Publications by authors named "Adam M Chaker"

22 Publications

  • Page 1 of 1

Allergen-specific immunotherapy induces the suppressive secretoglobin 1A1 in cells of the lower airways.

Allergy 2021 Feb 2. Epub 2021 Feb 2.

Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Munich, Germany.

Background: While several systemic immunomodulatory effects of allergen-specific immunotherapy (AIT) have been discovered, local anti-inflammatory mechanisms in the respiratory tract are largely unknown. We sought to elucidate local and epithelial mechanisms underlying allergen-specific immunotherapy in a genome-wide approach.

Methods: We induced sputum in hay fever patients and healthy controls during the pollen peak season and stratified patients by effective allergen immunotherapy or as untreated. Sputum was directly processed after induction and subjected to whole transcriptome RNA microarray analysis. Nasal secretions were analyzed for Secretoglobin1A1 (SCGB1A1) and IL-24 protein levels in an additional validation cohort at three defined time points during the 3-year course of AIT. Subsequently, RNA was extracted and subjected to an array-based whole transcriptome analysis.

Results: Allergen-specific immunotherapy inhibited pro-inflammatory CXCL8, IL24, and CCL26mRNA expression, while SCGB1A1, IL7, CCL5, CCL23, and WNT5BmRNAs were induced independently of the asthma status and allergen season. In our validation cohort, local increase of SCGB1A1 occurred concomitantly with the reduction of local IL-24 in upper airways during the course of AIT. Additionally, SCGB1A1 was identified as a suppressor of epithelial gene expression.

Conclusions: Allergen-specific immunotherapy induces a yet unknown local gene expression footprint in the lower airways that on one hand appears to be a result of multiple regulatory pathways and on the other hand reveals SCGB1A1 as novel anti-inflammatory mediator of long-term allergen-specific therapeutic intervention in the local environment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/all.14756DOI Listing
February 2021

Occupational rhinitis.

Allergol Select 2021 22;5:51-56. Epub 2021 Jan 22.

Department of Otolaryngology - Head and Neck Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

Occupational rhinitis (OR) has so far received little attention even though it shares common pathophysiological features and trigger factors and is closely associated with occupational asthma (OA). Work-related exposure to certain substances, such as animal dander, is considered to be the main factor for the development of OR. The new EAACI definition of OR stresses the causal relationship between workplace exposure and onset of rhinitis symptoms as opposed to previous definitions that mainly focused on a temporal relationship between workplace exposure and occurrence of nasal symptoms. Also, it has been suggested to use the term "work-related rhinitis" for classifying the different forms of rhinitis associated with the workplace. These forms can be subdivided into allergic or non-allergic OR, which is due to causes and conditions related to a particular work environment, as well as work-exacerbated rhinitis, which is defined as a pre-existing rhinitis exacerbated by exposure at the workplace. Even though taking a detailed patient history is especially important when it comes to diagnosing OR, the gold standard for confirming the diagnosis is nasal provocation testing. Best possible symptomatic relief and prevention of development of OA constitute the main therapeutic objectives in OR. Treatment options consist of total avoidance of trigger substances (main goal), reduction of exposure to certain substances, and pharmacotherapy. Furthermore, it is important to note that allergic OR is an occupational disease in Germany (Berufskrankheit No 4301) and needs to be reported to health authorities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5414/ALX02165EDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841416PMC
January 2021

Noninvasive and minimally invasive techniques for the diagnosis and management of allergic diseases.

Allergy 2021 04;76(4):1010-1023

Center of Allergy and Environment (ZAUM), Technical University and Helmholtz Zentrum München, München, Germany.

Allergic diseases of the (upper and lower) airways, the skin and the gastrointestinal tract, are on the rise, resulting in impaired quality of life, decreased productivity, and increased healthcare costs. As allergic diseases are mostly tissue-specific, local sampling methods for respective biomarkers offer the potential for increased sensitivity and specificity. Additionally, local sampling using noninvasive or minimally invasive methods can be cost-effective and well tolerated, which may even be suitable for primary or home care sampling. Non- or minimally invasive local sampling and diagnostics may enable a more thorough endotyping, may help to avoid under- or overdiagnosis, and may provide the possibility to approach precision prevention, due to early diagnosis of these local diseases even before they get systemically manifested and detectable. At the same time, dried blood samples may help to facilitate minimal-invasive primary or home care sampling for classical systemic diagnostic approaches. This EAACI position paper contains a thorough review of the various technologies in allergy diagnosis available on the market, which analytes or biomarkers are employed, and which samples or matrices can be used. Based on this assessment, EAACI position is to drive these developments to efficiently identify allergy and possibly later also viral epidemics and take advantage of comprehensive knowledge to initiate preventions and treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/all.14645DOI Listing
April 2021

Management of patients with chronic rhinosinusitis during the COVID-19 pandemic-An EAACI position paper.

