Mechanisms of allergen immunotherapy for inhaled allergens and predictive biomarkers

Allergen immunotherapy is effective in patients with IgEdependent allergic rhinitis and asthma. When immunotherapy is given continuously for 3 years, there is persistent clinical benefit for several years after its discontinuation. This diseasemodifying effect is both antigen-specific and antigen-driven. Clinical improvement is accompanied by decreases in numbers of effector cells in target organs, including mast cells, basophils, eosinophils, and type 2 innate lymphoid cells. Immunotherapy results in the production of blocking IgG/IgG4 antibodies that can inhibit IgE-dependent activation mediated through both high-affinity IgE receptors (FcεRI) on mast cells and basophils and low-affinity IgE receptors (FcεRII) on B cells. Suppression of TH2 immunity can occur as a consequence of either deletion or anergy of antigen-specific T cells; induction of antigenspecific regulatory T cells; or immune deviation in favor of TH1 responses. It is not clear whether the altered long-term memory resides within the T-cell or the B-cell compartment. Recent data highlight the role of IL-10–producing regulatory B cells and ‘‘protective’’ antibodies that likely contribute to long-term tolerance. Understanding mechanisms underlying induction and persistence of tolerance should identify predictive biomarkers of clinical response and discover novel and more effective strategies for immunotherapy

UK Immunotherapy Study: reanalysis by a combined symptom and medication score

Reanalysis of UK22 subcutaneous immunotherapy trial according to WAO/EAACI recommendations revealed clinically relevant improvements at both doses. Starting at the lower dose should enable efficacy with lower risk of adverse events

Sublingual grass allergen tablet immunotherapy provides sustained clinical benefit with progressive immunologic changes over 2 years

Background: This is an interim analysis of a randomized, double-blind, placebo-controlled phase III trial with 3 years of daily treatment with grass tablet immunotherapy (GRAZAX; ALK-Abello A/S, Horsholm, Denmark) or placebo, followed by 2 years of follow-up to assess the persistent efficacy. Objective: We sought to evaluate the efficacy and safety of specific immunotherapy with grass allergen tablets compared with placebo after treatment covering 2 consecutive grass pollen seasons. Methods: The interim analyses included 351 adult participants with moderate-to-severe allergic rhinoconjunctivitis caused by grass pollen. Participants were treated with active (n = 189) or placebo (n = 162) tablets for an average of 22 months. All participants were allowed to use symptomatic rescue medication. Results: The primary efficacy analysis showed highly significant mean reductions of 36% in rhinoconjunctivitis symptom score (P Conclusion: Grass allergen tablet immunotherapy showed progressive immunologic changes and highly significant efficacy over 2 years of continued treatment

Protocol for a randomised, double-blind, placebo-controlled study of grass allergen immunotherapy tablet for seasonal allergic rhinitis: time course of nasal, cutaneous and immunological outcomes

BACKGROUND: 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. METHODS/DESIGN: 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. DISCUSSION: The trial will end in April 2017. The trial is registered with ClinicalTrials.gov and the trial identifying number is NCT02005627. TRIAL REGISTRATION: 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

The MIF antagonist ISO-1 attenuates corticosteroid-insensitive inflammation and airways hyperresponsiveness in an ozone-induced model of COPD

Copyright © 2016 Russell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine associated with acute and chronic inflammatory disorders and corticosteroid insensitivity. Its expression in the airways of patients with chronic obstructive pulmonary disease (COPD), a relatively steroid insensitive inflammatory disease is unclear, however. Methods. Sputum, bronchoalveolar lavage (BAL) macrophages and serum were obtained from nonsmokers, smokers and COPD patients. To mimic oxidative stress-induced COPD, mice were exposed to ozone for six-weeks and treated with ISO-1, a MIF inhibitor, and/or dexamethasone before each exposure. BAL fluid and lung tissue were collected after the final exposure. Airway hyperresponsiveness (AHR) and lung function were measured using whole body plethysmography. HIF-1α binding to the Mif promoter was determined by Chromatin Immunoprecipitation assays. Results. MIF levels in sputum and BAL macrophages from COPD patients were higher than those from non-smokers, with healthy smokers having intermediate levels. MIF expression correlated with that of HIF-1α in all patients groups and in ozone-exposed mice. BAL cell counts, cytokine mRNA and protein expression in lungs and BAL, including MIF, were elevated in ozone-exposed mice and had increased AHR. Dexamethasone had no effect on these parameters in the mouse but ISO-1 attenuated cell recruitment, cytokine release and AHR. Conclusion MIF and HIF-1α levels are elevated in COPD BAL macrophages and inhibition of MIF function blocks corticosteroid-insensitive lung inflammation and AHR. Inhibition of MIF may provide a novel anti-inflammatory approach in COPD

