Duncan R. Wilson

Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis*

Allergic rhinitis is a common condition which, at its most severe, can significantly impair quality of life despite optimal treatment with antihistamines and topical nasal corticosteroids. Allergen injection immunotherapy significantly reduces symptoms and medication requirements in allergic rhinitis but its use is limited by the possibility of severe systemic reactions. There has therefore been considerable interest in alternative routes for delivery of allergen immunotherapy, particularly the sublingual route. The objective was to evaluate the efficacy of sublingual immunotherapy (SLIT), compared with placebo, for reductions in symptoms and medication requirements. The Cochrane Controlled Clinical Trials Register, MEDLINE (1966–2002), EMBASE (1974–2002) and Scisearch were searched, up to September 2002, using the terms (Rhin* OR hay fever) AND (immunotherap* OR desensiti*ation) AND (sublingual). All studies identified by the searches were assessed by the reviewers to identify Randomized Controlled Trials involving participants with symptoms of allergic rhinitis and proven allergen sensitivity, treated with SLIT or corresponding placebo. Data from identified studies was abstracted onto a standard extraction sheet and subsequently entered into RevMan 4.1. Analysis was performed by the method of standardized mean differences (SMD) using a random effects model. P‐values < 0.05 were considered statistically significant. Subgroup analyses were performed according to the type of allergen administered, the age of participants and the duration of treatment. Twenty‐two trials involving 979 patients, were included. There were six trials of SLIT for house dust mite allergy, five for grass pollen, five for parietaria, two for olive and one each for, ragweed, cat, tree and cupressus. Five studies enrolled exclusively children. Seventeen studies administered the allergen by sublingual drops subsequently swallowed, three by drops subsequently spat out and two by sublingual tablets. Eight studies involved treatment for less than 6 months, 10 studies for 6–12 months and four studies for greater than 12 months. All included studies were double‐blind placebo‐controlled trials of parallell group design. Concealment of treatment allocation was considered adequate in all studies and the use of identical placebo preparations was almost universal. There was significant heterogeneity, most likely due to widely differing scoring systems between studies, for most comparisons. Overall there was a significant reduction in both symptoms (SMD −0.42, 95% confidence interval −0.69 to −0.15; P = 0.002) and medication requirements [SMD −0.43 (−0.63, −0.23); P = 0.00003] following immunotherapy. Subgroup analyses failed to identify a disproportionate benefit of treatment according to the allergen administered. There was no significant reduction in symptoms and medication scores in those studies involving only children but total numbers of participants was too small to make this a reliable conclusion. Increasing duration of treatment does not clearly increase efficacy. The total dose of allergen administered may be important but insufficient data was available to analyse this factor.

Grass pollen sublingual immunotherapy for seasonal rhinoconjunctivitis: a randomized controlled trial

Background Previous studies suggest that sublingual immunotherapy (SLIT) represents a safer alternative to injection immunotherapy but equivalent efficacy is yet to be confirmed.

Grass pollen immunotherapy for hayfever is associated with increases in local nasal but not peripheral Th1 : Th2 cytokine ratios

Grass pollen immunotherapy is the only treatment for hayfever that is both effective and confers long‐term benefit. Immunotherapy may act by altering the local nasal mucosal T helper type 2 (Th2) to type 1 (Th1) cytokine balance either by down‐regulation and/or immune deviation of T‐lymphocyte responses. There is controversy as to whether these changes are detectable in peripheral blood. We therefore examined both local nasal and peripheral T‐cell responses to allergen exposure in the same subjects before and after immunotherapy. In a double‐blind trial of grass pollen immunotherapy, nasal biopsies were obtained at baseline and during the peak pollen season following 2 years of immunotherapy. Placebo‐treated patients showed a seasonal increase in CD3+ T cells (P = 0·02) and in interleukin‐5 (IL‐5) mRNA+ cells (P = 0·03) and no change in interferon‐γ (IFN‐γ ) mRNA+ cells (P = 0·2) in the nasal mucosa. In contrast, in the immunotherapy‐treated group, there were no changes in the number of CD3+ T cells (P = 0·3) and IL‐5 mRNA+ cells (P = 0·2) but a significant increase in the number of IFN‐γ mRNA+ cells (P = 0·03). Furthermore, clinical improvement in the immunotherapy‐treated group was accompanied by a seasonal increase in the ratio of IFN‐γ to IL‐5 mRNA+ cells in the nasal mucosa (P = 0·03). In contrast, there were no significant changes in peripheral T‐cell proliferative responses or cytokine production for IFN‐γ or IL‐5 in response to grass pollen either within or between the two treatment groups. We conclude that successful grass pollen immunotherapy was associated with an increase in the ratio of IFN‐γ to IL‐5 mRNA+ cells in the nasal mucosa, whereas these changes were not reflected by alterations in peripheral blood T‐cell proliferative responses or cytokine production before/after treatment.

Persistent IgE synthesis in the nasal mucosa of hay fever patients

The location of IgE synthesis has been a longstanding controversy, with previous evidence favoring either the mucosa or lymphoid tissue in the region of allergen entry. The evidence for IgE synthesis in mucosal tissues has always been circumstantial. We have developed a novel explant culture system, using ELISA and radioactive amino acid incorporation, to measure de novo IgE protein synthesis in the nasal mucosa of hay fever patients. Surprisingly, IgE synthesis continues between seasons in the explants from grass pollen‐sensitive patients and a higher proportion of this IgE compared to serum IgE is allergen specific. Persistent IgE synthesis may ensure the expression of immediate hypersensitivity in the mucosa and promote rapid amplification of the allergic response in the local lymphoid tissue on allergen provocation. Our work demonstrates definitively for the first time that the local mucosa is a site of ongoing IgE synthesis.

Grass pollen immunotherapy inhibits seasonal increases in basophils and eosinophils in the nasal epithelium

Background Symptoms of allergic rhinitis are accompanied by infiltration of the nasal mucosa with inflammatory cells, predominantly eosinophils and metachromatic cells (basophils and mast cells). Specific immunotherapy (IT) reduces mucosal eosinophilia and numbers of metachromatic cells in the epithelium. A specific marker distinguishing basophils from mast cells was recently developed.

CCR4 in human allergen-induced late responses in the skin and lung

We studied the regulation of CCR4 expression in peripheral blood and in human models of cutaneous and pulmonary allergen challenge. CCR4 expression was detectable on freshly isolated CD4+ lymphocytes and in CD4+ and CD8+ T cell lines derived from blood of atopic donors. Numbers of CCR4+ cells were up‐regulated in T cell lines expanded in the presence of IL‐4. CCR4 mRNA was absent at baseline in normal subjects in lung and skin, but present at baseline in the lung of some atopics. Baseline expression of CCR4 mRNA and protein was higher in lung vs. skin, but allergen‐induced increases in CCR4 mRNA+ cells were observed in both organs. CCR4 protein+ cells were present at higher levels after allergen challenge in atopics compared to normal subjects. CCR4 may be important in the recruitment of T lymphocytes at sites of allergic inflammation, in a non‐organ‐specific manner.