Allergy 2021 03;76(3):677-688

Department of Otorhinolaryngology, Amsterdam University Medical Centers, location AMC, Amsterdam, The Netherlands.

Background: Chronic rhinosinusitis is regarded as a chronic airway disease. According to WHO recommendations, it may be a risk factor for COVID-19 patients. In most CRSwNP cases, the inflammatory changes affecting the nasal and paranasal mucous membranes are type-2 (T2) inflammation endotypes.

Methods: The current knowledge on COVID-19 and on treatment options for CRS was analyzed by a literature search in Medline, Pubmed, international guidelines, the Cochrane Library and the Internet.

Results: Based on international literature, on current recommendations by WHO and other international organizations as well as on previous experience, a panel of experts from EAACI and ARIA provided recommendations for the treatment of CRS during the COVID-19 pandemic.

Conclusion: Intranasal corticosteroids remain the standard treatment for CRS in patients with SARS-CoV-2 infection. Surgical treatments should be reduced to a minimum and surgery preserved for patients with local complications and for those with no other treatment options. Systemic corticosteroids should be avoided. Treatment with biologics can be continued with careful monitoring in noninfected patients and should be temporarily interrupted during the course of the COVID-19 infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/all.14629DOI Listing
March 2021

Inflammatory macrophage memory in nonsteroidal anti-inflammatory drug-exacerbated respiratory disease.

J Allergy Clin Immunol 2021 Feb 12;147(2):587-599. Epub 2020 Jun 12.

Center of Allergy and Environment, Technical University of Munich and Helmholtz Zentrum München, Munich, Germany. Electronic address:

Background: Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is a chronic inflammatory condition, which is driven by an aberrant arachidonic acid metabolism. Macrophages are major producers of arachidonic acid metabolites and subject to metabolic reprogramming, but they have been neglected in N-ERD.

Objective: This study sought to elucidate a potential metabolic and epigenetic macrophage reprogramming in N-ERD.

Methods: Transcriptional, metabolic, and lipid mediator profiles in macrophages from patients with N-ERD and healthy controls were assessed by RNA sequencing, Seahorse assays, and LC-MS/MS. Metabolites in nasal lining fluid, sputum, and plasma from patients with N-ERD (n = 15) and healthy individuals (n = 10) were quantified by targeted metabolomics analyses. Genome-wide methylomics were deployed to define epigenetic mechanisms of macrophage reprogramming in N-ERD.

Results: This study shows that N-ERD monocytes/macrophages exhibit an overall reduction in DNA methylation, aberrant metabolic profiles, and an increased expression of chemokines, indicative of a persistent proinflammatory activation. Differentially methylated regions in N-ERD macrophages included genes involved in chemokine signaling and acylcarnitine metabolism. Acylcarnitines were increased in macrophages, sputum, nasal lining fluid, and plasma of patients with N-ERD. On inflammatory challenge, N-ERD macrophages produced increased levels of acylcarnitines, proinflammatory arachidonic acid metabolites, cytokines, and chemokines as compared to healthy macrophages.

Conclusions: Together, these findings decipher a proinflammatory metabolic and epigenetic reprogramming of macrophages in N-ERD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2020.04.064DOI Listing
February 2021

Considerations on biologicals for patients with allergic disease in times of the COVID-19 pandemic: An EAACI statement.

Allergy 2020 11;75(11):2764-2774

Translational Medicine Program, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, ON, Canada.

