Publications by authors named "Stefan Vieths"

199 Publications

Does the Food Ingredient Pectin Provide a Risk for Patients Allergic to Non-Specific Lipid-Transfer Proteins?

Foods 2021 Dec 21;11(1). Epub 2021 Dec 21.

Paul-Ehrlich-Institut (PEI), Federal Institute for Vaccines and Biomedicines, 63225 Langen, Germany.

Pectin, a dietary fiber, is a polysaccharide that is widely used in food industry as a gelling agent. In addition, prebiotic and beneficial immunomodulatory effects of pectin have been demonstrated, leading to increased importance as food supplement. However, as cases of anaphylactic reactions after consumption of pectin-supplemented foods have been reported, the present study aims to evaluate the allergy risk of pectin. This is of particular importance since most of the pectin used in the food industry is extracted from citrus or apple pomace. Both contain several allergens such as non-specific lipid transfer proteins (nsLTPs), known to induce severe allergic reactions, which could impair the use of pectins in nsLTP allergic patients. Therefore, the present study for the first time was performed to analyze residual nsLTP content in two commercial pectins using different detection methods. Results showed the analytical sensitivity was diminished by the pectin structure. Finally, spiking of pectin with allergenic peach nsLTP Pru p 3 led to the conclusion that the potential residual allergen content in both pectins is below the threshold to induce anaphylactic reactions in nsLTP-allergic patients. This data suggests that consumption of the investigated commercial pectin products provides no risk for inducing severe reactions in nsLTP-allergic patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/foods11010013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750200PMC
December 2021

The Fusion Protein rFlaA:Betv1 Modulates DC Responses by a p38-MAPK and COX2-Dependent Secretion of PGE from Epithelial Cells.

Cells 2021 12 4;10(12). Epub 2021 Dec 4.

Molecular Allergology, Paul-Ehrlich-Institut, 63225 Langen, Germany.

Developing new adjuvants/vaccines and better understanding their mode-of-action is an important task. To specifically improve birch pollen allergy treatment, we designed a fusion protein consisting of major birch pollen allergen Betv1 conjugated to the TLR5-ligand flagellin (rFlaA:Betv1). This study investigates the immune-modulatory effects of rFlaA:Betv1 on airway epithelial cells. LA-4 mouse lung epithelial cells were stimulated with rFlaA:Betv1 in the presence/absence of various inhibitors with cytokine- and chemokine secretion quantified by ELISA and activation of intracellular signaling cascades demonstrated by Western blot (WB). Either LA-4 cells or LA-4-derived supernatants were co-cultured with BALB/c bone marrow-derived myeloid dendritic cells (mDCs). Compared to equimolar amounts of flagellin and Betv1 provided as a mixture, rFlaA:Betv1 induced higher secretion of IL-6 and the chemokines CCL2 and CCL20 from LA-4 cells and a pronounced MAPK- and NFB-activation. Mechanistically, rFlaA:Betv1 was taken up more strongly and the induced cytokine production was inhibited by NFB-inhibitors, while ERK- and p38-MAPK-inhibitors only suppressed IL-6 and CCL2 secretion. In co-cultures of LA-4 cells with mDCs, rFlaA:Betv1-stimulated LA-4 cells p38-MAPK- and COX2-dependently secreted PGE, which modulated DC responses by suppressing pro-inflammatory IL-12 and TNF-α secretion. Taken together, these results contribute to our understanding of the mechanisms underlying the strong immune-modulatory effects of flagellin-containing fusion proteins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells10123415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8700022PMC
December 2021

The Flagellin:Allergen Fusion Protein rFlaA:Betv1 Induces a MyD88- and MAPK-Dependent Activation of Glucose Metabolism in Macrophages.

Cells 2021 10 1;10(10). Epub 2021 Oct 1.

Vice Presidents Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, 63225 Langen, Germany.

TLR5 ligand flagellin-containing fusion proteins are potential vaccine candidates for many diseases. A recombinant fusion protein of flagellin A and the major birch pollen allergen Bet v 1 (rFlaA:Betv1) modulates immune responses in vitro and in vivo. We studied the effects of rFlaA:Betv1 on bone marrow-derived macrophages (BMDMs). BMDMs differentiated from BALB/c, C57BL/6, TLR5, or MyD88 mice were pre-treated with inhibitors, stimulated with rFlaA:Betv1 or respective controls, and analyzed for activation, cytokine secretion, metabolic state, RNA transcriptome, and modulation of allergen-specific Th2 responses. Stimulation of BMDMs with rFlaA:Betv1 resulted in MyD88-dependent production of IL-1β, IL-6, TNF-α, IL-10, CD69 upregulation, and a pronounced shift towards glycolysis paralleled by activation of MAPK, NFB, and mTOR signaling. Inhibition of either mTOR (rapamycin) or SAP/JNK-MAPK signaling (SP600125) resulted in dose-dependent metabolic suppression. In BMDM and T cell co-cultures, rFlaA:Betv1 stimulation suppressed rBet v 1-induced IL-5 and IL-13 secretion while inducing IFN-γ production. mRNA-Seq analyses showed HIF-1a, JAK, STAT, phagosome, NLR, NFB, TNF, TLR, and chemokine signaling to participate in the interplay of cell activation, glycolysis, and immune response. rFlaA:Betv1 strongly activated BMDMs, resulting in MyD88-, MAPK-, and mTOR-dependent enhancement of glucose metabolism. Our results suggest macrophages are important target cells to consider during restauration of allergen tolerance during AIT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells10102614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534024PMC
October 2021

