Targeting dendritic cells in allergen immunotherapy

Allergen immunotherapy is a well-established strategy for treating allergic diseases with the goal of inducing allergen-specific tolerance. Identified mechanisms contributing to the therapeutic effect of immunotherapy include a shift of T helper 2 (Th2)-type immune responses to a modified Th2 immune response, a change of the balance of IgE-producing B cells to the production of IgG subtypes, in addition to increased IL-10 and TGF-beta secretion and activation of the suppressive functions of regulatory T-cells. Dendritic cells (DCs), which as outposts of the immune system are capable of T-cell priming through efficient allergen uptake by IgE receptors expressed on their cell surface. Most of the hypotheses concerning the function of DCs as facilitators of allergen-specific tolerance in allergen immunotherapy remain speculative. Therefore, studies must focus on the functional changes of DCs under immunotherapy to close the gap of knowledge about their exact role. These experimental data should help confirm the hypothesis of DCs as efficient silencers and potential target cells and take advantage of the bivalent character and tolerogenic properties of DCs.     

The allergen specific B-cell response during immunotherapy

The paper examines the allergen specific B-cell response in peripheral blood from patients undergoing immunotherapy with house dust mite extract. The 12 patients were part of a double blind placebo controlled study, and they were treated with either Dermatophagoides pteronyssinus (n = 4), Dermatophagoides farinae extract (n = 3) (Alutard SQ, ALK, Denmark) or placebo (n = 5). Blood was taken every fortnight on day seven after hyposensitization and tested for IgM, IgG, IgA and IgE antibody secreting cells (AbSC) to D. pteronyssinus and D. farinae allergens and for the total number of immunoglobulin secreting cells (IgSC). The data showed a maximum of approximately 120 Der f I+II specific AbSC/10(6) mononuclear cells (MNC). A comparison of specific AbSC to the major allergens of the two house dust mites demonstrated that there was no measurable species specificity in the B-cell response that could be correlated to immunotherapy with either of the two extracts. The specific IgM, IgG, and IgA response to Der f I+II was examined in the placebo (39 measurements) and the actively treated (56 measurements) groups, and the results demonstrated a significant rise in specific IgM and IgA AbSC following immunotherapy. The number of specific IgG AbSC did not change. There was a mean of less than one specific IgE AbSC/10(6) MNC, and no detectable change following the treatment. It is speculated that immunotherapy to inhalant allergens causes the induction of specific IgA AbSC. It would then be these partly differentiated plasma cells that are detected on their way to the bronchial or gut mucosa to exert their protective function mediated by allergen specific secretory IgA.     

Effect of allergen immunotherapy on nasal responses in guinea-pigs with allergic rhinitis

Methods We have investigated the effects of allergen immunotherapy on the nasal responses in the guinea-pigs with allergic rhinitis. Thirty-three male Hartley guinea-pigs with allergic rhinitis were divided into three groups; those receiving intradermal injection of saline (Group 1) or 0.1% ovalbumin (Group 2) 6 days after the last intranasal sensitization, and those injected with 0.1% ovalbumin intradermally once daily for 6 consecutive days from the next day after the last intranasal sensitization (Group 3). Results The dye leakage and histamine content into the nasal lavage significantly decreased at 30min after antigen challenge in Group 3, compared with Group 1 or 2. We also observed the change of mast cell numbers in superficial nasal mucosa, lamina propria and injected dorsal skin. The number of mast cells in superficial nasal mucosa significantly decreased in Group 3 compared with Group 1 or 2, but not those in nasal lamina propria or dorsal skin. Conclusions These results suggest that the improvements of nasal responses such as dye leakage and histamine content may be caused by the decrease of mast cell numbers in the superficial mucosal layer after the specific immunotherapy. which may be developing tolerance and one of the mechanisms underlying the beneficial effect of immunotherapy.     