The outbreak of the SARS-CoV-2-induced coronavirus disease 2019 (COVID-19) pandemic re-shaped doctor-patient interaction and challenged capacities of healthcare systems. It created many issues around the optimal and safest way to treat complex patients with severe allergic disease. A significant number of the patients are on treatment with biologicals, and clinicians face the challenge to provide optimal care during the pandemic. Uncertainty of the potential risks for these patients is related to the fact that the exact sequence of immunological events during SARS-CoV-2 is not known. Severe COVID-19 patients may experience a "cytokine storm" and associated organ damage characterized by an exaggerated release of pro-inflammatory type 1 and type 3 cytokines. These inflammatory responses are potentially counteracted by anti-inflammatory cytokines and type 2 responses. This expert-based EAACI statement aims to provide guidance on the application of biologicals targeting type 2 inflammation in patients with allergic disease. Currently, there is very little evidence for an enhanced risk of patients with allergic diseases to develop severe COVID-19. Studies focusing on severe allergic phenotypes are lacking. At present, noninfected patients on biologicals for the treatment of asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, or chronic spontaneous urticaria should continue their biologicals targeting type 2 inflammation via self-application. In case of an active SARS-CoV-2 infection, biological treatment needs to be stopped until clinical recovery and SARS-CoV-2 negativity is established and treatment with biologicals should be re-initiated. Maintenance of add-on therapy and a constant assessment of disease control, apart from acute management, are demanded.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/all.14407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300800PMC
November 2020

An anti-inflammatory eicosanoid switch mediates the suppression of type-2 inflammation by helminth larval products.

Sci Transl Med 2020 04;12(540)

Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, 80802 Munich, Germany.

Eicosanoids are key mediators of type-2 inflammation, e.g., in allergy and asthma. Helminth products have been suggested as remedies against inflammatory diseases, but their effects on eicosanoids are unknown. Here, we show that larval products of the helminth (), known to modulate type-2 responses, trigger a broad anti-inflammatory eicosanoid shift by suppressing the 5-lipoxygenase pathway, but inducing the cyclooxygenase (COX) pathway. In human macrophages and granulocytes, the -driven induction of the COX pathway resulted in the production of anti-inflammatory mediators [e.g., prostaglandin E (PGE) and IL-10] and suppressed chemotaxis. also abrogated the chemotaxis of granulocytes from patients suffering from aspirin-exacerbated respiratory disease (AERD), a severe type-2 inflammatory condition. Intranasal treatment with extract attenuated allergic airway inflammation in mice, and intranasal transfer of -conditioned macrophages led to reduced airway eosinophilia in a COX/PGE-dependent fashion. The induction of regulatory mediators in macrophages depended on p38 mitogen-activated protein kinase (MAPK), hypoxia-inducible factor-1α (HIF-1α), and glutamate dehydrogenase (GDH), which we identify as a major immunoregulatory protein in GDH activity was required for anti-inflammatory effects of in macrophages, and local administration of recombinant GDH to the airways abrogated allergic airway inflammation in mice. Thus, a metabolic enzyme present in helminth larvae can suppress type-2 inflammation by inducing an anti-inflammatory eicosanoid switch, which has important implications for the therapy of allergy and asthma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aay0605DOI Listing
April 2020

[Therapy of Allergies and Allergy Immunotherapy in Children].

Laryngorhinootologie 2020 01 14;99(1):56-66. Epub 2020 Jan 14.

Adequate diagnostical workup for respiratory allergies and consequent therapy in children determine the individual course of disease. Therapy consists first of symptomatic treatment and includes in the next step the important option of allergy immunotherapy (AIT) as a causative treatment of disease. Children are an important target group for AIT, since AIT offers a proven longterm effect including secondary preventive properties with not only transiently reduced symptoms but moreover longstanding and beneficial disease modification.New strategies with AIT as primary and secondary preventive interventions are being evaluated with the aim to reduce clinical appearance and the amount and extent of sensitizations to allergens in high-risk children. Until implementation of such potentially preventive strategies the currently more attractive early intervention is the early adoption of AIT within the first 12 to 24 months of onset of symptoms as a first-line treatment of allergic rhinitis.Simplified treatment protocols can improve the willingness to perform an AIT and the adherence and compliance of children and their parents. The overall goal is to make AIT as the most important treatment modality available to more affected children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-0899-1202DOI Listing
January 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/all.14077DOI Listing
December 2019

Treatment considerations for cervical and cervicothoracic spondylodiscitis associated with esophageal fistula due to cancer history or accidental injury: a 9-patient case series.

Acta Neurochir (Wien) 2019 09 29;161(9):1877-1886. Epub 2019 Jun 29.

Department of Neurosurgery, Klinikum rechts der Isar, Technical University Munich, Ismaninger Straße 22, 81675, Munich, Germany.

