted by the use of better adjuvants. Finally, novel formulations might be more efficient and might improve the patient's adherence to the treatment. This user's guide reviews current knowledge and aims to provide clinical guidance to healthcare professionals taking care of children undergoing allergen immunotherapy.
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http://dx.doi.org/10.1111/pai.13189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317851PMC
May 2020

Perspectives in allergen immunotherapy: 2019 and beyond.

Allergy 2019 12;74 Suppl 108:3-25

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Zurich, Switzerland.

The seventh "Future of the Allergists and Specific Immunotherapy (FASIT)" workshop held in 2019 provided a platform for global experts from academia, allergy clinics, regulatory authorities and industry to review current developments in the field of allergen immunotherapy (AIT). Key domains of the meeting included the following: (a) Biomarkers for AIT and allergic asthma; (b) visions for the future of AIT; (c) progress and data for AIT in asthma and the updates of GINA and EAACI Asthma Guidelines (separated for house dust mite SCIT, SLIT tablets and SLIT drops; patient populations) including a review of clinically relevant endpoints in AIT studies in asthma; (d) regulatory prerequisites such as the "Therapy Allergen Ordinance" in Germany; (e) optimization of trial design in AIT clinical research; (f) challenges planning and conducting phase III (field) studies and the future role of Allergen Exposure Chambers (AEC) in AIT product development from the regulatory point of view. We report a summary of panel discussions of all six domains and highlight unmet needs and possible solutions for the future.
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http://dx.doi.org/10.1111/all.14077DOI Listing
December 2019

Apolipoprotein A-IV acts as an endogenous anti-inflammatory protein and is reduced in treatment-naïve allergic patients and allergen-challenged mice.

Allergy 2020 02 10;75(2):392-402. Epub 2019 Sep 10.

Division of Pharmacology, Otto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria.

Background: Recent studies pointed to a crucial role for apolipoproteins in the pathogenesis of inflammatory diseases. However, the role of apolipoprotein-IV (ApoA-IV) in allergic inflammation has not been addressed thoroughly thus far.

Objective: Here, we explored the anti-inflammatory effects and underlying signaling pathways of ApoA-IV on eosinophil effector function in vitro and in vivo.

Methods: Migratory responsiveness, Ca -flux and apoptosis of human peripheral blood eosinophils were assessed in vitro. Allergen-driven airway inflammation was assessed in a mouse model of acute house dust mite-induced asthma. ApoA-IV serum levels were determined by ELISA.

Results: Recombinant ApoA-IV potently inhibited eosinophil responsiveness in vitro as measured by Ca -flux, shape change, integrin (CD11b) expression, and chemotaxis. The underlying molecular mechanism involved the activation of Rev-ErbA-α and induced a PI3K/PDK1/PKA-dependent signaling cascade. Systemic application of ApoA-IV prevented airway hyperresponsiveness (AHR) and airway eosinophilia in mice following allergen challenge. ApoA-IV levels were decreased in serum from allergic patients compared to healthy controls.

Conclusion: Our data suggest that ApoA-IV is an endogenous anti-inflammatory protein that potently suppresses effector cell functions in eosinophils. Thus, exogenously applied ApoA-IV may represent a novel pharmacological approach for the treatment of allergic inflammation and other eosinophil-driven disorders.
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http://dx.doi.org/10.1111/all.14022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065107PMC
February 2020

Possible utility of basophil activation test in dual honeybee and vespid sensitization.

J Allergy Clin Immunol Pract 2020 01 22;8(1):392-394.e5. Epub 2019 Jun 22.

Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria; Allergy Outpatient Clinic Reumannplatz, Vienna, Austria. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2019.06.008DOI Listing
January 2020

Risk factors and indicators of severe systemic insect sting reactions.

Allergy 2020 03 16;75(3):535-545. Epub 2019 Jul 16.

Department of Dermatology, Venereology and Allergy & Allergy Center Mainfranken, University Hospital Würzburg, Würzburg, Germany.

Hymenoptera venom allergy ranks among the top three causes of anaphylaxis worldwide, and approximately one-quarter of sting-induced reactions are classified as severe. Fatal sting reactions are exceedingly rare, but certain factors may entail a considerably higher risk. Delayed administration of epinephrine and upright posture are situational risk factors which may determine an unfavorable outcome of the acute anaphylactic episode and should be addressed during individual patient education. Systemic mastocytosis and senior age are major, unmodifiable long-term risk factors and thus reinforce the indication for venom immunotherapy. Vespid venom allergy and male sex likewise augment the risk of severe or even fatal reactions. Further studies are required to assess the impact of specific cardiovascular comorbidities. Available data regarding potential effects of beta-blockers and/or ACE inhibitors in coexisting venom allergy are inconclusive and do not justify recommendations to discontinue guideline-directed antihypertensive treatment. The absence of urticaria/angioedema during sting-induced anaphylaxis is indicative of a severe reaction, serum tryptase elevation, and mast cell clonality. Determination of basal serum tryptase levels is an established diagnostic tool for risk assessment in Hymenoptera venom-allergic patients. Measurement of platelet-activating factor acetylhydrolase activity represents a complementary approach but is not available for routine diagnostic use.
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http://dx.doi.org/10.1111/all.13945DOI Listing
March 2020

Allergic rhinitis is associated with complex alterations in high-density lipoprotein composition and function.

