Guy W. Scadding

Sublingual grass pollen immunotherapy is associated with increases in sublingual Foxp3-expressing cells and elevated allergen-specific immunoglobulin G4, immunoglobulin A and serum inhibitory activity for immunoglobulin E-facilitated allergen binding to B cells

Background The mechanisms of sublingual immunotherapy (SLIT) are less well understood than those of subcutaneous immunotherapy (SCIT).

Optimisation of grass pollen nasal allergen challenge for assessment of clinical and immunological outcomes.

Nasal allergen challenge can be used to assess the clinical and immunological aspects of rhinitis due to inhalant allergens. We aimed to develop a reproducible technique for grass pollen nasal allergen challenge and to study biomarkers within nasal secretions. 20 Grass pollen allergic individuals underwent nasal challenges with purified Timothy grass allergen. An initial dose-titration challenge was used to determine dose-response characteristics. Subsequently, volunteers underwent 3 further challenges using individualised threshold doses. Symptom scores, visual analogue scores, and peak nasal inspiratory flow (PNIF) were recorded at baseline and up to 6h after challenge. Nasal secretions were collected at each time point using synthetic filter papers or absorptive polyurethane sponges and analysed for IL-4, -5, -10, -13, IFN-γ, Tryptase and Eosinophil Cationic Protein (ECP). Challenges gave reproducible symptom scores and decreased PNIF. Tryptase levels in nasal fluid peaked at 5 min after challenge and returned to baseline levels at 1h. ECP, IL-5, IL-13 and IL-4 levels were increased from 2-3 h and showed progressive increases to 5-6 h. Sponges proved the superior nasal fluid sampling technique. We have developed a reproducible nasal allergen challenge technique. This may be used as a surrogate clinical endpoint in trials assessing the efficacy of treatments for allergic rhinitis. Tryptase in local nasal secretions is a potential biomarker of the early phase response; ECP and the Th2 cytokines IL-5, -13 and -4 markers of late phase allergic responses. Our model allows correlation between clinical responses and local biomarkers following nasal allergen challenge.

CC Chemokine Receptor 4 (CCR4) in human allergen-induced late nasal responses

To cite this article: Banfield G, Watanabe H, Scadding G, Jacobson MR, Till SJ, Hall DA, Robinson DS, Lloyd CM, Nouri‐Aria KT, Durham SR. CC Chemokine Receptor 4 (CCR4) in human allergen‐induced late nasal responses. Allergy 2010; 65: 1126–1133.

Effect of 2 Years of Treatment With Sublingual Grass Pollen Immunotherapy on Nasal Response to Allergen Challenge at 3 Years Among Patients With Moderate to Severe Seasonal Allergic Rhinitis: The GRASS Randomized Clinical Trial

Importance Sublingual immunotherapy and subcutaneous immunotherapy are effective in seasonal allergic rhinitis. Three years of continuous treatment with subcutaneous immunotherapy and sublingual immunotherapy has been shown to improve symptoms for at least 2 years following discontinuation of treatment. Objective To assess whether 2 years of treatment with grass pollen sublingual immunotherapy, compared with placebo, provides improved nasal response to allergen challenge at 3-year follow-up. Design, Setting, and Participants A randomized double-blind, placebo-controlled, 3–parallel-group study performed in a single academic center, Imperial College London, of adult patients with moderate to severe seasonal allergic rhinitis (interfering with usual daily activities or sleep). First enrollment was March 2011, last follow-up was February 2015. Interventions Thirty-six participants received 2 years of sublingual immunotherapy (daily tablets containing 15 µg of major allergen Phleum p 5 and monthly placebo injections), 36 received subcutaneous immunotherapy (monthly injections containing 20 µg of Phleum p 5 and daily placebo tablets) and 34 received matched double-placebo. Nasal allergen challenge was performed before treatment, at 1 and 2 years of treatment, and at 3 years (1 year after treatment discontinuation). Main Outcomes and Measures Total nasal symptom scores (TNSS; range; 0 [best] to 12 [worst]) were recorded between 0 and 10 hours after challenge. The minimum clinically important difference for change in TNSS within an individual is 1.08. The primary outcome was TNSS comparing sublingual immunotherapy vs placebo at year 3. Subcutaneous immunotherapy was included as a positive control. The study was not powered to compare sublingual immunotherapy with subcutaneous immunotherapy. Results Among 106 randomized participants (mean age, 33.5 years; 34 women [32.1%]), 92 completed the study at 3 years. In the intent-to-treat population, mean TNSS score for the sublingual immunotherapy group was 6.36 (95% CI, 5.76 to 6.96) at pretreatment and 4.73 (95% CI, 3.97 to 5.48) at 3 years, and for the placebo group, the score was 6.06 (95% CI, 5.23 to 6.88) at pretreatment and 4.81 (95% CI, 3.97 to 5.65) at 3 years. The between-group difference (adjusted for baseline) was −0.18 (95% CI, −1.25 to 0.90; [P = .75]). Conclusions and Relevance Among patients with moderate to severe seasonal allergic rhinitis, 2 years of sublingual grass pollen immunotherapy was not significantly different from placebo in improving the nasal response to allergen challenge at 3-year follow-up. Trial Registration clinicaltrials.gov Identifier: NCT01335139; EudraCT Number: 2010-023536-16

Effect of grass pollen immunotherapy on clinical and local immune response to nasal allergen challenge

Nasal allergen provocations may be useful in investigating the pathophysiology of allergic rhinitis and effects of treatments.