Background: The combination of cervical spondylodiscitis and esophageal fistula is rare but life-threatening. Due to both the rarity of these conditions' coincidence and the complexity and heterogeneity of individual cases, there is no optimal treatment or management approach. The aims of this study are to obtain an overview of patients' outcomes and to discuss treatment options.

Method: This study is a retrospective analysis of patients who presented with cervical spondylodiscitis and associated esophageal fistula between January 2010 and November 2018. We examined reports of 59 patients who suffered from cervical spondylodiscitis and included nine patients (15.25%) who had an esophageal fistula as the underlying cause. We assessed clinical findings, treatment, and outcome.

Results: Three of the nine patients were female, and the mean age of the sample was 64.56 years. Six of the patients had a history of esophagopharyngeal cancer and had undergone tumor resection followed by radiotherapy. Two of the remaining patients' fistulas were caused by an iatrogenic injury during cervical spine surgery and a swallowed toothpick; in the final case, the origin remained unclear. Five patients presented with tetraparesis or tetraplegia, and the other four patients were neurologically intact. In seven cases, dorsal instrumentation was initially performed. Three patients secondarily received a ventral approach for debridement, and one received explantation of the ventral implants. Two patients died during the hospital stay, and three were transferred to a palliative care unit. Thus, the spondylodiscitis and esophageal fistula were cured in only four patients. At discharge, two patients were neurologically intact, two others remained in tetraparesis.

Conclusions: Cervical spondylodiscitis in association with an esophageal fistula carries high morbidity and high mortality. Because patients whose infections are not cured have high morbidity, we recommend using interdisciplinary and individual management, including definite surgical treatment of the discitis and fistula, in every case.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00701-019-03985-3DOI Listing
September 2019

Early IL-10 producing B-cells and coinciding Th/Tr17 shifts during three year grass-pollen AIT.

EBioMedicine 2018 Oct 11;36:475-488. Epub 2018 Oct 11.

Center of Allergy & Environment (ZAUM), German Research Center for Environmental Health, Member of the German Center for Lung Research (DZL), Helmholtz Center Munich, Technical University of Munich (TUM), Biedersteiner Str. 29, Munich 80802, Germany; Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Ismaninger Str. 22, Munich 81675, Germany. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2018.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197437PMC
October 2018

Biomatrix for upper and lower airway biomarkers in patients with allergic asthma.

J Allergy Clin Immunol 2018 12 16;142(6):1980-1983. Epub 2018 Aug 16.

Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), CPC-M, Munich, Germany; Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Munich, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2018.07.027DOI Listing
December 2018

[Biologics in Rhinology - Forthcoming Personalized Concepts: the Future Starts Today].

Authors:
Adam M Chaker

Laryngorhinootologie 2018 Mar 22;97(S 01):S142-S184. Epub 2018 Mar 22.

Klinik für Hals-Nasen-Ohrenheilkunde und Zentrum für Allergie und Umwelt, Klinikum rechts der Isar, Technische Universität München.

Sinunasale Erkrankungen zählen mit zu den häufigsten chronischen Erkrankungen und führen zu einer erheblichen Störung der Lebensqualität, ein komorbides Asthma ist häufig. Trotz leitliniengerechter Therapie ist anzunehmen, dass mind. 20% der Patienten ihre Erkrankungssymptome nicht adäquat kontrollieren können. Neben den etablierten chirurgischen und konservativen Therapieoptionen finden sich nun vielversprechende Therapieansätze, die bspw. mittels therapeutischer Antikörper mechanistisch gezielt in die Pathophysiologie der Erkrankungen eingreifen können. Die Auswahl der geeigneten Patienten durch geeignete Biomarker und die richtige Therapie zum richtigen Stadium der Erkrankung anbieten zu können, ist das Ziel stratifizierter Medizin und eine wichtige Perspektive für die HNO.Chronic diseases of the nose and the paranasal sinuses are most common, frequently associated with bronchial asthma, and result in substantial reduction of quality of life. Despite optimal treatment according to guidelines, approx. 20 % of the patients will report inadequate control of symptoms. Apart from well established surgical and conservative approaches in therapy new therapeutic antibodies are available that aim specifically pathophysiological targets. The optimal allocation of effective therapy for patients using appropriate biomarkers at the most suitable timepoint is the hallmark of stratified medicine and an important perspective in ENT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0043-123484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541111PMC
March 2018

Activin-A Is a Pro-Inflammatory Regulator in Type-2-Driven Upper Airway Disease.