Biochim Biophys Acta Mol Cell Biol Lipids 2019 10 8;1864(10):1280-1292. Epub 2019 Jun 8.

Division of Pharmacology, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.; BioTechMed Graz, Mozartgasse 12/II, 8010 Graz, Austria. Electronic address:

Despite strong evidence that high-density lipoproteins (HDLs) modulate the immune response, the role of HDL in allergies is still poorly understood. Many patients with allergic rhinitis (AR) develop a late-phase response, characterized by infiltration of monocytes and eosinophils into the nasal submucosa. Functional impairment of HDL in AR-patients may insufficiently suppress inflammation and cell infiltration, but the effect of AR on the composition and function of HDL is not understood. We used apolipoprotein (apo) B-depleted serum as well as isolated HDL from AR-patients (n = 43) and non-allergic healthy controls (n = 20) for detailed compositional and functional characterization of HDL. Both AR-HDL and apoB-depleted serum of AR-patients showed decreased anti-oxidative capacity and impaired ability to suppress monocyte nuclear factor-κB expression and pro-inflammatory cytokine secretion, such as interleukin (IL)-4, IL-6, IL-8, tumor necrosis factor alpha and IL-1 beta. Sera of AR-patients showed decreased paraoxonase and cholesteryl-ester transfer protein activities, increased lipoprotein-associated phospholipase A2 activity, while lecithin-cholesterol acyltransferase activity and cholesterol efflux capacity were not altered. Surprisingly, apoB-depleted serum and HDL from AR-patients showed an increased ability to suppress eosinophil effector responses upon eotaxin-2/CCL24 stimulation. Mass spectrometry and biochemical analyses showed reduced levels of apoA-I and phosphatidylcholine, but increased levels of apoA-II, triglycerides and lyso-phosphatidylcholine in AR-HDL. The changes in AR-HDL composition were associated with altered functional properties. In conclusion, AR alters HDL composition linked to decreased anti-oxidative and anti-inflammatory properties but improves the ability of HDL to suppress eosinophil effector responses.
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http://dx.doi.org/10.1016/j.bbalip.2019.06.007DOI Listing
October 2019

EAACI Guidelines on Allergen Immunotherapy: House dust mite-driven allergic asthma.

Allergy 2019 05;74(5):855-873

Department of Clinical Immunology, Wroclaw Medical University, Wroclaw, Poland.

Allergen immunotherapy (AIT) has been in use for the treatment of allergic disease for more than 100 years. Asthma treatment relies mainly on corticosteroids and other controllers recommended to achieve and maintain asthma control, prevent exacerbations, and improve quality of life. AIT is underused in asthma, both in children and in adults. Notably, patients with allergic asthma not adequately controlled on pharmacotherapy (including biologics) represent an unmet health need. The European Academy of Allergy and Clinical Immunology has developed a clinical practice guideline providing evidence-based recommendations for the use of house dust mites (HDM) AIT as add-on treatment for HDM-driven allergic asthma. This guideline was developed by a multi-disciplinary working group using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. HDM AIT was separately evaluated by route of administration and children and adults: subcutaneous (SCIT) and sublingual AIT (SLIT), drops, and tablets. Recommendations were formulated for each. The important prerequisites for successful treatment with HDM AIT are (a) selection of patients most likely to respond to AIT and (b) use of allergen extracts and desensitization protocols of proven efficacy. To date, only AIT with HDM SLIT-tablet has demonstrated a robust effect in adults for critical end points (exacerbations, asthma control, and safety). Thus, it is recommended as an add-on to regular asthma therapy for adults with controlled or partially controlled HDM-driven allergic asthma (conditional recommendation, moderate-quality evidence). HDM SCIT is recommended for adults and children, and SLIT drops are recommended for children with controlled HDM-driven allergic asthma as the add-on to regular asthma therapy to decrease symptoms and medication needs (conditional recommendation, low-quality evidence).
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http://dx.doi.org/10.1111/all.13749DOI Listing
May 2019

Medical Algorithms: Diagnosis and treatment of Hymenoptera venom allergy.

Allergy 2019 10 2;74(10):2016-2018. Epub 2019 Jun 2.

Mozartpraxis, Paediatric Respiratory and Allergy Outpatient Practice, Graz, Austria.