Grass allergen tablet immunotherapy relieves individual seasonal eye and nasal symptoms, including nasal blockage

BACKGROUND: Symptoms of allergic rhinitis have a considerable impact on the quality of life of the sufferer. Sneezing, runny nose, blocked nose and headache are some of the most common symptoms of allergic rhinitis, which affects work, home and social life for many patients. Sublingual immunotherapy has shown to induce a protective immune response and provide sustained symptom prevention for allergic patients. AIMS OF THE TRIAL: The overall aims were to investigate the efficacy and safety of a sublingual grass allergen tablet (Grazax) 75 000 SQ-T; ALK-Abelló A/S, Denmark). Reported here are the effects of Grazax on individual eye and nasal symptoms. METHODS: The trial was a double-blind placebo-controlled trial including 634 participants with significant rhinoconjunctivitis because of grass pollen. Participants were randomized 1 : 1 to Grazax (a fast dissolving, once daily immunotherapy tablet for home administration) or placebo and received treatment for at least 16 weeks prior to and continuing during the grass pollen season of 2005. Four nasal symptoms and two eye symptoms were scored on a scale from 0 (no symptoms) to 3 (severe symptoms) every day during the entire grass pollen season. Nasal symptoms included runny nose, blocked nose, sneezing and itchy nose; eye symptoms included gritty feeling/red/itchy eyes and watery eyes. RESULTS: Consistent and highly significant reductions in individual eye and nasal symptoms (from 22 to 44%) were observed following treatment with Grazax as compared with placebo (P < 0.0001). CONCLUSIONS: Grazax has effects on multiple allergic symptoms, including nasal blockage, and is an effective treatment of rhinoconjunctivitis, thereby reducing the need for topical anti-allergic drugs.     

Metachromatic cells in nasal mucosa after allergen challenge

Metachromatic cells in the nasal mucosa were studied in relation to symptoms in 16 schoolchildren and 11 adults with hay fever who were challenged with pollen outside the pollen season, using either a gentle scraping-cytocentrifugation method for collection of mucosal specimens or biopsies. There was a temporary redistribution of metachromatic cells towards the mucosal surface appearing 5-24 h after challenge, with a correlation between the quantity of metachromatic cells and symptom scores. Thus, a single exposure to high doses of allergen may contribute to priming in susceptible individuals.     

Changes in bronchial responsiveness following nasal provocation with allergen.

The relationship between upper airway inflammation and asthma is controversial. In the current study, we sought to investigate the relationship between allergic rhinitis and lower airway dysfunction by performing double-blind, randomized nasal challenges with allergen or placebo. Subjects were selected for a prior history of asthma exacerbations after the onset of seasonal allergic rhinitis symptoms. After the induction of a marked nasal-allergic reaction (with a technique of nasal provocation that limited allergen delivery to the nose), there were no changes in FEV1, specific conductance, or lung volumes either 30 minutes or 4 1/2 hours after nasal allergen challenge, nor any changes in peak flow rates followed hourly until the next day. However, nasal provocation with allergen resulted in a relative increase in bronchial responsiveness to methacholine compared with that to placebo (p = 0.011 at 30 minutes and p = 0.0009 at 4 1/2 hours after challenge). Our study suggests that, although a nasal-allergic response does not induce airflow limitation of the lower airways, it can alter bronchial responsiveness.     

Antigen presenting cells in the nasal mucosa of patients with allergic rhinitis during allergen provocation

Background The role of antigen presenting cells (APC) in allergic rhinitis is underexposed. Allergen presentation to T lymphocytes is probably an important aspect of the pathophysiological mechanism of allergic rhinitis. Objectives The aim of the study was to investigate the presence and dynamics of APC with special emphasis on Langcrhans cells (LC) in the nasal mucosa of patients with an isolated grass pollen allergy during an out-of-season 2-week allergen exposure, mimicking the natural grass pollen season. Methods Seventeen patients with isolated grass pollen allergy and four control subjects were challenged daily with allergen during a 2-week period in the winter. Biopsy specimens were obtained once before, six times during and once after the provocation period. Biopsy sections were stained with monoclonal antibodies: OKT6 (CDla-Langerhans cells). Ki-M6 (CD68 macrophages), L25 (dendritic cells), anti-IgE, HLA-DR and HLA-DQ (Major Histoeompatibihty Complex Class II - antigen presenting eells), as well as staining with acid phosphatase. Results APC with different characteristics are present in the epithelium and lamina propria of the nasal mucosa. The number of LC increased significantly in epithelium and lamina propria. IgE⁺-LC were present in the nasal mucosa and increase during provocation, HLA-DR⁺ cells with dendritic and lymphocytic morphology and HLA-DQ⁺ cells were found. The number of these cells increased during provocation in epithelium and lamina propria. The number of HLA-DR⁺ epithelial cells did not change. A significant increase in the number of Ki-M6⁺ cells (macrophages) was found in the lamina propria. However, Ki-M6⁺ cells increased to the same extent in the lamina propria in the control group. Conclusion APC are influenced by allergen provocation. This study supports the hypothesis that (IgE⁺) LC are involved in allergic rhinitis. The role macrophages play remains doubtful.     