Int Arch Allergy Immunol 2018 13;176(1):15-25. Epub 2018 Apr 13.

Center of Allergy and Environment (ZAUM), Technical University of Munich (TUM) and Helmholtz Center Munich, German Research Center for Environmental Health, Member of the German Center for Lung Research (DZL), Munich, Germany.

Background: Allergic upper airway disease involves pro-inflammatory type-2 cytokines such as IL-5 and regulatory tissue repair mediators, in particular transforming growth factor (TGF)-β1. The TGF-β-superfamily member activin-A displays multiple biological functions and shares certain signalling pathways with TGF-β1. We aimed to examine the coregulation of mucosal activin-A and TGF-β1 in acute allergic and chronic Th2-driven upper airway disease.

Methods: We investigated mucosal cytokine expression profiles and kinetics using RT-PCR after nasal allergen challenges in patients with seasonal allergic rhinitis. Furthermore, we analysed mucosal specimens from patients with chronic upper airway disease with nasal polyps using ELISPOTs and confocal microscopy. In addition, we stimulated nasal mucosa ex vivo from patients with nasal polyps as well as primary nasal cell cultures from healthy donors.

Results: Mucosal activin-A expression revealed increasing correlation with IL-5 and TGF-β1 at 0.25, 6, and 24 h, respectively, and was significantly upregulated at 6 h after allergen challenge. The correlated expression was found to be more pronounced in chronic disease with nasal polyps, showing substantially (48-fold) increased activin-A-producing cells in nasal polyps by ELISPOT, while submucosal downstream signalling as determined by confocal microscopy was decreased. Ex vivo stimulations of nasal tissue suggested that activin-A and TGF-β1 mutually regulate each other's expression at the mRNA level and, when combined, enhance IL-5 expression.

Conclusion: Activin-A in allergic upper airway disease acts as a pro-inflammatory mediator and TGF-β1 modifier. Our data in the upper airways oppose the view of potentially anti-inflammatory properties in contrast to lymphatic compartments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000487930DOI Listing
May 2018

Endotypes in Chronic Rhinosinusitis: Biomarkers Based on a Mechanistic Insight for Targeted Treatment?

ORL J Otorhinolaryngol Relat Spec 2017 24;79(1-2):78-84. Epub 2017 Feb 24.

Department of Otorhinolaryngology and Head and Neck Surgery, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Chronic rhinosinusitis is an umbrella term for several phenotypes and mechanistically distinct inflammatory diseases of the nose and the paranasal sinuses affecting around 11% of the population in Europe and the USA. Approximately 20% of the patients present with uncontrolled disease despite adequate treatment, and revision surgery is common. While a clinical characterization alone does not improve treatment results, novel but expensive biologics have increasingly become available, but they require a better understanding of the mechanism. Mechanistic markers of disease may help to allocate the optimal drug to a patient, thus reducing undesirable side effects and avoiding unnecessary treatment and costs with respect to potential non-responders, thereby increasing responder rates and compliance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000455721DOI Listing
December 2017

Biomarkers in Allergic Airway Disease: Simply Complex.

ORL J Otorhinolaryngol Relat Spec 2017 24;79(1-2):72-77. Epub 2017 Feb 24.

Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Munich, Germany.

Clinical diagnoses of allergic airway disease need confirmation of a relevant sensitization to allergens. Serum-based component-resolved diagnosis has become increasingly popular and allows the precise assessment of specific IgE to molecular allergens. Molecular allergen diagnosis has improved our understanding of disease phenotypes in allergic patients, including cross-reactive patterns and food allergy. Beyond sensitization profiles, characterization of the (endo-)type and severity of a local allergic disease is useful for targeted therapy with biologics in advanced allergic airway disease. Surrogate markers of treatment efficacy are increasingly under validation. Prognostic and predictive biomarkers will represent a promising option for stratified prevention strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000455725DOI Listing
December 2017

Anti-inflammatory effects of the petasin phyto drug Ze339 are mediated by inhibition of the STAT pathway.

Biofactors 2017 May 31;43(3):388-399. Epub 2017 Jan 31.

Chair and institute of environmental medicine, UNIKA-T, Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Augsburg, Germany.