Persistence of infectious SARS-CoV-2 particles for up to 37 days in patients with mild COVID-19.

Allergy 2021 Oct 12. Epub 2021 Oct 12.

Division of Virology, Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Langen, Germany.

Background: People suffering from COVID-19 are typically considered non-infectious 14 days after diagnosis if symptoms have disappeared for at least 48 h. We describe three patients who independently acquired their infection. These three patients experienced mild COVID-19 and completely recovered symptomatically within 10 days, but remained PCR-positive in deep pharyngeal samples for at least 38 days. We attempted to isolate virus from pharyngeal swabs to investigate whether these patients still carried infectious virus.

Methods: Infectious virus was amplified in Vero E6 cells and characterized by electron microscopy and WGS. The immune response was investigated by ELISA and peptide arrays.

Results: In all three cases, infectious and replication-competent virus was isolated and amplified in Vero E6 cells. Virus replication was detected by RT-PCR and immunofluorescence microscopy. Electron microscopy confirmed the formation of intact SARS-CoV-2 particles. For a more detailed analysis, all three isolates were characterized by whole-genome sequencing (WGS). The sequence data revealed that the isolates belonged to the 20A or 20C clade, and two mutations in ORF8 were identified among other mutations that could be relevant for establishing a long-term infection. Characterization of the humoral immune response in comparison to patients that had fully recovered from mild COVID-19 revealed a lack of antibodies binding to sequential epitopes of the receptor-binding domain (RBD) for the long-term infected patients.

Conclusion: Thus, a small portion of COVID-19 patients displays long-term infectivity and termination of quarantine periods after 14 days, without PCR-based testing, should be reconsidered critically.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/all.15138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8652783PMC
October 2021

The History, Present and Future of Allergen Standardization in the United States and Europe.

Front Immunol 2021 14;12:725831. Epub 2021 Sep 14.

Paul-Ehrlich-Institut, Langen, Germany.

The topic of standardization in relation to allergen products has been discussed by allergists, regulators, and manufacturers for a long time. In contrast to synthetic medicinal products, the natural origin of allergen products makes the necessary comparability difficult to achieve. This holds true for both aspects of standardization: Batch-to-batch consistency (or product-specific standardization) and comparability among products from different manufacturers (or cross-product comparability). In this review, we focus on how the United States and the European Union have tackled the topic of allergen product standardization in the past, covering the early joint standardization efforts in the 1970s and 1980s as well as the different paths taken by the two players thereafter until today. So far, these two paths have been based on rather classical immunological methods, including the corresponding benefits like simple feasability. New technologies such as mass spectrometry present an opportunity to redefine the field of allergen standardization in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.725831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477030PMC
January 2022

The Dietary Fiber Pectin: Health Benefits and Potential for the Treatment of Allergies by Modulation of Gut Microbiota.

Curr Allergy Asthma Rep 2021 09 10;21(10):43. Epub 2021 Sep 10.

Molecular Allergology, Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich-Institut, Langen, Germany.

Purpose Of Review: The incidence of allergies is increasing and has been associated with several environmental factors including westernized diets. Changes in environment and nutrition can result in dysbiosis of the skin, gut, and lung microbiota altering the production of microbial metabolites, which may in turn generate epigenetic modifications. The present review addresses studies on pectin-mediated effects on allergies, including the immune modulating mechanisms by bacterial metabolites.

Recent Findings: Recently, microbiota have gained attention as target for allergy intervention, especially with prebiotics, that are able to stimulate the growth and activity of certain microorganisms. Dietary fibers, which cannot be digested in the gastrointestinal tract, can alter the gut microbiota and lead to increased local and systemic concentrations of gut microbiota-derived short chain fatty acids (SCFAs). These can promote the generation of peripheral regulatory T cells (T) by epigenetic modulation and suppress the inflammatory function of dendritic cells (DCs) by transcriptional modulation. The dietary fiber pectin (a plant-derived polysaccharide commonly used as gelling agent and dietary supplement) can alter the ratio of Firmicutes to Bacteroidetes in gut and lung microbiota, increasing the concentrations of SCFAs in feces and sera, and reducing the development of airway inflammation by suppressing DC function. Pectin has shown immunomodulatory effects on allergies, although the underlying mechanisms still need to be elucidated. It has been suggested that the different types of pectin may exert direct and/or indirect immunomodulatory effects through different mechanisms. However, little is known about the relation of certain pectin structures to allergies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11882-021-01020-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433104PMC
September 2021

β-(1→4)-Mannobiose Acts as an Immunostimulatory Molecule in Murine Dendritic Cells by Binding the TLR4/MD-2 Complex.

