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Background: Grass pollen-specific immunotherapy involves immunomodulation of allergen-specific T H 2 responses and induction of IL-10 + and/or TGF-β + CD4 + CD25 + regulatory T cells (induced Treg cells). IL-35 + CD4 + CD25 + forkhead box protein 3-negative T (IL-35-inducible regulatory T [iT R 35]) cells have been reported as a novel subset of induced Treg cells with modulatory characteristics., Objective: We sought to investigate mechanisms underlying the induction and maintenance of immunologic tolerance induced by IL-35 and iT R 35 cells., Methods: The biological effects of IL-35 were assessed on group 2 innate lymphoid cells (ILC2s); dendritic cells primed with thymic stromal lymphopoietin, IL-25, and IL-33; and B and T H 2 cells by using flow cytometry and quantitative RT-PCR. Grass pollen-driven T H 2 cell proliferation and cytokine production were measured by using tritiated thymidine and Luminex MagPix, respectively. iT R 35 cells were quantified in patients with grass pollen allergy (seasonal allergic rhinitis [SAR] group, n = 16), sublingual immunotherapy (SLIT)-treated patients (SLIT group, n = 16), and nonatopic control subjects (NACs; NAC group, n = 16)., Results: The SAR group had increased proportions of ILC2s (P = .002) and IL-5 + cells (P = .042), IL-13 + cells (P = .042), and IL-5 + IL-13 + ILC2s (P = .003) compared with NACs. IL-35 inhibited IL-5 and IL-13 production by ILC2s in the presence of IL-25 or IL-33 (P = .031) and allergen-driven T H 2 cytokines by effector T cells. IL-35 inhibited CD40 ligand-, IL-4-, and IL-21-mediated IgE production by B cells (P = .015), allergen-driven T-cell proliferation (P = .001), and T H 2 cytokine production mediated by primed dendritic cells. iT R 35 cells suppressed T H 2 cell proliferation and cytokine production. In addition, allergen-driven IL-35 levels and iT R 35 cell counts were increased in patients receiving SLIT (all, P < .001) and NACs (all, P < .001) compared with patients with SAR., Conclusion: IL-35 and iT R 35 cells are potential novel immune regulators induced by SLIT. The clinical relevance of SLIT can be underscored by restoration of protective iT R 35 cells., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cat allergen is widely distributed in homes and schools; allergic sensitization is common., Objective: To develop a model of cat allergen nasal challenge to establish dose-response and time-course characteristics and investigate local and systemic biomarkers of allergic inflammation., Methods: Nineteen cat-allergic individuals underwent titrated nasal challenge, range 0.243 to 14.6 μg/mL Fel d1, and matched diluent-only provocation. Clinical response to 8 h was assessed by symptom scores and peak nasal inspiratory flow (PNIF). Nasal fluid was collected using polyurethane sponges and analysed by ImmunoCAP and multiplex assays. Whole blood flow cytometry for basophil surface CD63, CD107a, and CD203c was carried out at baseline and 6 h post-challenge., Results: A dose-response to allergen was seen in symptom scores and PNIF, maximal at 10 000 BU/mL (4.87 μg/mL Fel d1), P < 0.0001 vs. diluent. Nasal fluid tryptase was elevated at 5 min after challenge (P < 0.05 vs. diluent); eotaxin, IL-4, -5, -9, and -13 were increased at 8 h (P < 0.05 to P < 0.0001 vs. diluent); TSLP was undetectable; IL-10, IL-17A, and IL-33 were unchanged compared to diluent challenge. Nasal fluid IL-5 and IL-13 correlated inversely with PNIF after challenge (IL-5, r = -0.79, P < 0.0001; IL-13, r = -0.60, P = 0.006). Surface expression of CD63 and CD107a was greater at 6 h than at baseline, both in the presence (both P < 0.05) and absence (CD63, P < 0.01; CD107a, P < 0.05) of in vitro allergen stimulation; no changes were seen on diluent challenge day., Conclusions: Cat allergen nasal challenge produces local and systemic Th2-driven inflammatory responses and has potential as a surrogate outcome measure in clinical trials., (© 2014 John Wiley & Sons Ltd.)

