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Title: Nasal allergen provocation : validation of clinical and immunologic markers and response to grass pollen immunotherapy
Author: Scadding, Guy
ISNI:       0000 0004 5917 6561
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Background: Allergen-specific immunotherapy is an effective treatment for seasonal allergic rhinitis. Clinical trials may be confounded by variable allergen exposure. Nasal allergen provocation might provide a useful surrogate to assess the efficacy of immunotherapy and identify biomarkers of response. Objective: Nasal allergen provocation was used to assess the efficacy of allergen immunotherapy and identify local and systemic immune biomarkers. Methods: Dose and time course responses to grass-pollen nasal provocations were studied in 20 allergic individuals. Different matrices were compared for absorption and isolation of nasal mucosal fluid for immunoassay of inflammatory mediators. Optimised techniques were then applied to cat-allergen nasal provocation in 18 allergic individuals, along with assessment of in vitro basophil allergen-induced activation. Finally, in a cross-sectional study, responses to grass-pollen provocation were compared in 14 untreated grass-pollen allergics, 18 immunotherapy-treated patients, and 14 non-atopic controls. Results: Nasal responses to allergen were dose-dependent. Symptoms peaked at 5 minutes post challenge; overall, there was no distinct late-phase clinical response. Nasal fluid tryptase peaked at 5 minutes; IL-4, -5, -9, -13 and eotaxin peaked at 8 hours. Basophil allergen-induced activation in vitro was enhanced at 6 hours compared to pre-challenge. Grass-pollen immunotherapy-treated patients had lower symptom scores (45% lower, p=0.04) and higher peak nasal inspiratory flow, PNIF (54% higher, p=0.02) after challenge than untreated-allergics. They had reduced early (27% lower, p=0.0007) and late (51% lower, p < 0.0001) skin responses, and lower retrospective seasonal symptom scores (60% lower, p < 0.0001). Nasal challenge response correlated with seasonal symptoms (symptoms: r=0.52, p < 0.003; PNIF: r=-0.57, p < 0.001). Immunotherapy-treated patients had reduced nasal fluid IL-4, IL-9 and eotaxin (p < 0.05), and trends for reduced IL-13 and tryptase levels (p=0.07). Conclusions: Nasal allergen challenge is sensitive in the detection of clinical and biological effects of allergen immunotherapy and may be a useful surrogate marker of treatment efficacy in future studies.
Supervisor: Durham, Stephen Sponsor: Wellcome Trust
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available