Cells 2021 07 14;10(7). Epub 2021 Jul 14.

Laboratory of Food and Biomolecular Science, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan.

Some β-mannans, including those in coffee bean and soy, contain a mannose backbone with β-(1→4) bonds. Such mannooligosaccharides could have immunological functions involving direct interaction with immune cells, in addition to acting as prebiotics. This study aimed at assessing the immunological function of mannooligosaccharides with β-(1→4) bond, and elucidating their mechanism of action using bone marrow-derived murine dendritic cells (BMDCs). When BMDCs were stimulated with the mannooligosaccharides, only β-Man-(1→4)-Man significantly induced production of cytokines that included IL-6, IL-10, TNF-α, and IFN-β, and enhanced CD4 T-cell stimulatory capacity. Use of putative receptor inhibitors revealed the binding of β-Man-(1→4)-Man to TLR4/MD2 complex and involvement with the complement C3a receptor (C3aR) for BMDC activation. Interestingly, β-Man-(1→4)-Man prolonged the production of pro-inflammatory cytokines (IL-6 and TNF-α), but not of the IL-10 anti-inflammatory cytokine during extended culture of BMDCs, associated with high glucose consumption. The results suggest that β-Man-(1→4)-Man is an immunostimulatory molecule, and that the promotion of glycolysis could be involved in the production of pro-inflammatory cytokine in β-Man-(1→4)-Man-stimulated BMDCs. This study could contribute to development of immune-boosting functional foods and a novel vaccine adjuvant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells10071774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305851PMC
July 2021

Standardisation of allergen products: 4. Validation of a candidate European Pharmacopoeia standard method for quantification of major grass pollen allergen Phl p 5.

Allergy 2021 Jul 9. Epub 2021 Jul 9.

Paul-Ehrlich-Institut, Langen, Germany.

Background: The aim of the BSP090 project is the establishment of European Pharmacopoeia Chemical Reference Substances (CRSs) in combination with corresponding standard ELISA methods for quantification of major allergens in allergen products. Here, we present data of a Phl p 5-specific sandwich ELISA that proved suitable for the quantification of Phl p 5, one of the major Timothy grass (Phleum pratense) pollen allergens.

Methods: A Phl p 5-specific ELISA system was assessed with respect to accuracy, precision, inter-assay (within laboratory) and inter-laboratory variations, in a ring trial including 14 laboratories in Europe and the USA. Model samples containing recombinant Phl p 5a CRS as well as native grass pollen extracts were analysed. Each participant was instructed to perform at least one preliminary assay to familiarise with the protocol, followed by three independent assays.

Results: The candidate standard ELISA proved suitable to quantify recombinant and native Phl p 5 with satisfactory precision (93% of results within ±30% acceptance range). Inter-assay variation (max. GCV 24%) and especially inter-laboratory variation (max. GCV 13%) showed conclusive results. When assessing accuracy by means of recovery of recombinant spikes from a grass pollen extract matrix, similarly satisfactory spike recovery results were observed for the two spikes with higher concentrations (all within ±30% acceptance range), whereas recovery of the lowest concentration spike was slightly poorer with mean results of six laboratories exceeding acceptance range.

Conclusions: Based on the collaborative study results, the assessed Phl p 5-specific immunoassay is appropriate to be proposed as European Pharmacopoeia standard method.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/all.15003DOI Listing
July 2021

Contribution to the ongoing discussion on fluoride toxicity.

Arch Toxicol 2021 07 6;95(7):2571-2587. Epub 2021 Jun 6.

Department of Nutrition and Food Sciences, Nutritional Epidemiology, Rheinische Friedrich-Wilhelms University Bonn, Bonn, Germany.

Since the addition of fluoride to drinking water in the 1940s, there have been frequent and sometimes heated discussions regarding its benefits and risks. In a recently published review, we addressed the question if current exposure levels in Europe represent a risk to human health. This review was discussed in an editorial asking why we did not calculate benchmark doses (BMD) of fluoride neurotoxicity for humans. Here, we address the question, why it is problematic to calculate BMDs based on the currently available data. Briefly, the conclusions of the available studies are not homogeneous, reporting negative as well as positive results; moreover, the positive studies lack control of confounding factors such as the influence of well-known neurotoxicants. We also discuss the limitations of several further epidemiological studies that did not meet the inclusion criteria of our review. Finally, it is important to not only focus on epidemiological studies. Rather, risk analysis should consider all available data, including epidemiological, animal, as well as in vitro studies. Despite remaining uncertainties, the totality of evidence does not support the notion that fluoride should be considered a human developmental neurotoxicant at current exposure levels in European countries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00204-021-03072-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241794PMC
July 2021

Human monocyte-derived type 1 and 2 macrophages recognize Ara h 1, a major peanut allergen, by different mechanisms.