Diagnosis of Hymenoptera venom allergy (HVA) is straightforward in the majority of patients, but can be challenging in double positive and test negative patients. Test results sometimes can be confusing as patients with high skin test reactivity and high specific IgE (sIgE) levels are not at risk for severe systemic sting reactions (SSR), and conversely, patients with weakly positive or even negative tests can experience severe SSR. Venom immunotherapy (VIT) is safe, highly effective, and recommended in patients with moderate to severe SSR and in patients with SSR confined to generalized skin symptoms if quality of life is impaired.
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http://dx.doi.org/10.1111/all.13817DOI Listing
October 2019

2019 ARIA Care pathways for allergen immunotherapy.

Allergy 2019 11 15;74(11):2087-2102. Epub 2019 Jul 15.

Unité de pneumo-allergologie de l'enfant, pôle pédiatrique, CHU de Clermont-Ferrand-Estaing, Clermont-Ferrand, France.

Allergen immunotherapy (AIT) is a proven therapeutic option for the treatment of allergic rhinitis and/or asthma. Many guidelines or national practice guidelines have been produced but the evidence-based method varies, many are complex and none propose care pathways. This paper reviews care pathways for AIT using strict criteria and provides simple recommendations that can be used by all stakeholders including healthcare professionals. The decision to prescribe AIT for the patient should be individualized and based on the relevance of the allergens, the persistence of symptoms despite appropriate medications according to guidelines as well as the availability of good-quality and efficacious extracts. Allergen extracts cannot be regarded as generics. Immunotherapy is selected by specialists for stratified patients. There are no currently available validated biomarkers that can predict AIT success. In adolescents and adults, AIT should be reserved for patients with moderate/severe rhinitis or for those with moderate asthma who, despite appropriate pharmacotherapy and adherence, continue to exhibit exacerbations that appear to be related to allergen exposure, except in some specific cases. Immunotherapy may be even more advantageous in patients with multimorbidity. In children, AIT may prevent asthma onset in patients with rhinitis. mHealth tools are promising for the stratification and follow-up of patients.
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http://dx.doi.org/10.1111/all.13805DOI Listing
November 2019

EAACI guidelines on allergen immunotherapy: Prevention of allergy.

Pediatr Allergy Immunol 2017 Dec 27;28(8):728-745. Epub 2017 Oct 27.

Food Allergy Referral Centre Veneto Region, Department of Woman and Child Health, Padua University Hospital.

Allergic diseases are common and frequently coexist. Allergen immunotherapy (AIT) is a disease-modifying treatment for IgE-mediated allergic disease with effects beyond cessation of AIT that may include important preventive effects. The European Academy of Allergy and Clinical Immunology (EAACI) has developed a clinical practice guideline to provide evidence-based recommendations for AIT for the prevention of (i) development of allergic comorbidities in those with established allergic diseases, (ii) development of first allergic condition, and (iii) allergic sensitization. This guideline has been developed using the Appraisal of Guidelines for Research & Evaluation (AGREE II) framework, which involved a multidisciplinary expert working group, a systematic review of the underpinning evidence, and external peer-review of draft recommendations. Our key recommendation is that a 3-year course of subcutaneous or sublingual AIT can be recommended for children and adolescents with moderate-to-severe allergic rhinitis (AR) triggered by grass/birch pollen allergy to prevent asthma for up to 2 years post-AIT in addition to its sustained effect on AR symptoms and medication. Some trial data even suggest a preventive effect on asthma symptoms and medication more than 2 years post-AIT. We need more evidence concerning AIT for prevention in individuals with AR triggered by house dust mites or other allergens and for the prevention of allergic sensitization, the first allergic disease, or for the prevention of allergic comorbidities in those with other allergic conditions. Evidence for the preventive potential of AIT as disease-modifying treatment exists but there is an urgent need for more high-quality clinical trials.
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http://dx.doi.org/10.1111/pai.12807DOI Listing
December 2017

Reply.

J Allergy Clin Immunol 2017 03 4;139(3):1067-1068. Epub 2017 Jan 4.

Department of Dermatology and Venerology, Medical University of Graz, Graz, Austria.

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http://dx.doi.org/10.1016/j.jaci.2016.09.059DOI Listing
March 2017

Phosphoinositide-dependent protein kinase 1 (PDK1) mediates potent inhibitory effects on eosinophils.

Eur J Immunol 2015 May 27;45(5):1548-59. Epub 2015 Feb 27.

Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.

