Effective Allergen Immunotherapy Research Articles

Vitamin D Role in Childhood Mite Allergy and Allergen Immunotherapy (AIT).

The post hoc analysis presented here aimed to address the influence of endogenous vitamin D in the immunological mechanism underlying effective mite allergoid immunotherapy (AIT). Previously, we have shown that in allergic children, after 12 months of this immunoactive treatment, functionally potentiated memory regulatory T cells are identified. Indeed, AIT is the only known treatment that is able to reshape the detrimental immune response against the allergen into a non-noxious one. Besides, VD is widely considered an immunoregulatory molecule that is endogenously produced and exogenously provided by foods and supplements that might interact with the AIT mechanism, thus affecting its outcome. Therefore, a post hoc analysis of the clinical and immunological data from three different cohorts of allergic patients was performed. One cohort (N = 70) was on a standard symptom-controlling pharmacological treatment, while the other two (N = 60 and N = 35) were treated with AIT for 12 months. In the first cohort, a lower mean endogenous VD level (<22 ng/mL) was observed along with worse symptoms and a greater use of medications. Remarkably, the comparison between two sub-cohorts of patients with a serum VD level above (N = 32) or below (N = 28) a cut-off value set at the mean value (27 ng/mL) revealed that optimal improvement of all clinical and immune parameters was achieved (as expected from effective AIT), irrespective of the VD level. Notably, the third analysis, carried out on one cohort of AIT patients that were also concomitantly taking VD3 as a food supplement (N = 19), was distinguished by an uppermost overall treatment outcome (the amelioration of symptoms, the lowest medication requirements, and a reduction in the total and allergen-specific IgE levels), as well as an increase in the allergen-specific tolerogenic memory T regulatory cells. These findings suggest that the endogenous VD level affects the allergy severity and allergen immunotherapy effectiveness. In addition, VD3 might be investigated as an add-on supplement to obtain the best out of immunotherapy in VD-deficient/-insufficient allergic patients. The immunogenic, but low-allergenic, mite allergoid used as the bioactive agent might have contributed to minimizing the allergic response and highlighting the immunological effects described here.

Allergen-specific immunotherapy andevidence: A European regulatoryperspective.

Allergen immunotherapy (AIT) has been performed for 112 years. In this article we summarize regulatory standards and challenges based on scientific evidence on AIT. Most crucial and timely aspects concerning AIT are addressed from the regulatory perspective of the authors as employees of a national competent authority in Europe: (1) product specificity; (2) clinical efficacy; (3) treatment for adults and children (needs for extrapolation); (4) allergen exposure chambers; (5) biomarkers; (6) standardization; (7) real-world evidence; (8) independent official batch release (benefit and challenges); (9) harmonization on the EU level. The Paul-Ehrlich-Institut (PEI), the Federal Institute for Vaccines and Biomedicines, in Langen near Frankfurt/Main in Germany, examines and evaluates the benefits and risks of AIT products within the course of clinical development, marketing authorization, and subsequently throughout their entire life cycle to ensure high-quality, safe, and effective AIT products.

Immunopathogenesis and immunotherapy of Culicoides hypersensitivity in horses: an update

Culicoides hypersensitivity (CH) is a strongly pruritic dermatitis of horses, characterised histologically by mixed perivascular to diffuse cellular infiltrates of mononuclear cells and eosinophils, and caused by helper T cell (Th)2, immunoglobulin (Ig)E‐mediated reactions to antigens present in the saliva of biting Culicoides midges. As treatment of CH is still not satisfactory, a better knowledge of the pathogenesis of CH is needed for the development of new therapeutic modalities. Accordingly, availability of pure Culicoides allergens instead of crude whole body extracts is essential for the improvement of in vitro diagnosis of CH and development of a more effective allergen immunotherapy (AIT). Beside the Th2 cytokines interleukin (IL)‐4 and IL‐13, recent studies have shown the involvement of thymic stromal lymphopoietin, IL‐5 and IL‐31 in the pathogenesis of CH. The importance of IL‐5 and IL‐31 has been confirmed through targeting these cytokines by active immunisation of CH patients, resulting in a significant decrease of CH lesion scores. Thirty Culicoides salivary allergens have been described over the last 10 years and produced as pure recombinant (r‐) proteins. Use of a protein microarray has allowed the identification of the most relevant Culicoides r‐allergens for CH in central and northern Europe. An immunisation protocol has been developed for preventive AIT against CH. Small amounts of r‐Culicoides allergens injected into the submandibular lymph nodes with Alum/MPLA as adjuvants seem to induce a suitable immune response for both preventive and therapeutic AIT. The next years will reveal whether these recent advancements will translate into an improved diagnosis, treatment and prevention of CH.

Allergen-specific immunotherapy induces the suppressive secretoglobin 1A1 in cells of the lower airways.