Sci Rep 2021 05 12;11(1):10141. Epub 2021 May 12.

VPr1 Research Group "Molecular Allergology", Paul-Ehrlich-Institut, Langen, Germany.

Evidence has suggested that major peanut allergen Ara h 1 activates dendritic cells (DCs) via interaction with DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin), a C-type lectin receptor, and contributes to development of peanut allergy. Since macrophages, as well as DCs, play a crucial role in innate immunity, we investigated whether natural Ara h 1 (nAra h 1) activates two different subsets of macrophages, human monocyte derived macrophage type 1 (hMDM1: pro-inflammatory model) and type 2 (hMDM2: anti-inflammatory model). hMDM1 and hMDM2 predominantly produced pro-inflammatory cytokines (IL-6 and TNF-α) and an anti-inflammatory cytokine (IL-10) in response to nAra h 1, respectively. hMDM2 took up nAra h 1 and expressed DC-SIGN at higher levels than hMDM1. However, small interfering RNA knockdown of DC-SIGN did not suppress nAra h 1 uptake and nAra h 1-mediated cytokine production in hMDM2. Inhibitors of scavenger receptor class A type I (SR-AI) suppressed the response of hMDM2, but not of hMDM1, suggesting that SR-AI is a major receptor in hMDM2 for nAra h 1 recognition and internalization. nAra h 1 appears to exert stimulatory capacity on DC and macrophages via different receptors. This study advances our understanding how a major peanut allergen interacts with innate immunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-89402-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115286PMC
May 2021

Regulatory concepts to guide and promote the accelerated but safe clinical development and licensure of COVID-19 vaccines in Europe.

Allergy 2022 01 21;77(1):72-82. Epub 2021 May 21.

Department of Virology, Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Langen, Germany.

The ongoing COVID-19 pandemic caused by the SARS-CoV-2 coronavirus has affected the health of tens of millions of people worldwide. In particular, in elderly and frail individuals the infection can lead to severe disease and even fatal outcomes. Although the pandemic is primarily a human health crisis its consequences are much broader with a tremendous impact on global economics and social systems. Vaccines are considered the most powerful measure to fight the pandemic and protect people from COVID-19. Based on the concerted activities of scientists, manufacturers and regulators, the urgent need for effective countermeasures has provoked the development and licensure of novel COVID-19 vaccines in an unprecedentedly fast and flexible manner within <1 year. To ensure the safety and efficacy of these novel vaccines during the clinical development and the routine use in post-licensure vaccination campaigns existing regulatory requirements and procedures had to be wisely and carefully adapted to allow for an expedited evaluation without compromising the thoroughness of the regulatory and scientific assessment. In this review, we describe the regulatory procedures, concepts and requirements applied to guide and promote the highly accelerated development and licensure of safe and efficacious COVID-19 vaccines in Europe.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/all.14868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251031PMC
January 2022

Vaccines and allergic reactions: The past, the current COVID-19 pandemic, and future perspectives.

Allergy 2021 06 4;76(6):1640-1660. Epub 2021 Jun 4.

Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Vaccines are essential public health tools with a favorable safety profile and prophylactic effectiveness that have historically played significant roles in reducing infectious disease burden in populations, when the majority of individuals are vaccinated. The COVID-19 vaccines are expected to have similar positive impacts on health across the globe. While serious allergic reactions to vaccines are rare, their underlying mechanisms and implications for clinical management should be considered to provide individuals with the safest care possible. In this review, we provide an overview of different types of allergic adverse reactions that can potentially occur after vaccination and individual vaccine components capable of causing the allergic adverse reactions. We present the incidence of allergic adverse reactions during clinical studies and through post-authorization and post-marketing surveillance and provide plausible causes of these reactions based on potential allergenic components present in several common vaccines. Additionally, we review implications for individual diagnosis and management and vaccine manufacturing overall. Finally, we suggest areas for future research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/all.14840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251022PMC
June 2021

The Role of Lipid Transfer Proteins as Food and Pollen Allergens Outside the Mediterranean Area.

Curr Allergy Asthma Rep 2021 02 3;21(2). Epub 2021 Feb 3.

Molecular Allergology, Paul-Ehrlich-Institut, Paul-Ehrlich Str. 51-59, 63225, Langen, Germany.

Purpose Of Review: To provide an overview of the prevalence and clinical manifestation of non-specific lipid transfer proteins (LTP)-mediated allergies outside the Mediterranean area and to address potential reasons for the different geographical significance of LTP-driven allergies.