Prostaglandin E2 (PGE2 ) protects against allergic responses via binding to prostanoid receptor EP4, which inhibits eosinophil migration in a PI3K/PKC-dependent fashion. The phosphoinositide-dependent protein kinase 1 (PDK1) is known to act as a downstream effector in PI3K signaling and has been implicated in the regulation of neutrophil migration. Thus, here we elucidate whether PDK1 mediates inhibitory effects of E-type prostanoid receptor 4 (EP4) receptors on eosinophil function. Therefore, eosinophils were isolated from human peripheral blood or differentiated from mouse BM. PDK1 signaling was investigated in shape change, chemotaxis, CD11b, respiratory burst, and Ca(2+) mobilization assays. The specific PDK1 inhibitors BX-912 and GSK2334470 prevented the inhibition by prostaglandin E2 and the EP4 agonist ONO-AE1-329. Depending on the cellular function, PDK1 seemed to act through PI3K-dependent or PI3K-independent mechanisms. Stimulation of EP4 receptors caused PDK1 phosphorylation at Ser396 and induced PI3K-dependent nuclear translocation of PDK1. EP4-induced inhibition of shape change and chemotaxis was effectively reversed by the Akt inhibitor triciribine. In support of this finding, ONO-AE1-329 induced a PI3K/PDK1-dependent increase in Akt phosphorylation. In conclusion, our data illustrate a critical role for PDK1 in transducing inhibitory signals on eosinophil effector function. Thus, our results suggest that PDK1 might serve as a novel therapeutic target in diseases involving eosinophilic inflammation.
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http://dx.doi.org/10.1002/eji.201445196DOI Listing
May 2015

Unusual reactions to hymenoptera stings: what should we keep in mind?

Clin Rev Allergy Immunol 2014 Aug;47(1):91-9

Department of Allergology and Clinical Immunology, "Mother Theresa" School of Medicine, Tirana, Albania,

This review includes a variety of extremely rare and unusual hymenoptera sting (HS) circumstances with regard to sting localization, geographic region, massivity of multiple stings, and particularly related to clinical symptoms. Such reactions occur in a temporal relationship to HS (s), differ from typical allergic symptomatology, and sometimes need follow-up during many months. With respect to pathogenesis, the major mechanisms involved are toxic, autoimmune, and other delayed immunological ones. While delayed inflammatory symptoms of the nervous system are considered as delayed hypersensitization or autoimmune entities, generalized rhabdomyolysis and consecutive acute kidney injury is considered a toxic reaction, mostly induced by massive envenomation to wasps or "Africanized" bees. Hemorrhagic episodes of targeted organ (s) could be additional potential risk for acute kidney injury, while the bee venom-induced hemorrhage is proposed to be a nonimmune-mediated anaphylactic symptom. The hemodynamic involvement of vital organs and systems with hypoxia and hypovolemia together with simultaneous immunoglobulin E (IgE) sensitization are considered potential indications for venom immunotherapy. In contrast, patients who have experienced various complications with unknown or nonallergic mechanisms should be informed about the importance of epinephrine's use and additional measures on future sting avoidance. In conclusion, although unusual reactions are extremely rare, it is important to keep them in mind.
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http://dx.doi.org/10.1007/s12016-014-8434-yDOI Listing
August 2014

Specificity of conventional and Ves v 5-spiked venom decreases with increasing total IgE.

J Allergy Clin Immunol 2014 Sep 13;134(3):739-41. Epub 2014 May 13.

Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2014.03.038DOI Listing
September 2014

Sensitization to Hymenoptera venoms is common, but systemic sting reactions are rare.

J Allergy Clin Immunol 2014 Jun 22;133(6):1635-43.e1. Epub 2013 Dec 22.

Department of Dermatology, Division of Environmental Dermatology and Venerology, Medical University of Graz, Graz, Austria.

Background: Sensitization to Hymenoptera venom without systemic sting reactions (SSRs) is commonly observed in the general population. Clinical relevance for a future sting has not yet been investigated.

Objective: We aimed to evaluate the effect of these debatable sensitizations with deliberate sting challenges and to monitor serologic changes for up to 2 years.

Methods: One hundred thirty-one challenges with bees and wasps were performed in 94 subjects with a hitherto irrelevant sensitization. The clinical outcome was recorded, and results of specific IgE (sIgE) determinations, skin tests, and basophil activation tests were correlated to the sting reaction. sIgE levels were monitored in reactors and nonreactors after 3 hours, 1 week, 4 weeks, and 1 year.

Results: Only 5 (5.3%) patients had SSRs, but 41 (43.6%) had large local reactions (LLRs) after the sting. Compared with the general population, there was a 9.5-fold higher risk for LLRs but not for SSRs. Three hours after the sting, sIgE levels slightly decreased, but none of the 94 subjects' results turned negative. After 1 week, sIgE levels already increased, increasing up to 3.5-fold (range, 0.2- to 34.0-fold) baseline levels after 4 weeks. To assess the clinical relevance of this increase, we randomly selected 18 patients for a re-sting. Again, 50% had an LLR, but none had an SSR.

