Seasonal Allergic Rhinitis is characterised by inflammation of the nasal mucosa upon exposure to common aeroallergens, affecting up to 20-25 % of the population. For those patients whose symptoms are not controlled by standard medical treatment, allergen specific immunotherapy is a therapeutic alternative. Although several studies have shown changes in immunologic responses as well as long term tolerance following treatment with a sublingual allergy immunotherapy tablet, a detailed time course of the early mechanistic changes of local and systemic T and B cell responses and the effects on B cell repertoire in the nasal mucosa have not been fully examined.This is a randomized, double-blind, single-centre, placebo controlled, two arm time course study based in the United Kingdom comparing sublingual allergy immunotherapy tablet (GRAZAX(®), ALK-Abello Horsholm, Denmark) plus standard treatment with placebo plus standard treatment. Up to 50 moderate to severe grass pollen allergic participants will be enrolled to ensure randomisation of at least 44. Further, we shall enrol 20 non-atopic volunteers. Screening will be completed before eligible atopic participants are randomised to one of the two treatment arms in a 1 to 1 ratio. The primary endpoint will be the total nasal symptom score assessed over 60 min following grass pollen nasal allergen challenge after 12 months of treatment. Clinical assessments and/or mechanistic analyses on blood, nasal fluid, brushing and biopsies will be performed at baseline at 1, 2, 3, 4 (coinciding with the peak pollen season), 6 and 12 months of treatment. After 12 months of treatment, unblinding will take place. Those atopic participants receiving active treatment will continue therapy for another 12 months followed by a post treatment phase of 12 months. Assessments and collection of biologic samples from these participants will take place again at 24 and at 36 months from the start of treatment. The 20 healthy, non-atopic controls will undergo screening and one visit only coinciding with the 12 month visit for the atopic participants.The trial will end in April 2017. The trial is registered with ClinicalTrials.gov and the trial identifying number is NCT02005627.Primary Registry: ClinicalTrials.gov, Trial Identifying number: NCT02005627, Secondary identifying numbers: EudraCT number: 2013-003732-72 REC: 13/EM/0351, Imperial College London (Sponsor): 13IC0847, Protocol Version 6.0, Date: 16.05.2014.
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Approximately 5-10% of asthmatic patients worldwide suffer from severe asthma. Experimental and clinical studies have demonstrated that IL-13 is an important cytokine in chronic airways inflammation. IL-13 is involved in Th2 inflammation and has been identified as a possible therapeutic target in the treatment of asthma. Two different human monoclonal antibodies (mAbs) anti-IL-13 (tralokinumab and lebrikizumab) block binding and signaling of IL-13 to its receptors, IL-13Rα1 and IL-13Rα2. Several randomized, double-blind, placebo-controlled multicenter studies have evaluated the safety and efficacy of tralokinumab and lebrikizumab in the treatment of adult patients with severe asthma, but all have failed to meet their primary endpoints. No serious adverse events related to the treatment with these anti-IL-13 mAbs have been reported in these studies. These negative clinical results contrast with positive findings from blocking IL-13 signaling in experimental models of asthma, raising doubts about the transferrable value of some models. Interestingly, dupilumab, a mAb which blocks both IL-4 and IL-13 signaling reduces exacerbation rates and improves lung function in severe asthmatics. These results suggest that IL-4 and IL-13 share some, but not all functional activities in airway inflammation. Tralokinumab might show efficacy in a highly selected cohort of asthmatics characterized by overexpression of IL-13.
The allergen provocation test is an established model of allergic airway diseases, including asthma and allergic rhinitis, allowing the study of allergen-induced changes in respiratory physiology and inflammatory mechanisms in sensitised individuals as well as their associations. In the upper airways, allergen challenge is focused on the clinical and pathophysiological sequelae of the early allergic response, and is applied both as a diagnostic tool and in research settings. In contrast, bronchial allergen challenge has almost exclusively served as a research tool in specialised research settings with a focus on the late asthmatic response and the underlying type 2 inflammation. The allergen-induced late asthmatic response is also characterised by prolonged airway narrowing, increased nonspecific airway hyperresponsiveness and features of airway remodelling including the small airways, and hence allows the study of several key mechanisms and features of asthma. In line with these characteristics, allergen challenge has served as a valued tool to study the cross-talk of the upper and lower airways and in proof-of-mechanism studies of drug development. In recent years, several new insights into respiratory phenotypes and endotypes including the involvement of the upper and small airways, innovative biomarker sampling methods and detection techniques, refined lung function testing as well as targeted treatment options further shaped the applicability of the allergen provocation test in precision medicine. These topics, along with descriptions of subject populations and safety, in line with the updated Global Initiative for Asthma 2021 document, will be addressed in this review.
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