Background: 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., Methods: Twelve participants with seasonal allergic rhinitis underwent a control (diluent) challenge followed by NAC after an interval of 14 days. Nasal symptoms and peak nasal inspiratory flow (PNIF) were recorded along with peripheral basophil, T-cell and dendritic cell responses (flow cytometry), T-cell proliferative responses (thymidine incorporation), and cytokine expression (FluoroSpot assay)., Results: Robust increases in nasal symptoms and decreases in PNIF were observed during the early (0-1 h) response and modest significant changes during the late (1-24 h) response. Sequential peaks in peripheral blood basophil activation markers were observed (CD107a at 3 h, CD63 at 6 h, and CD203c(bright) at 24 h). T effector/memory cells (CD4(+) CD25(lo) ) were increased at 6 h and accompanied by increases in CD80(+) and CD86(+) plasmacytoid dendritic cells (pDCs). Ex vivo grass antigen-driven T-cell proliferative responses and the frequency of IL-4(+) CD4(+) T cells were significantly increased at 6 h after NAC when compared to the control day., Conclusion: Basophil, T-cell, and dendritic cell activation increased the frequency of allergen-driven IL-4(+) CD4(+) T cells, and T-cell proliferative responses are detectable in the periphery after NAC. These data confirm systemic cellular activation following a local nasal provocation., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: CC Chemokine receptor 4 (CCR4) is preferentially expressed on Th2 lymphocytes. CCR4-mediated inflammation may be important in the pathology of allergic rhinitis. Disruption of CCR4 - ligand interaction may abrogate allergen-induced inflammation., Methods: Sixteen allergic rhinitics and six nonatopic individuals underwent both allergen and control (diluent) nasal challenges. Symptom scores and peak nasal inspiratory flow were recorded. Nasal biopsies were taken at 8 h post challenge. Sections were immunostained and examined by light or dual immunofluorescence microscopy for eosinophils, T-lymphocytes, CCR4(+)CD3(+) and CXCR3(+)CD3(+) cells and examined by in situ hybridization for CCR4, IL-4 and IFN-gamma mRNA(+) cells. Peripheral blood mononuclear cells were obtained from peripheral blood of nine normal donors and the CCR4(+)CD4(+) cells assessed for actin polymerization in response to the CCR4 ligand macrophage-derived chemokine (MDC/CCL22) and the influence of a CCR4 antagonist tested., Results: Allergic rhinitics had increased early and late phase symptoms after allergen challenge compared to diluent; nonatopics did not respond to either challenge. Eosinophils, but not total numbers of CD3(+) T cells, were increased in rhinitics following allergen challenge. In rhinitics, there was an increase in CCR4(+)CD3(+) protein-positive cells relative to CXCR3(+)CD3(+) cells; CCR4 mRNA+ cells were increased and IL-4 increased to a greater extent than IFN-gamma. CCR4(+)CD4(+) T cells responded to MDC in vitro, and this response was inhibited by the selective CCR4 antagonist., Conclusion: Lymphocyte CCR4 expression is closely associated with induction of human allergen-induced late nasal responses. Blocking CCR4-ligand interaction may provide a novel therapeutic approach in allergic disease.

Background: Several clinical and experimental observations suggest that allergen deposition in the nose may partially be responsible for the induction of conjunctival symptoms in allergic rhinitis. The aims of this study were to evaluate the induction of conjunctival symptoms by selective nasal allergen provocation and to assess the feasibility of the different tools for evaluation of conjunctival allergic inflammation., Methods: Grass pollen allergic subjects with rhinoconjunctivitis symptoms during the pollen season (n = 12) underwent a nasal sham and grass pollen provocation extra-seasonally. Nasal and conjunctival symptoms were scored using the Visual Analogue Scale (VAS) system at baseline, 15 min, 1 h and 24 h after provocation. In addition to Peak Nasal Inspiratory flow (PNIF) measurements, conjunctival inflammation and vascular congestion were evaluated and histamine and substance P levels in tear fluid were measured., Results: Selective nasal grass pollen provocation induced ocular pruritus, lacrimation and conjunctival vascular congestion. PNIF values correlated inversely with lacrimation (r = -0.71, P < 0.001) and ocular pruritus (r = -0.41, P < 0.05). Four out of 11 patients showed a conjunctival eosinophilic inflammation and levels of histamine (r = 0.73, P < 0.05) and substance P (r = 0.67, P = 0.05) in tear fluid correlated with conjunctival symptoms., Conclusion: Selective nasal grass pollen provocation induced conjunctival inflammation, ocular pruritus and lacrimation, which correlated with histamine and substance P levels in tear fluid and inversely with the PNIF values. These data show a naso-ocular interaction in allergic rhinitis and offer objective tools for evaluation of conjunctival inflammation in allergic rhinoconjunctivitis.