Conclusion: Although sensitization to Hymenoptera venoms was common, the risk of SSRs in sensitized subjects was low in our study. The sIgE level increase after the sting was not an indicator for conversion into symptomatic sensitization. Currently available tests were not able to distinguish between asymptomatic sensitization, LLRs, and SSRs.
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http://dx.doi.org/10.1016/j.jaci.2013.10.046DOI Listing
June 2014

Inconsistent results of diagnostic tools hamper the differentiation between bee and vespid venom allergy.

PLoS One 2011 15;6(6):e20842. Epub 2011 Jun 15.

Division of Environmental Dermatology and Venerology, Department of Dermatology, Medical University of Graz, Graz, Austria.

Background: Double sensitization (DS) to bee and vespid venom is frequently observed in the diagnosis of hymenoptera venom allergy, but clinically relevant DS is rare. Therefore it is sophisticated to choose the relevant venom for specific immunotherapy and overtreatment with both venoms may occur. We aimed to compare currently available routine diagnostic tests as well as experimental tests to identify the most accurate diagnostic tool.

Methods: 117 patients with a history of a bee or vespid allergy were included in the study. Initially, IgE determination by the ImmunoCAP, by the Immulite, and by the ADVIA Centaur, as well as the intradermal test (IDT) and the basophil activation test (BAT) were performed. In 72 CAP double positive patients, individual IgE patterns were determined by western blot inhibition and component resolved diagnosis (CRD) with rApi m 1, nVes v 1, and nVes v 5.

Results: Among 117 patients, DS was observed in 63.7% by the Immulite, in 61.5% by the CAP, in 47.9% by the IDT, in 20.5% by the ADVIA, and in 17.1% by the BAT. In CAP double positive patients, western blot inhibition revealed CCD-based DS in 50.8%, and the CRD showed 41.7% of patients with true DS. Generally, agreement between the tests was only fair and inconsistent results were common.

Conclusion: BAT, CRD, and ADVIA showed a low rate of DS. However, the rate of DS is higher than expected by personal history, indicating that the matter of clinical relevance is still not solved even by novel tests. Furthermore, the lack of agreement between these tests makes it difficult to distinguish between bee and vespid venom allergy. At present, no routinely employed test can be regarded as gold standard to find the clinically relevant sensitization.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0020842PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3115969PMC
November 2011

Inhibitory effect of prostaglandin I2 on bone marrow kinetics of eosinophils in the guinea pig.

J Leukoc Biol 2011 Aug 17;90(2):285-91. Epub 2011 May 17.

Institute for Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.

Enhanced eosinophil trafficking from bone marrow to the tissue is a hallmark of allergic diseases. We have shown previously that PGI(2) markedly attenuates the locomotion of human eosinophils in vitro. Here, we set out to determine the effect of PGI(2) on the trafficking of bone marrow eosinophils in the guinea pig. Shape change of bone marrow eosinophils was determined by flow cytometry, and chemotaxis assays were performed using a transwell migration system. Eosinophil release from bone marrow of guinea pigs was investigated in the isolated, perfused hind-limb preparation. We found that PGI(2) prevented the mobilization of eosinophils from bone marrow and attenuated the shape change and chemotactic responses of bone marrow eosinophils. These effects were mimicked by iloprost and were prevented by the IP antagonist CAY10441 and the adenylyl cyclase inhibitor SQ22536. Immunohistochemical staining of bone marrow confirmed the expression of IPs by bone marrow eosinophils. The rate-limiting enzyme of PGI(2) formation, PGIS, was found in large mononuclear cells. These data show that IP activation negatively modulates the mobilization and locomotion of bone marrow eosinophils and might therefore also protect against exaggerated recruitment of eosinophils to inflammatory sites.
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http://dx.doi.org/10.1189/jlb.0211087DOI Listing
August 2011

CD203c-based basophil activation test in allergy diagnosis: characteristics and differences to CD63 upregulation.

Cytometry B Clin Cytom 2010 Sep 14;78(5):308-18. Epub 2010 Apr 14.

Institute of Experimental and Clinical Pharmacology, Center of Molecular Medicine, Medical University of Graz, Austria.

Background: The basophil activation test (BAT) based on CD203c upregulation has been validated as a reliable tool for the diagnosis of IgE-mediated allergies. Nevertheless, CD203c-based BAT is hardly comparable with that of CD63-based tests, as the mechanisms of CD203c versus CD63 induction differ considerably. The aim of the present study was to identify potent influencing factors of the CD203c-based BAT and to emphasize differences between CD63 and CD203c detection.

Methods: CD203c-based BAT was determined in 82 healthy controls and in 79 allergic patients. The effects of interleukin (IL)-3 and degranulation enhancing substances were investigated and compared with CD63 upregulation. Furthermore, the influence of different storage conditions and incubation times was evaluated and the impact of antiallergic drugs on the test results was assessed.