Fatalities following allergen immunotherapy

Allergen immunotherapy has been in use for nearly 100 yr and has become an important method of reducing allergic symptoms in select patients with allergic rhinitis, asthma, and insect venom hypersensitivity. Unfortunately, immunotherapy has been associated with anaphylaxis and death. Although the relative risk of severe reactions to immunotherapy is low, the number of such reactions has increased since the introduction of standardized and more potent extracts. There are a number of risk factors associated with such severe anaphylactic reactions. Such risk factors include errors in dosage, failure to reduce the dosage after a longer than scheduled interval, administration of the wrong extract, inadvertent intravenous administration, failure to postpone injection because of infection or asthma exacerbation, failure to observe patients for appropriate length of time, failure to adhere to guidelines for established contraindications, concurrent use of beta-adrenergic blocking agents, uses of mixtures of allergens, immunotherapy during the active allergy season, and types of allergens. In this review, we focus on these and other risk factors in attempts to reduce the risk of anaphylaxis following allergen immunotherapy.     

Local reactions during allergen immunotherapy do not require dose adjustment

BACKGROUND: The recent World Health Organization position paper on allergen immunotherapy states that local reactions to immunotherapy are not predictive of subsequent systemic reactions. Nevertheless, in clinical practice dose adjustment after local reactions continues to be recommended, presumably in an effort to prevent future systemic reactions. OBJECTIVE: We sought to determine whether dose adjustment versus no adjustment for local reactions during allergen immunotherapy influences the occurrence of subsequent systemic reactions. METHODS: In a single-site allergy clinic before October 1, 1997, local reactions after allergen vaccine injection resulted in adjustment of the subsequent dose. After October 1, 1997, no dose adjustments were made for immediate and late local reactions. For the same 9-month period before and after the change in local reaction dose-adjustment policy, systemic reaction rates were compared retrospectively. For individuals experiencing a systemic reaction, local reaction rates and local reactions immediately preceding a systemic reaction were also compared before and after the policy change. RESULTS: Comparing the 9-month period (October 1996-June 1997) preceding the policy change and the 9 months (October 1997-June 1998) after the change in policy, the systemic reaction rates (0.80% and 1.01%, respectively) were not statistically different (P =.24). Among those experiencing a systemic reaction, the rate of local reactions was unchanged (7.3% and 4.7%, respectively; P =.07), and the rate of local reactions immediately preceding a systemic reaction did not increase (18.8% and 10.5%, respectively; P =.37). The sensitivity of a local reaction predicting a systemic reaction at the next immunotherapy dose was 15%. CONCLUSIONS: A local reaction is a very insensitive predictor for a subsequent systemic reaction at the next allergen vaccine dose. Dose adjustment for most local reactions is unnecessary and may delay therapy, increase costs, and put the patient at increased risk of dose administration errors.     

Effects of combination treatment with tezepelumab and allergen immunotherapy on nasal responses to allergen: A randomized controlled trial

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Mechanisms of subcutaneous allergen immunotherapy

Allergen-specific immunotherapy (SIT) is the only curative approach in the?treatment of allergic diseases defined up-to-date. Peripheral T-cell tolerance to allergens, the goal of successful allergen-SIT, is the primary mechanism in healthy immune responses to allergens. By repeated administration of increased doses of the causative allergen, allergen-SIT induces a state of immune tolerance to allergens through the constitution of T regulatory (Treg) cells, including allergen-specific interleukin (IL)-10-secreting Treg type 1 cells and CD4(+)CD25(+)Treg cells; induction of suppressive cytokines, such as IL-10 and transforming growth factor β; suppression of allergen-specific IgE and induction of IgG4 and IgA; and suppression of mast cells, basophils, eosinophils, and inflammatory dendritic cells. This review summarizes the current knowledge on the mechanisms of allergen-SIT with emphasis on the roles of Treg cells in allergen-SIT.