Acoustic rhinometry was used to assess nasal airway patency objectively and was compared with the more established method of anterior rhinomanometry. Ten patients with allergic rhinitis underwent 15 nasal challenges with allergen to which they showed positive skin-prick tests. Responses were assessed by measuring the minimum nasal cross-sectional area (Amin.) using acoustic rhinometry and by measuring nasal airway resistance (NAR) using anterior rhinomanometry. The measurements of Amin. and NAR showed a significant negative correlation. Acoustic rhinometry appears to be superior to anterior rhinomanometry in quantifying the response to nasal allergen challenge and may be particularly useful in patients with initial nasal blockage.

Rhinitis causes both clinical and social discomfort to patients, and in clinical practice is often underdiagnosed. We have examined a simple method for the assessment of a positive nasal provocation test to help in the diagnosis of rhinitis. In patients with histories suggestive of house dust mite (HDM) sensitivity and positive skin-prick tests or specific IgE to Dermatophagoides pteronyssinus, there was a fall in nasal inspiratory peak flow (NIPF) following nasal challenge with allergen. This was not seen in control subjects or in pollen-sensitive patients when challenged with house dust mite. Frequency of sneezing and degree of rhinorrhoea increased in these patients following challenge, and based on these findings we propose a simplified scoring system for the diagnosis of allergic rhinitis. We examined non-specific nasal reactivity using hyperosmolar solutions as a challenge system and found that allergic subjects responded with a fall in NIPF, although the clinical response was not identical to that seen with allergen. Control subjects did not respond to hyperosmolar challenge.

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. [ABSTRACT FROM AUTHOR]

Rhinitis is a common problem in childhood and adolescence and impacts negatively on physical, social and psychological well-being. This position paper, prepared by the European Academy of Allergy and Clinical Immunology Taskforce on Rhinitis in Children, aims to provide evidence-based recommendations for the diagnosis and therapy of paediatric rhinitis. Rhinitis is characterized by at least two nasal symptoms: rhinorrhoea, blockage, sneezing or itching. It is classified as allergic rhinitis, infectious rhinitis and nonallergic, noninfectious rhinitis. Similar symptoms may occur with other conditions such as adenoidal hypertrophy, septal deviation and nasal polyps. Examination by anterior rhinoscopy and allergy tests may help to substantiate a diagnosis of allergic rhinitis. Avoidance of relevant allergens may be helpful for allergic rhinitis ( AR). Oral and intranasal antihistamines and nasal corticosteroids are both appropriate for first-line AR treatment although the latter are more effective. Once-daily forms of corticosteroids are preferred given their improved safety profile. Potentially useful add-on therapies for AR include oral leukotriene receptor antagonists, short bursts of a nasal decongestant, saline douches and nasal anticholinergics. Allergen-specific immunotherapy is helpful in IgE-mediated AR and may prevent the progression of allergic disease. There are still a number of areas that need to be clarified in the management of rhinitis in children and adolescents. [ABSTRACT FROM AUTHOR]