Recent Findings: LTPs are major allergens in the Mediterranean area, which frequently can elicit severe reactions. Pru p 3 the LTP from peach is reported as genuine allergen and is considered a prototypic marker for LTP-mediated allergies. However, both food and pollen LTP allergies exist outside the Mediterranean area, but with lower clinical significance, different immunogenicity, and less clarified role. Evidence has been reported that in areas with high exposure to pollen, in particular to mugwort, pollen-derived LTPs can act as a primary sensitizer to trigger secondary food allergies. Co-sensitization to unrelated allergens might be causative for less severe reactions in response to LTPs. However, the reason for the geographical different sensitization patterns to LTPs remains unclear.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11882-020-00982-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858557PMC
February 2021

EAACI statement on the diagnosis, management and prevention of severe allergic reactions to COVID-19 vaccines.

Allergy 2021 06;76(6):1629-1639

Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Inflammation, Repair and Development, National Heart and Lung Institute, Imperial College London. Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK.

The first approved COVID-19 vaccines include Pfizer/BioNTech BNT162B2, Moderna mRNA-1273 and AstraZeneca recombinant adenoviral ChAdOx1-S. Soon after approval, severe allergic reactions to the mRNA-based vaccines that resolved after treatment were reported. Regulatory agencies from the European Union, Unites States and the United Kingdom agree that vaccinations are contraindicated only when there is an allergy to one of the vaccine components or if there was a severe allergic reaction to the first dose. This position paper of the European Academy of Allergy and Clinical Immunology (EAACI) agrees with these recommendations and clarifies that there is no contraindication to administer these vaccines to allergic patients who do not have a history of an allergic reaction to any of the vaccine components. Importantly, as is the case for any medication, anaphylaxis may occur after vaccination in the absence of a history of allergic disease. Therefore, we provide a simplified algorithm of prevention, diagnosis and treatment of severe allergic reactions and a list of recommended medications and equipment for vaccine centres. We also describe potentially allergenic/immunogenic components of the approved vaccines and propose a workup to identify the responsible allergen. Close collaboration between academia, regulatory agencies and vaccine producers will facilitate approaches for patients at risks, such as incremental dosing of the second injection or desensitization. Finally, we identify unmet research needs and propose a concerted international roadmap towards precision diagnosis and management to minimize the risk of allergic reactions to COVID-19 vaccines and to facilitate their broader and safer use.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/all.14739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013422PMC
June 2021

[Immunotherapies-Where are we?]

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2020 Nov;63(11):1319-1321

Paul-Ehrlich-Institut, Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel, Paul-Ehrlich-Str. 51-59, 63225, Langen, Deutschland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00103-020-03233-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645002PMC
November 2020

[Immunotherapy of allergies: current status].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2020 Nov 2;63(11):1341-1356. Epub 2020 Nov 2.

Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, 63225, Langen, Deutschland.

Allergen immunotherapy (AIT) is the only causally effective, disease-modifying form of therapy that, in addition to alleviating allergic symptoms, counteracts disease progression.This article provides an up-to-date overview of immunological, regulatory and practical aspects of AIT. Current literature was included and recent conceptual regulatory developments from the Division of Allergology at the higher federal authority (Paul-Ehrlich-Institut) are presented.The 62 AIT products currently approved in Germany and further 61 AIT products under the development program of the Therapy Allergen Ordinance (TAO) include 95 products for subcutaneous (SCIT) and 28 for sublingual (SLIT) treatment of birch/alder/hazel pollen, grass pollen, weed pollen, house dust mite and insect venom allergies. Native and chemically modified allergen extracts (allergoids) adsorbed to aluminium, tyrosine (partly monophosphoryl lipid A-adjuvanted) or lactose or based on lyophilisates are used as active ingredients.These 123 AIT products are subject to official state batch release testing. This does not apply to named patient products (NPPs) available for the treatment of less prevalent allergies (e.g. to olive pollen, animal hair, storage mites or moulds). There is a particular need for development of AIT products for children.As a new class of active ingredients, food allergens are in clinical phase II and III studies. A first food preparation for oral AIT of peanut allergy in children is currently undergoing a central European marketing authorization (MA) procedure. MA can only be granted if the benefit-risk balance is positive. Science and regulation are in continuous exchange on the development of AIT products that correspond to the current state of clinical research and regulation in the EU and enable early causal treatment of widespread allergies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00103-020-03224-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647996PMC
November 2020

[Recombinant allergens, peptides, and virus-like particles for allergy immunotherapy].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2020 Nov 23;63(11):1412-1423. Epub 2020 Oct 23.

Paul-Ehrlich-Institut, Bundesinstitut für Impfstoffe und Biomedizinische Arzneimittel (PEI), Paul-Ehrlich-Straße 51-59, 63225, Langen, Deutschland.