Results: CD203c and CD63 expression was rapidly upregulated reaching a maximum after 20-30 min. Basophil CD203c upregulation assayed after storage times up to 48 h declined already after 4 h. IL-3 treatment increased CD203c and CD63 baseline levels and decreased basophil CD203c responses in a dose-dependent manner. In contrast, cytochalasin B and latrunculin B did not affect CD203c responses but decreased CD63-based BAT. Finally, therapeutic concentrations of dimetindene and desloratadine did not affect CD203c upregulation.

Conclusion: CD203c-based basophil activation test should be performed preferentially within 4 h after taking the blood samples. Priming and degranulation-enhancing factors are not required for CD203c-based BAT. In contrast to skin testing, CD203c-based BAT can be performed in patients undergoing antiallergic treatment. © 2010 International Clinical Cytometry Society.
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http://dx.doi.org/10.1002/cyto.b.20526DOI Listing
September 2010

Prostaglandin E2 inhibits eosinophil trafficking through E-prostanoid 2 receptors.

J Immunol 2008 Nov;181(10):7273-83

Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.

The accumulation of eosinophils in lung tissue is a hallmark of asthma, and it is believed that eosinophils play a crucial pathogenic role in allergic inflammation. Prostaglandin (PG) E(2) exerts anti-inflammatory and bronchoprotective mechanisms in asthma, but the underlying mechanisms have remained unclear. In this study we show that PGE(2) potently inhibits the chemotaxis of purified human eosinophils toward eotaxin, PGD(2), and C5a. Activated monocytes similarly attenuated eosinophil migration, and this was reversed after pretreatment of the monocytes with a cyclooxygenase inhibitor. The selective E-prostanoid (EP) 2 receptor agonist butaprost mimicked the inhibitory effect of PGE(2) on eosinophil migration, whereas an EP2 antagonist completely prevented this effect. Butaprost, and also PGE(2), inhibited the C5a-induced degranulation of eosinophils. Moreover, selective kinase inhibitors revealed that the inhibitory effect of PGE(2) on eosinophil migration depended upon activation of PI3K and protein kinase C, but not cAMP. In animal models, the EP2 agonist butaprost inhibited the rapid mobilization of eosinophils from bone marrow of the in situ perfused guinea pig hind limb and prevented the allergen-induced bronchial accumulation of eosinophils in OVA-sensitized mice. Immunostaining showed that human eosinophils express EP2 receptors and that EP2 receptor expression in the murine lungs is prominent in airway epithelium and, after allergen challenge, in peribronchial infiltrating leukocytes. In summary, these data show that EP2 receptor agonists potently inhibit eosinophil trafficking and activation and might hence be a useful therapeutic option in eosinophilic diseases.
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http://dx.doi.org/10.4049/jimmunol.181.10.7273DOI Listing
November 2008

Asymptomatic sensitization to hymenoptera venom is related to total immunoglobulin E levels.

Int Arch Allergy Immunol 2009 10;148(3):261-4. Epub 2008 Oct 10.

Department of Dermatology, Division of Environmental Dermatology and Venerology, Medical University of Graz, Graz, Austria.

Background: The detection of specific serum immunoglobulin E (sIgE) to Hymenoptera venoms is an established diagnostic tool to diagnose insect venom hypersensitivity. However, the specificity of sIgE detection is a debated issue.

Methods: In 145 subjects, total IgE (tIgE) and sIgE to Hymenoptera venoms as well as sIgE to rapeseed as a marker of cross-reactive carbohydrate determinants were measured. In addition, an atopy score was determined for each patient. We looked for a possible association between tIgE and the presence of sIgE in subjects with a negative history of large local or systemic reactions to insect stings.

Results: Fifteen of 65 subjects (23.1%) with low levels of tIgE (<50 kU/l) had sIgE for bee or wasp venom, and 23 of 47 subjects (48.9%) with a tIgE from 50 to 250 kU/l showed sIgE. The highest rate of asymptomatic sensitization (22 of 33; 66.7%) was found in patients with tIgE levels higher than 250 kU/l. Median sIgE was approximately 4.8 times higher in subjects with tIgE levels above 250 kU/l than in those with tIgE levels <50 kU/l. Interestingly, a significant difference in median tIgE was recorded between individuals with and without sIgE to rapeseed [776.5 kU/l (25, 75% percentiles: 252.5, 2,000.0) vs. 50.5 kU/l (20.1, 172.0), respectively; p < 0001].

Conclusion: Specific antibodies are frequently seen in individuals with high tIgE, but appear to be largely irrelevant in clinical terms. This might lead to misdiagnosis in persons with an inconclusive sting history.
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http://dx.doi.org/10.1159/000161586DOI Listing
March 2009

Hierarchy of eosinophil chemoattractants: role of p38 mitogen-activated protein kinase.