Cytokine Profiles in Allergic Rhinitis

Allergic rhinitis, particularly seasonal allergic rhinitis, is considered a classic Th2-mediated disease, with important contributions to pathology by interleukins 4, 5 and 13. As such, allergic rhinitis is an excellent model for studying allergic inflammation, with findings potentially relevant to the mechanism of lower airways inflammation seen in allergic asthma. However, recent evidence has revealed roles for additional non-Th2 cytokines in asthma, including IL-17 family cytokines and epithelial-derived cytokines. Additionally, putative roles for epithelial-derived cytokines and innate lymphoid cells have been described in chronic rhinosinusitis with nasal polyps. Here, evidence for the involvement of different cytokines and cytokine groups in allergic rhinitis is considered.

Recent advances in antileukotriene therapy.

Purpose of reviewDespite profound effects of leukotrienes in experimental models, clinical responses to antileukotriene drugs are highly heterogeneous. This review discusses recent advances concerning the molecular mechanisms of antileukotrienes as well as their efficacy in various clinical scenarios and patient groups. Recent findingsAppreciation of the role of leukotriene E4 and the existence of its distinct receptors may explain the limited efficacy of current leukotriene receptor antagonists. Pharmacogenetic studies highlight the influence of several leukotriene pathway genes on clinical responsiveness. Benefits of addition of antileukotrienes to inhaled corticosteroids in chronic adult asthmatics have been shown, but their role in acute asthma is unclear. Evidence suggests they are not a first-line treatment for allergic rhinitis or urticaria, but may provide useful additional therapy. In children antileukotrienes provide symptomatic benefit in preschool wheezers, but have no clear role in bronchiolitis or acute asthma. Adherence to montelukast appears superior to inhaled corticosteroids. Use in sleep-disordered breathing and eosinophilic gastroenteropathies warrants further investigation. Despite recent concerns thorough analysis of existing data suggests antileukotrienes are well tolerated drugs. The possible link with Churg-Strauss syndrome requires further investigation. SummaryThe leukotriene pathway remains an attractive target in asthma and allergic disease, particularly in light of renewed appreciation of the role of leukotriene E4. Clarification of the clinical role of antileukotrienes is needed.

Mechanisms of Sublingual Immunotherapy

Sublingual immunotherapy (SLIT) has been shown to be effective in the treatment of seasonal allergic rhinoconjunctivitis. Despite comparable clinical efficacy to traditional subcutaneous immunotherapy, the mechanisms of SLIT have yet to be fully established. This article considers the role of the local oral mucosa and regional lymphoid tissues in the processing of allergen during SLIT and the subsequent effects on T-cell and B-cell immune compartments and at mucosal sites. The likely time course of events and the evidence for long-lasting tolerance following SLIT are discussed.

Effector cell signature in peripheral blood following nasal allergen challenge in grass pollen allergic individuals

Several studies have demonstrated the time course of inflammatory mediators in nasal fluids following nasal allergen challenge (NAC), whereas the effects of NAC on cells in the periphery are unknown. We examined the time course of effector cell markers (for basophils, dendritic cells and T cells) in peripheral blood after nasal grass pollen allergen challenge.

Dropouts in sublingual allergen immunotherapy trials – a systematic review

Participant dropouts can reduce the power of allergen immunotherapy clinical trials. Evaluation of the dropout rate and reasons for dropout are important not only in the planning of clinical studies but are also relevant for adherence to immunotherapy in daily clinical practice. A systematic review was carried out in order to establish the overall dropout rate among published double‐blind, placebo‐controlled randomized clinical trials of sublingual immunotherapy for respiratory allergic diseases. Dropouts were analysed in regards to allergen, formulation, treatment schedule, participant age, study size, number of centres and type of allergic disease. Relative dropout rates in placebo and active groups as well as reasons for dropout were also assessed. A total of 81 studies, comprising 9998 patients, were included. Dropout rates in sublingual immunotherapy controlled studies do not appear to be a major problem with a composite dropout percentage of 14% (95% CI:11.9–16). Furthermore, they are not different for active compared to placebo‐treated participants. This lends support to the positive clinical outcomes seen in meta‐analyses of these trials.