Specific allergen immunotherapy for the treatment of atopic eczema: a Cochrane systematic review

Background Specific allergen immunotherapy (SIT) is an effective allergy treatment, but it is unclear whether SIT is effective for atopic eczema (AE). We undertook a systematic review to assess SIT efficacy and safety for treating AE. Methods We searched databases, ongoing clinical trials registers, and conference proceedings up to July 2015. Randomized controlled trials (RCTs) of SIT using standardized allergen extracts, compared with placebo/control, for treating AE in patients with allergic sensitization were eligible. Results We identified 12 eligible trials with 733 participants. Interventions included subcutaneous (six trials), sublingual (four trials), oral or intradermal SIT in children/adults allergic to house dust mite (10 trials), grass pollen or other inhalants. Risk of bias was moderate, with high loss to follow‐up and nonblinding as the main concerns. For our primary outcomes, three studies (208 participants) reported no significant difference – patient‐reported global disease severity improvement RR 0.75 (95% CI 0.45, 1.26); and eczema symptoms mean difference −0.74 on a 20‐point scale (95% CI −1.98, 0.50). Two studies (85 participants) reported a significant difference – SIT improved global disease severity RR 2.85 (95% CI 1.02, 7.96); and itch mean difference −4.20 on a 10‐point scale (95% CI −3.69, −4.71). Meta‐analysis was limited due to extreme statistical heterogeneity. For some secondary outcomes, meta‐analyses showed benefits for SIT, for example investigator‐rated improvement in eczema severity RR 1.48 (95% CI 1.16, 1.88; six trials, 262 participants). We found no evidence of adverse effects. The overall quality of evidence was low. Conclusion We found no consistent evidence that SIT is effective for treating AE, but due to the low quality of evidence further research is needed to establish whether SIT has a role in AE treatment

A Recombinant Fragment of Human Surfactant Protein D Suppresses Basophil Activation, Th2 and B Cell Responses in Grass Pollen-induced Allergic Inflammation

Rationale: rfhSP-D has been shown to suppress house dust mite and Aspergillus 74 fumigatus-induced allergic inflammation in murine models. 75 Objectives: We sought to elucidate the effect of rfhSP-D on FcεRI and CD23- 76 mediated grass pollen induced allergic inflammatory responses. 77 Methods: rfhSP-D, containing homotrimeric neck and lectin domains, was 78 expressed in Escherichia coli BL21 (λDE3) pLysS. PBMCs and sera were obtained 79 from grass pollen allergic individuals (n=27). The effect of rfhSP-D on basophil 80 activation and histamine release was measured by flow cytometry. IgE-facilitated 81 allergen binding and presentation was assessed by flow cytometry. Th2 cytokines 82 were measured in cell culture supernatants. The effect of rfhSP-D on IgE production 83 by B cells when stimulated with CD40L, IL-4 and IL-21 was also determined. 84 Results: rfhSP-D bound to Phleum pratense in a dose- and calcium-dependent 85 manner. Allergen-induced basophil responsiveness and histamine release was 86 inhibited in the presence of rfhSP-D, as measured by CD63, CD203c 87 (P=0.0086,P=0.04205), and intracellular-labelled DAO (P=0.0003,P=0.0148). The 88 binding of allergen-IgE complexes to B cells was reduced by 51%(P=0.002) in the 89 presence of rfhSP-D. This decrease was concomitant with reduction in CD23 90 expression on B cells (P<0.001). rfhSP-D suppressed allergen-driven CD27- 91 CD4+CRTH2+ T cell proliferation (P<0.01), IL-4 and IL-5 levels (all, P<0.01). 92 Moreover, rfhSP-D inhibited CD40L/IL-4 and IL-21-mediated IgE production(77.12%; 93 P=0.02) by B cells. 94 Conclusion: For the first time, we show that rfhSP-D inhibited allergen-induced 95 basophil responses at a single cell, level and suppressed CD23-mediated facilitated 5 allergen presentation and Th2 cytokine production. 96 In addition, rfhSP-D inhibited IgE 97 synthesis by B cells, which is also a novel observation.This research was funded by Royal Brompton Hospital charity research funds