Ze339, an herbal extract from Petasites hybridus leaves is effective in treatment of allergic rhinitis by inhibition of a local production of IL-8 and eicosanoid LTB in allergen-challenged patients. However, the mechanism of action and anti-inflammatory potential in virally induced exacerbation of the upper airways is unknown. This study investigates the anti-inflammatory mechanisms of Ze339 on primary human nasal epithelial cells (HNECs) upon viral, bacterial and pro-inflammatory triggers. To investigate the influence of viral and bacterial infections on the airways, HNECs were stimulated with viral mimics, bacterial toll-like-receptor (TLR)-ligands or cytokines, in presence or absence of Ze339. The study uncovers Ze339 modulated changes in pro-inflammatory mediators and decreased neutrophil chemotaxis as well as a reduction of the nuclear translocation and phosphorylation of STAT molecules. Taken together, this study suggests that phyto drug Ze339 specifically targets STAT-signalling pathways in HNECs and has high potential as a broad anti-inflammatory drug that exceeds current indication. © 2016 BioFactors, 43(3):388-399, 2017.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/biof.1349DOI Listing
May 2017

Age dictates a steroid-resistant cascade of Wnt5a, transglutaminase 2, and leukotrienes in inflamed airways.

J Allergy Clin Immunol 2017 Apr 20;139(4):1343-1354.e6. Epub 2016 Aug 20.

Center of Allergy and Environment (ZAUM), Member of the German Center for Lung Research (DZL), Technical University of Munich and Helmholtz Center Munich, Munich, Germany. Electronic address:

Background: Airway remodeling is a detrimental and refractory process showing age-dependent clinical manifestations that are mechanistically undefined. The leukotriene (LT) and wingless/integrase (Wnt) pathways have been implicated in remodeling, but age-specific expression profiles and common regulators remained elusive.

Objective: We sought to study the activation of the LT and Wnt pathways during early- or late-onset allergic airway inflammation and to address regulatory mechanisms and clinical relevance in normal human bronchial epithelial cells (NHBEs) and nasal polyp tissues.

Methods: Mice were sensitized with house dust mite (HDM) allergens from days 3, 15, or 60 after birth. Remodeling factors in murine bronchoalveolar lavage fluid, lung tissue, or human nasal polyp tissue were analyzed by means of Western blotting, immunoassays, or histology. Regulatory mechanisms were studied in cytokine/HDM-stimulated NHBEs and macrophages.

Results: Bronchoalveolar lavage fluid LT levels were increased in neonatal and adult but reduced in juvenile HDM-sensitized mice. Lungs of neonatally sensitized mice showed increased 5-lipoxygenase levels, whereas adult mice expressed more group 10 secretory phospholipase A, Wnt5a, and transglutaminase 2 (Tgm2). Older mice showed colocalization of Wnt5a and LT enzymes in the epithelium, a pattern also observed in human nasal polyps. IL-4 promoted epithelial Wnt5a secretion, which upregulated macrophage Tgm2 expression, and Tgm2 inhibition in turn reduced LT release. Tgm2, group 10 secretory phospholipase A, and LT enzymes in NHBEs and nasal polyps were refractory to corticosteroids.

Conclusion: Our findings reveal age differences in LT and Wnt pathways during airway inflammation and identify a steroid-resistant cascade of Wnt5a, Tgm2, and LTs, which might represent a therapeutic target for airway inflammation and remodeling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2016.07.014DOI Listing
April 2017

Short-term subcutaneous grass pollen immunotherapy under the umbrella of anti-IL-4: A randomized controlled trial.

J Allergy Clin Immunol 2016 Feb 31;137(2):452-461.e9. Epub 2015 Oct 31.

Allergy and Clinical Immunology, Imperial College, National Heart and Lung Institute, London, United Kingdom; Center of Allergy and Environment (ZAUM), Technische Universität and Helmholtz Center Munich, Munich, Germany. Electronic address:

Background: Allergen immunotherapy is currently the only disease-modifying treatment available for allergic rhinitis and allergic asthma.

Objectives: We sought to evaluate the induction of sustained tolerance to allergen when anti-IL-4 was combined with a suboptimal course of grass pollen subcutaneous immunotherapy (SCIT) using the allergen-induced skin late-phase response (LPR) and exploratory immune monitoring as surrogate markers of therapeutic response.