Eur J Immunol 2006 Sep;36(9):2401-9

Institute of Experimental and Clinical Pharmacology, Medical University Graz, Graz, Austria.

Several chemoattractants can regulate the recruitment of eosinophils to sites of inflammation, but the hierarchy among them is unknown. We observed here that eosinophil chemotaxis towards eotaxin or 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) was amplified up to sixfold in the presence of prostaglandin (PG) D2. This effect was only seen in eosinophils, and not in neutrophils or basophils. Pretreatment with the chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2) antagonist ramatroban prevented the PGD2 enhancement of eosinophil migrations. In contrast, eotaxin or 5-oxo-ETE inhibited the migration of eosinophils towards PGD2. 5-oxo-ETE enhanced the chemotaxis to eotaxin, while eotaxin had no effect on 5-oxo-ETE-induced migration. 5-oxo-ETE induced the phosphorylation of p38 mitogen-activated protein kinase, and inhibition of p38 mitogen-activated protein kinase by SB-202190 converted the effect of 5-oxo-ETE on the chemotaxis to PGD2 from inhibition to enhancement. The presence of blood or plasma markedly decreased the sensitivity of eosinophils to eotaxin or 5-oxo-ETE, while responses to PGD2 were unaltered. In conclusion, PGD2 might be an initial chemoattractant, since it maintains its potency in the circulation and augments the responsiveness of eosinophils to other chemoattractants. In contrast, eotaxin seems to be an end-point chemoattractant, since it has reduced efficacy in blood and is capable of down-modulating eosinophil responsiveness to other chemoattractants.
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http://dx.doi.org/10.1002/eji.200535672DOI Listing
September 2006

5-Oxo-6,8,11,14-eicosatetraenoic acid is a potent chemoattractant for human basophils.

J Allergy Clin Immunol 2005 Nov 3;116(5):1014-9. Epub 2005 Oct 3.

Department of Experimental and Clinical Pharmacology, Medical University of Graz, Austria.

Background: 5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a chemoattractant for eosinophils and neutrophils, and the messenger RNA for its receptor, the oxo-eicosatetraenoic acid receptor (OXE), has been detected in several tissues.

Objectives: This study aimed at clarifying the role of 5-oxo-ETE in the regulation of basophil function.

Methods: Basophil responses were determined in assays of flow-cytometric shape change, Ca(2+) flux, chemotaxis, and histamine release. Messenger RNA for OXE was detected by real-time PCR.

Results: We observed that human eosinophils were 3 to 10 times more sensitive to 5-oxo-ETE than neutrophils in flow-cytometric shape change and Ca(2+) flux assays, as estimated from the half-maximal responses of the cells. Basophils responded to 5-oxo-ETE in the shape change assay with a sensitivity similar to that of eosinophils. 5-Oxo-ETE was a weak inducer of Ca(2+) flux in basophils and did not cause histamine release but was a highly effective chemoattractant for basophils in the low nanomolar concentration range in a pertussis toxin-sensitive manner. In agreement with these functional studies, the messenger RNA for the 5-oxo-ETE receptor, OXE, was detectable in basophils as in monocytes, eosinophils, and neutrophils, but not in fibroblasts. Specimens from sinus mucosa, tonsils, and adenoids also contained detectable levels of messenger RNA for OXE.

Conclusion: Our data suggest that 5-oxo-ETE is potentially involved in the regulation of basophil recruitment and might hence be a useful therapeutic target in atopic disease.
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http://dx.doi.org/10.1016/j.jaci.2005.08.001DOI Listing
November 2005

Stem cell factor stimulates the chemotaxis, integrin upregulation, and survival of human basophils.

J Allergy Clin Immunol 2005 Oct 2;116(4):820-6. Epub 2005 Aug 2.

Department of Experimental and Clinical Pharmacology, Medical University of Graz, Austria.

Background: Little is known about the mechanisms that regulate the selective recruitment of basophils to sites of allergic inflammation.

Objective: Here we examine the role of stem cell factor (SCF) in the regulation of basophil function.

Methods: Human basophils were isolated from peripheral blood, and their migration was investigated in chemotaxis assays. Apoptosis was detected by means of annexin V and propidium iodide staining. The expression of cell-surface molecules was measured by means of flow cytometry.

Results: SCF amplified the chemotactic responsiveness of human peripheral blood basophils to the chemoattractants eotaxin, monocyte chemotactic protein 2 and macrophage inflammatory protein 1alpha, and C5a, without being chemotactic or chemokinetic by itself. SCF synergized with chemoattractants in causing basophil upregulation of the integrin CD11b, and this effect was inhibited by a c-kit antibody, the tyrosine kinase inhibitor imatinib mesylate (STI-571), and a phosphatidylinositol 3 kinase inhibitor but not by inhibitors of p38 mitogen-activated protein kinase or mitogen-activated protein kinase/extracellular signal-regulated kinase kinase. Basophils bound fluorescence-labeled SCF and expressed its receptor, c-kit, which was markedly upregulated in culture for 24 to 48 hours in the presence of IL-3. Moreover, SCF prolonged basophil survival in concert with IL-3 by delaying apoptosis. These effects of SCF were selective for basophils because chemotaxis and CD11b upregulation of eosinophils or neutrophils were unchanged.