Currently, extract-based therapeutic allergens from natural allergen sources (e.g., house dust mites, tree and grass pollen) are used for allergen-specific immunotherapy (AIT), the only causative therapy that can exhibit positive disease-modifying effects by tolerance induction and prevention of disease progression. Due to variations in the natural composition of the starting materials and different manufacturing processes, there are variations in protein content, allergen composition, and allergenic activity of similar products, which poses specific challenges for their standardization. The identification of the nucleotide sequences of allergenic proteins led to the development of molecular AIT approaches. This allows for the application of exclusively relevant structures as chemically synthesized peptides, recombinant single allergens, or molecules with hypoallergenic properties that potentially allow for an up-dosing with higher allergen-doses without allergic side effects leading more quickly to effective cumulative doses. Further modifications of AIT preparations to improve allergenic and immunogenic properties may be achieved, e.g., by including the use of virus-like particles (VLPs). To date, the herein described therapeutic approaches have been tested in clinical trials only. This article provides an overview of published molecular approaches for allergy treatment used in clinical AIT studies. Their added value and challenges compared to established therapeutic allergens are discussed. The aim of these approaches is to develop highly effective and well-tolerated AIT preparations with improved patient acceptance and adherence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00103-020-03231-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648003PMC
November 2020

Walnut Allergy Across Europe: Distribution of Allergen Sensitization Patterns and Prediction of Severity.

J Allergy Clin Immunol Pract 2021 01 8;9(1):225-235.e10. Epub 2020 Sep 8.

Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam University Medical Center, Amsterdam, The Netherlands.

Background: Walnut allergy is common across the globe, but data on the involvement of individual walnut components are scarce.

Objectives: To identify geographical differences in walnut component sensitization across Europe, explore cosensitization and cross-reactivity, and assess associations of clinical and serological determinants with severity of walnut allergy.

Methods: As part of the EuroPrevall outpatient surveys in 12 European cities, standardized clinical evaluation was conducted in 531 individuals reporting symptoms to walnut, with sensitization to all known walnut components assessed in 202 subjects. Multivariable Lasso regression was applied to investigate predictors for walnut allergy severity.

Results: Birch-pollen-related walnut sensitization (Jug r 5) dominated in Northern and Central Europe and lipid transfer protein sensitization (Jug r 3) in Southern Europe. Profilin sensitization (Jug r 7) was prominent throughout Europe. Sensitization to storage proteins (Jug r 1, 2, 4, and 6) was detected in up to 10% of subjects. The walnut components that showed strong correlations with pollen and other foods differed between centers. The combination of determinants best predicting walnut allergy severity were symptoms upon skin contact with walnut, atopic dermatitis (ever), family history of atopic disease, mugwort pollen allergy, sensitization to cat or dog, positive skin prick test result to walnut, and IgE to Jug r 1, 5, 7, or carbohydrate determinants (area under the curve = 0.81; 95% CI, 0.73-0.89).

Conclusions: Walnut-allergic subjects across Europe show clear geographical differences in walnut component sensitization and cosensitization patterns. A predictive model combining results from component-based serology testing with results from extract-based testing and information on clinical background allows for good discrimination between mild to moderate and severe walnut allergy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaip.2020.08.051DOI Listing
January 2021

Identification and Characterization of IgE-Reactive Proteins and a New Allergen (Cic a 1.01) from Chickpea (Cicer arietinum).

Mol Nutr Food Res 2020 10 21;64(19):e2000560. Epub 2020 Sep 21.

Division Allergology and Section Molecular Allergology, Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 2, 63225, Langen, Germany.

Scope: Chickpea (Cicer arietinum) allergy has frequently been reported particularly in Spain and India. Nevertheless, chickpea allergens are poorly characterized. The authors aim to identify and characterize potential allergens from chickpea.

Methods And Results: Candidate proteins are selected by an in silico approach or immunoglobuline E (IgE)-testing. Potential allergens are prepared as recombinant or natural proteins and characterized for structural integrity by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), circular dichroism (CD)-spectroscopy, and mass spectrometry (MS) analysis. IgE-sensitization pattern of Spanish chickpea allergic and German peanut and birch pollen sensitized patients are investigated using chickpea extracts and purified proteins. Chickpea allergic patients show individual and heterogeneous IgE-sensitization profiles with extracts from raw and boiled chickpeas. Chickpea proteins pathogenesis related protein family 10 (PR-10), a late embryogenesis abundant protein (LEA/DC-8), and a vicilin-containing fraction, but not 2S albumin, shows IgE reactivity with sera from chickpea, birch pollen, and peanut sensitized patients. Remarkably, allergenic vicilin, DC-8, and PR-10 are detected in the extract of boiled chickpeas.

Conclusion: Several IgE-reactive chickpea allergens are identified. For the first time a yet not classified DC-8 protein is characterized as minor allergen (Cic a 1). Finally, the data suggest a potential risk for peanut allergic patients by IgE cross-reactivity with homologous chickpea proteins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mnfr.202000560DOI Listing
October 2020

New guidance on the regulation of allergen products: key aspects and outcomes.

Curr Opin Allergy Clin Immunol 2020 12;20(6):624-630

Paul-Ehrlich-Institut, Langen, Germany.