Methods: In this randomized, double-blind, 3-group parallel design trial, 37 participants with seasonal allergic rhinitis received suboptimal SCIT (30,000 standardized quality units) in combination with anti-IL-4 (VAK694) and suboptimal SCIT (30,000 standardized quality units) plus placebo antibody or double placebo (placebo SCIT and placebo antibody) restricted to 13 weeks before the grass pollen season. The primary end point was the size of the LPR at 12 months. Exploratory end points included measures of the immunomodulatory activity of treatment by using IL-4 and IL-10 FluoroSpot assays, flow cytometry of T cells, and measurement of IgE, IgG4, and facilitated antigen binding.

Results: Both active treatment arms led to a substantial and sustained reduction of the LPR with no additional suppression with addition of anti-IL-4. Treatment with anti-IL-4 and SCIT compared with SCIT alone led to a sustained reduction in allergen-specific IL-4-producing cell counts (P < .01). Both active treatment arms led to induction of dual IL-4/IL-10-producing cells during the pollen season.

Conclusion: The combination of anti-IL-4 with SCIT provided no additional benefit over SCIT alone in suppressing the allergen-induced skin LPR. A larger trial is needed to assess whether the observed ex vivo downregulation of TH2 responses might translate into clinical benefit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2015.08.046DOI Listing
February 2016

[Individualized, personalized and stratified medicine: a challenge for allergology in ENT?].

HNO 2015 May;63(5):334-42

HNO-Klinik und ZAUM, Klinikum rechts der Isar, Technische Universität München, München, Deutschland.

Individualized, personalized or stratified medicine approaches offer emerging opportunities in the field of allergy and ENT. Avoidance of side effects, targeted therapy approaches and stratified prevention promise better outcomes and optimal results for patients. Conceptual incongruencies remain with regard to definitions and perceptions of "personalized medicine". Serious ethical considerations have to be taken into account. The development of pharmacogenomics, molecular phenotyping, genomic sequencing and other -omics opens the door to unique mechanistic therapeutic advances. The molecular allergology and recombinant diagnostics available are tools that offer substantial improved diagnostics for the benefit of allergic patients, e. g. in anaphylaxis and food allergy. For stratified therapeutic approaches, however, regulatory affairs will have to keep pace with medical and scientific discovery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00106-015-0004-yDOI Listing
May 2015

Petasol butenoate complex (Ze 339) relieves allergic rhinitis-induced nasal obstruction more effectively than desloratadine.

J Allergy Clin Immunol 2011 Jun 13;127(6):1515-21.e6. Epub 2011 Apr 13.

Molecular Immunology, Section of Allergy and Clinical Immunology, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Background: Allergic rhinitis symptoms of itching, sneezing, rhinorrhea, and nasal obstruction significantly decrease patients' quality of life. Compared with histamine and leukotriene receptor antagonists, the petasol butenoate complex Ze 339 displays pharmacologically distinct properties. In vitro it inhibits the biosynthesis of leukotrienes and mediator release from activated eosinophils.

Objective: This study aimed to assess the efficacy and mode of action of Ze 339, desloratadine, and placebo on allergic rhinitis symptoms, nasal airflow, and local mediator levels after unilateral nasal allergen provocation.

Methods: In this double-blind, randomized, crossover study 18 subjects with allergic rhinitis to grass pollen received Ze 339, desloratadine, and placebo for 5 days before nasal allergen challenge with grass pollen extract. Rhinomanometry, symptom assessment, and local inflammatory mediator measurement were performed during the 24 hours after allergen challenge.

Results: With Ze 339, the patient's time to recovery (5.4 ± 1.6 hours) from nasal obstruction after allergen challenge (time for return to 90% of baseline value ± SEM) was significantly shorter than with placebo (9.1 ± 2.3 hours, P = .035) and desloratadine (10.7 ± 2.5 hours, P = .022). Likewise, Ze 339's standardized symptom assessment for nasal obstruction (3.2 ± 1.3 hours) showed significantly faster relief (time for return to baseline value ± SEM compared with placebo, 8.3 ± 2.4 hours; P = .027) and desloratadine (4.5 ± 1.2 hours, P = .030). One interesting finding was that Ze 339 significantly reduced IL-8 and leukotriene B(4) levels in nasal secretions before challenge.

Conclusion: When compared with desloratadine and placebo, Ze 339 shows better efficacy in relieving nasal obstruction symptoms and inhibiting critical components of the chemokine network and as such represents a novel symptomatic and possible prophylactic treatment for allergic rhinitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2011.02.045DOI Listing
June 2011