Background The mechanisms of sublingual immunotherapy (SLIT) are less well understood than those of subcutaneous immunotherapy (SCIT). Objectives To determine the effects of grass-pollen SLIT on oral mucosal immune cells, local regulatory cytokines, serum allergen-specific antibody subclasses and B cell IgE-facilitated allergen binding (IgE-FAB). Methods Biopsies from the sublingual mucosa of up to 14 SLIT-treated atopics, nine placebo-treated atopics and eight normal controls were examined for myeloid dendritic cells (mDCs) (CD1c), plasmacytoid dendritic cells (CD303), mast cells (AA1), T cells (CD3) and Foxp3 using immunofluorescence microscopy. IL-10 and TGF-β mRNA expression were identified by in situ hybridization. Allergen-specific IgG and IgA subclasses and serum inhibitory activity for binding of allergen-IgE complexes to B cells (IgE-FAB) were measured before, during and on the completion of SLIT. Results Foxp3+ cells were increased in the oral epithelium of SLIT- vs. placebo-treated atopics ( P=0.04). Greater numbers of subepithelial mDCs were present in placebo-treated, but not in SLIT-treated, atopics compared with normal controls ( P=0.05). There were fewer subepithelial mast cells and greater epithelial T cells in SLIT- compared with placebo-treated atopics ( P=0.1 for both). IgG1 and IgG4 were increased following SLIT ( P<0.001). Peak seasonal IgA1 and IgA2 were increased during SLIT ( P<0.05). There was a time-dependent increase in serum inhibitory activity for IgE-FAB in SLIT-treated atopics. Conclusions SLIT with grass pollen extract is associated with increased Foxp3+ cells in the sublingual epithelium and systemic humoral changes as observed previously for SCIT. Cite this as: G. W. Scadding, M. H. Shamji, M. R. Jacobson, D. I. Lee, D. Wilson, M. T. Lima, L. Pitkin, C. Pilette, K. Nouri-Aria and S. R. Durham, Clinical & Experimental Allergy, 2010 (40) 598–606. [ABSTRACT FROM AUTHOR]

This guidance for the management of patients with allergic and non-allergic rhinitis has been prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI). The guideline is based on evidence as well as on expert opinion and is for use by both adult physicians and paediatricians practicing in allergy. The recommendations are evidence graded. During the development of these guidelines, all BSACI members were included in the consultation process using a web-based system. Their comments and suggestions were carefully considered by the SOCC. Where evidence was lacking, consensus was reached by the experts on the committee. Included in this guideline are clinical classification of rhinitis, aetiology, diagnosis, investigations and management including subcutaneous and sublingual immunotherapy. There are also special sections for children, co-morbid associations and pregnancy. Finally, we have made recommendations for potential areas of future research. [ABSTRACT FROM AUTHOR]

This paper describes a pilot intervention study on the effectiveness of house dust mite allergen avoidance for 12 asthmatic children (two being controls). In addition to mite allergen removal, the study included tailored advice aimed at reducing mite population growth via changes in moisture production, heating and ventilation habits. This paper focuses on the effects of this advice on household behaviour, hygrothermal conditions and mite populations. The efficacy of monitoring and modelling techniques is also discussed. The study highlighted a number of interrelated confounding factors which have to be addressed in future similar larger scale studies, but the results are promising with regards to the effectiveness of such studies. Practical application: This study suggests that in temperate climates tailored advice on moisture production, heating and ventilation habits can lead to valuable changes in hygrothermal conditions, which in turn can result in reduced mite populations. However, pre-existing adverse building conditions may hinder such changes, and the effectiveness of tailored advice and of hygrothermal modifications is often difficult to assess. It is therefore recommended that any similar larger intervention study measures ventilation rates and adequately controls for a number of confounding variables - including the effect of changes in outdoor conditions and of the removal of existing mite populations. In this respect, hygrothermal population models can play a very useful role in the assessment of study effectiveness. [ABSTRACT FROM AUTHOR]

Allergic rhinitis is characterised by symptoms of sneezing, itching of the nose with watery secretions, and nasal obstruction. We have previously shown that patients can have the diagnosis of allergic rhinitis confirmed by nasal provocation tests and assessment of nasal inspiratory peak flow (NIPF) after specific allergen or hyperosmolar challenge. We now show that histamine is released into the nasal lavage fluid in response to such challenges. Saline lavage alone results in detectable histamine levels in the order of 5 ng/ml, but in the presence of allergen (HDM) there is a significant increase in histamine release in atopics but not in control subjects. With hyperosmolar challenge, atopics showed a biphasic response in that histamine release was increased with 1.8% and 3.6% saline but returned to baseline with 5.4% and 7.2% saline, then showing a further increase with 9.0% saline. This raises the possibility of two populations of responsive mast cells. Hyperosmolar challenge leads to symptoms of nasal itch and sneezing as well as histamine release in atopics but not in controls. This suggests that hyperosmolar challenge can be used as a simple diagnostic test for allergic rhinitis and may provide a model for nasal hyper-reactivity. [ABSTRACT FROM AUTHOR]