Purpose Of Review: Key aspects and outcomes from the recently published guidance on the regulation of allergen products are summarized.

Recent Findings: A new regulatory guideline has been published to enhance harmonized national approaches on the regulation of allergen products and thereby strengthen the availability of high-quality products across the European Union (EU). As the guideline was developed, critical aspects for allergen products regulation were identified and are discussed in the document, including recommendations on the regulatory procedures to be applied for diagnostics, allergen immunotherapy products and named-patient products.

Summary: The new guidance is expected to provide clarifications on and support harmonization of the regulation of allergen products in the EU.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/ACI.0000000000000687DOI Listing
December 2020

Toxicity of fluoride: critical evaluation of evidence for human developmental neurotoxicity in epidemiological studies, animal experiments and in vitro analyses.

Arch Toxicol 2020 05 8;94(5):1375-1415. Epub 2020 May 8.

Department of Nutrition and Food Sciences, Nutritional Epidemiology, Rheinische Friedrich-Wilhelms University Bonn, Bonn, Germany.

Recently, epidemiological studies have suggested that fluoride is a human developmental neurotoxicant that reduces measures of intelligence in children, placing it into the same category as toxic metals (lead, methylmercury, arsenic) and polychlorinated biphenyls. If true, this assessment would be highly relevant considering the widespread fluoridation of drinking water and the worldwide use of fluoride in oral hygiene products such as toothpaste. To gain a deeper understanding of these assertions, we reviewed the levels of human exposure, as well as results from animal experiments, particularly focusing on developmental toxicity, and the molecular mechanisms by which fluoride can cause adverse effects. Moreover, in vitro studies investigating fluoride in neuronal cells and precursor/stem cells were analyzed, and 23 epidemiological studies published since 2012 were considered. The results show that the margin of exposure (MoE) between no observed adverse effect levels (NOAELs) in animal studies and the current adequate intake (AI) of fluoride (50 µg/kg b.w./day) in humans ranges between 50 and 210, depending on the specific animal experiment used as reference. Even for unusually high fluoride exposure levels, an MoE of at least ten was obtained. Furthermore, concentrations of fluoride in human plasma are much lower than fluoride concentrations, causing effects in cell cultures. In contrast, 21 of 23 recent epidemiological studies report an association between high fluoride exposure and reduced intelligence. The discrepancy between experimental and epidemiological evidence may be reconciled with deficiencies inherent in most of these epidemiological studies on a putative association between fluoride and intelligence, especially with respect to adequate consideration of potential confounding factors, e.g., socioeconomic status, residence, breast feeding, low birth weight, maternal intelligence, and exposure to other neurotoxic chemicals. In conclusion, based on the totality of currently available scientific evidence, the present review does not support the presumption that fluoride should be assessed as a human developmental neurotoxicant at the current exposure levels in Europe.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00204-020-02725-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261729PMC
May 2020

Placebo effects in allergen immunotherapy-An EAACI Task Force Position Paper.

Allergy 2021 03;76(3):629-647

Department of Respiratory Medicine, Royal Sussex County Hospital, University of Sussex and University of Brighton, Brighton, UK.

The placebo (Latin "I will please") effect commonly occurs in clinical trials. The psychological and physiological factors associated with patients' expectations about a treatment's positive and negative effects have yet to be well characterized, although a functional prefrontal cortex and intense bidirectional communication between the central nervous system and the immune system appear to be prerequisites for a placebo effect. The use of placebo raises certain ethical issues, especially if patients in a placebo group are denied an effective treatment for a long period of time. The placebo effect appears to be relatively large (up to 77%, relative to pretreatment scores) in controlled clinical trials of allergen immunotherapy (AIT), such as the pivotal, double-blind, placebo-controlled (DBPC) randomized clinical trials currently required by regulatory authorities worldwide. The European Academy of Allergy and Clinical Immunology (EAACI) therefore initiated a Task Force, in order to better understand the placebo effect in AIT and its specific role in comorbidities, blinding issues, adherence, measurement time points, variability and the natural course of the disease. In this Position Paper, the EAACI Task Force highlights several important topics regarding the placebo effect in AIT such as a) regulatory aspects, b) neuroimmunological and psychological mechanisms, c) placebo effect sizes in AIT trials, d) methodological limitations in AIT trial design and e) potential solutions in future AIT trial design. In conclusion, this Position Paper aims to examine the methodological problem of placebo in AIT from different aspects and also to highlight unmet needs and possible solutions for future trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/all.14331DOI Listing
March 2021

In-vivo diagnostic test allergens in Europe: A call to action and proposal for recovery plan-An EAACI position paper.

Allergy 2020 09;75(9):2161-2169

Allergy Section, Department of Internal Medicine, Hospital Valld'Hebron, Barcelona, Spain.