Conclusion: SCF might be an important selective modulator of basophil function through a phosphatidylinositol 3 kinase-dependent pathway.
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http://dx.doi.org/10.1016/j.jaci.2005.06.008DOI Listing
October 2005

Identification of selective basophil chemoattractants in human nasal polyps as insulin-like growth factor-1 and insulin-like growth factor-2.

J Immunol 2004 Nov;173(10):6448-57

Leukocyte Biology Section, Biomedical Science Division, Faculty of Medicine, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom.

In a search for novel leukocyte chemoattractants at sites of allergic inflammation, we found basophil-selective chemoattractant activity in extracts of human nasal polyps. The extracts were fractionated by reverse phase HPLC, and the resulting fractions were tested for leukocyte-stimulating activity using sensitive shape change assays. The basophil-selective activity detected was not depleted by a poxvirus CC-chemokine-binding protein affinity column. This activity was further purified by HPLC, and proteins in the bioactive fractions were analyzed by tandem electrospray mass spectrometry. Insulin-like growth factor-2 (IGF-2) was identified in these HPLC fractions, and the basophil-stimulating activity was inhibited by an anti-IGF-2-neutralizing Ab. Recombinant IGF-2 induced a substantial shape change response in basophils, but not eosinophils, neutrophils, or monocytes. IGF-2 stimulated chemokinesis of basophils, but not eosinophils or neutrophils, and synergized with eotaxin-1/CCL11 in basophil chemotaxis. IGF-2 also caused up-regulation of basophil CD11b expression and inhibited apoptosis, but did not stimulate degranulation or Ca(2+) flux. Recombinant IGF-1 exhibited similar basophil-selective effects as IGF-2, and both growth factors were detected in nasal polyp extracts by ELISA. This is the first demonstration of chemokinetic factors that increase the motility of basophils, but do not act on other granulocytes or monocytes. IGF-1 and IGF-2 could play a role in the selective recruitment of basophils in vivo.
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http://dx.doi.org/10.4049/jimmunol.173.10.6448DOI Listing
November 2004

11-Dehydro-thromboxane B2, a stable thromboxane metabolite, is a full agonist of chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2) in human eosinophils and basophils.

J Biol Chem 2004 Feb 10;279(9):7663-70. Epub 2003 Dec 10.

Department of Experimental and Clinical Pharmacology, Medical University Graz, A-8010 Graz, Austria.

Thromboxane (TX) A(2), a cyclooxygenase-derived mediator involved in allergic responses, is rapidly converted in vivo to a stable metabolite, 11-dehydro-TXB(2), which is considered to be biologically inactive. In this study, we found that 11-dehydro-TXB(2), but not the TXA(2) analogue U46,619 or TXB(2), activated eosinophils and basophils, as assayed by flow cytometric shape change. 11-Dehydro-TXB(2) was also chemotactic for eosinophils but did not induce, nor inhibit, platelet aggregation. Chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2) is an important chemoattractant receptor expressed by eosinophils, basophils, and TH2 lymphocytes, and prostaglandin (PG)D(2) has been shown to be its principal ligand. 11-Dehydro-TXB(2) induced calcium flux mainly from intracellular stores in eosinophils, and this response was desensitized after stimulation with PGD(2) but not other eosinophil chemoattractants. Shape change responses of eosinophils and basophils to 11-dehydro-TXB(2) were inhibited by the thromboxane (TP)/CRTH2 receptor antagonist ramatroban, but not the selective TP antagonist SQ29,548, and were insensitive to pertussis toxin. The phospholipase C inhibitor U73,122 attenuated both 11-dehydro-TXB(2)- and PGD(2)-induced shape change. 11-Dehydro-TXB(2) also induced the chemotaxis of BaF/3 cells transfected with hCRTH2 but not naive BaF/3 cells. At a threshold concentration, 11-dehydro-TXB(2) had no antagonistic effect on CRTH2-mediated responses as induced by PGD2. These data show that 11-dehydro-TXB(2) is a full agonist of the CRTH2 receptor and hence might cause CRTH2 activation in cellular contexts where PGD-synthase is not present. Given its production in the allergic lung, antagonism of the 11-dehydro-TXB(2)/CRTH2axis may be of therapeutic relevance.
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http://dx.doi.org/10.1074/jbc.M310270200DOI Listing
February 2004