Diagnostic allergens are defined as medicinal products in the EU. Marketing authorization by national authorities is necessary; however, diagnostic allergens are not homogeneously regulated in different EU member states. Allergen manufacturers argue with increasing costs forcing them to continuously reduce the diagnostic allergen portfolios offered to allergists. In contrast, EAACI and national European Allergy Societies see the need for the availability of a wide range of high-quality diagnostic allergens for in vivo diagnosis of IgE-mediated allergies not only covering predominant but also less frequent allergen sources. In a recent EAACI task force survey, the current practice of allergy diagnosis was shown to rely on skin tests as first option in almost 2/3 of all types of allergic diseases and in 90% regarding respiratory allergies. With the need to ensure the availability of high-quality diagnostic allergens in the EU, an action plan has been set up by EAACI to analyse the current regulatory demands in EU member states and to define possible solutions stated in this document: (a) simplification of authorization for diagnostic allergens; (b) specific regulation of special types of diagnostic allergens; (c) new models beyond the current model of homologous groups; (d) simplification of pharmacovigilance reporting; (e) reduction of regulation fees for diagnostic allergens; (f) reimbursement for diagnostic allergens. Joining forces of allergists, manufacturers and authorities are of high importance to ensure remaining relevant allergens in the EU markets to facilitate a sustainable and comprehensive service for the diagnosis and treatment of allergic diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/all.14329DOI Listing
September 2020

Quality Criteria for Studies on Dietary Glycation Compounds and Human Health.

J Agric Food Chem 2019 Oct 3;67(41):11307-11311. Epub 2019 Oct 3.

Chair of Food Chemistry , Technische Universität Dresden , 01062 Dresden , Germany.

Current reports increasingly associate dietary "advanced glycation end products" ("AGEs") resulting from the Maillard reaction (glycation) between reducing sugars and amino compounds in foods with pathophysiological consequences, such as chronic inflammation, atherosclerosis, and metabolic syndrome. Heated foods are therefore suggested to pose a potential risk for human health. However, studies in this field are very often based on questionable quantitative data and inadequate structural characterization. To improve the situation, the present perspective suggests quality criteria for future studies and the assessment of the currently available literature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jafc.9b04172DOI Listing
October 2019

Manufacturing and quality assessment of allergenic extracts for immunotherapy: state of the art.

Curr Opin Allergy Clin Immunol 2019 12;19(6):640-645

Paul Ehrlich Institut, Langen, Germany.

Purpose Of Review: The recent developments in the manufacturing and quality assessment of allergenic extracts in Europe are summarized.

Recent Findings: Quality assessment has always been a fundamental part of allergen product evaluation. New analytical methods have been reported that fill currently existing gaps in the characterization of commonly used allergen products. New types of products require innovative considerations and concepts for their assessment. Advanced standardization efforts aim at increasing reliability and comparability of analytical tools applied for allergen product characterization. In consequence, regulatory requirements are updated in line with such developments.

Summary: Current demands on the quality of allergen products ensure production of well characterized products of consistent quality. While experience with manufacturing processes and successful product characterization approaches increase, accompanying and continuous re-evaluation of underlying quality control and assessment concepts is being performed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/ACI.0000000000000579DOI Listing
December 2019

Reply.

J Allergy Clin Immunol 2019 10 14;144(4):1140-1141. Epub 2019 Aug 14.

Division of Immunology/Allergy Section, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2019.07.007DOI Listing
October 2019

CCR8 leads to eosinophil migration and regulates neutrophil migration in murine allergic enteritis.

Sci Rep 2019 07 3;9(1):9608. Epub 2019 Jul 3.

Vice President Research Group "Molecular Allergology", Paul-Ehrlich-Institut, Langen, Germany.

Allergic enteritis (AE) is a gastrointestinal form of food allergy. This study aimed to elucidate cellular and molecular mechanisms of AE using a murine model. To induce AE, BALB/c wild type (WT) mice received intraperitoneal sensitization with ovalbumin (an egg white allergen) plus ALUM and feeding an egg white (EW) diet. Microarray analysis showed enhanced gene expression of CC chemokine receptor (CCR) 8 and its ligand, chemokine CC motif ligand (CCL) 1 in the inflamed jejunum. Histological and FACS analysis showed that CCR8 knock out (KO) mice exhibited slightly less inflammatory features, reduced eosinophil accumulation but accelerated neutrophil accumulation in the jejunums, when compared to WT mice. The concentrations of an eosinophil chemoattractant CCL11 (eotaxin-1), but not of IL-5, were reduced in intestinal homogenates of CCR8KO mice, suggesting an indirect involvement of CCR8 in eosinophil accumulation in AE sites by inducing CCL11 expression. The potential of CCR8 antagonists to treat allergic asthma has been discussed. However, our results suggest that CCR8 blockade may promote neutrophil accumulation in the inflamed intestinal tissues, and not be a suitable therapeutic target for AE, despite the potential to reduce eosinophil accumulation. This study advances our knowledge to establish effective anti-inflammatory strategies in AE treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-45653-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610106PMC
July 2019
-->