While several systemic immunomodulatory effects of allergen-specific immunotherapy (AIT) have been discovered, local anti-inflammatory mechanisms in the respiratory tract are largely unknown. We sought to elucidate local and epithelial mechanisms underlying allergen-specific immunotherapy in a genome-wide approach. We induced sputum in hay fever patients and healthy controls during the pollen peak season and stratified patients by effective allergen immunotherapy or as untreated. Sputum was directly processed after induction and subjected to whole transcriptome RNA microarray analysis. Nasal secretions were analyzed for Secretoglobin1A1 (SCGB1A1) and IL-24 protein levels in an additional validation cohort at three defined time points during the 3-year course of AIT. Subsequently, RNA was extracted and subjected to an array-based whole transcriptome analysis. Allergen-specific immunotherapy inhibited pro-inflammatory CXCL8, IL24, and CCL26mRNA expression, while SCGB1A1, IL7, CCL5, CCL23, and WNT5BmRNAs were induced independently of the asthma status and allergen season. In our validation cohort, local increase of SCGB1A1 occurred concomitantly with the reduction of local IL-24 in upper airways during the course of AIT. Additionally, SCGB1A1 was identified as a suppressor of epithelial gene expression. Allergen-specific immunotherapy induces a yet unknown local gene expression footprint in the lower airways that on one hand appears to be a result of multiple regulatory pathways and on the other hand reveals SCGB1A1 as novel anti-inflammatory mediator of long-term allergen-specific therapeutic intervention in the local environment.

Leukotriene A4 Hydrolase Is a Candidate Predictive Biomarker for Successful Allergen Immunotherapy.

BackgroundAllergic rhinitis is a common disorder that affects 10% to 40% of the population worldwide. Allergen immunotherapy (AIT) represents the only therapy that has the potential to resolve clinical symptoms of allergic rhinitis. However, up to 30% of patients do not respond to AIT. Biomarkers predicting the clinical efficacy of AIT as early as possible would significantly improve the patient selection and reduce unnecessary societal costs. Methods Artemisia pollen allergic patients who received at least 1-year AIT were enrolled. Clinical responses before and after 1-year AIT were evaluated to determine AIT responders. Artemisia specific IgE and IgG4 levels were measured by using ImmunoCAP and enzyme-linked immunosorbent assay (ELISA) separately. Stepwise regression analysis was performed to identify which rhinitis-relevant parameters explained the most variability in AIT results. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics was applied to identify the potential candidate biomarkers in the sera of responders and non-responders collected before and after 1-year therapy. The diagnostic performance of the potential biomarkers was then assessed using enzyme-linked immunosorbent assay (ELISA) in 30 responders and 15 non-responders.Results Artemisia specific IgE and IgG4 levels were elevated only in the responders. Regression analysis of allergic rhinitis-relevant parameters provided a robust model that included two most significant variables (sneeze and nasal congestion). Thirteen candidate biomarkers were identified for predicting AIT outcomes. Based on their association with allergy and protein fold change (more than 1.1 or less than 0.9), four proteins were identified to be potential biomarkers for predicting effective AIT. However, further ELISA revealed that only leukotriene A4 hydrolase (LTA4H) was consistent with the proteomics data. The LTA4H level in responders increased significantly (P < 0.001) after 1-year therapy, while that of non-responders remained unchanged. Assessment of LTA4H generated area under curve (AUC) value of 0.844 (95% confidence interval: 0.727 to 0.962; P < 0.05) in distinguishing responders from the non-responders, suggesting that serum LTA4H might be a potential biomarker for predicting the efficiency of AIT.ConclusionSerum LTA4H may be a potential biomarker for early prediction of an effective AIT.

Early Intervention Improves Clinical Responses to House Dust Mite Immunotherapy in Allergic Rhinitis Patients

Background: Allergen immunotherapy (AIT) is the unique causal treatment for respiratory allergy. As AIT is expensive and of long duration, the availability of a marker predicting AIT responders is of crucial relevance. Objective: To investigate clinical parameters correlated with effective AIT in allergic rhinitis (AR) patients. Methods: This is a prospective, nonrandomized open study in which a total of 284 AR patients who had received house dust mite (HDM) subcutaneous AIT were enrolled from January 2011 to December 2015, and then followed up for 3 consecutive years. Demographic data, clinical history, laboratory tests (specific and total IgE levels), symptoms score, concomitant medication, and adverse reactions during AIT were collected. An AIT responder patient was defined when a visual analog score (assessing global symptoms) had decreased by >30% compared to baseline and concomitant medication was equal to or less than before AIT. Results: Thirty-three patients dropped out, so 251 patients were analyzed; 175 (69.7%) patients were responders. This group had a higher baseline symptom score than the AIT nonresponder group (7.5 vs. 6.9). A significant negative correlation was found between AR symptom duration and the clinical response to AIT. Local reactions (LRs) during AIT had a positive correlation. Other variables such as a family history of atopy, combined asthma history, and the levels of specific and total IgE had no correlations with effective AIT. Conclusion: Early intervention with AIT helps to improve the efficacy of AR treatment. LRs might predict successful AIT. Highly symptomatic AR patients may develop increased clinical responses to AIT.

Applications and mechanisms of immunotherapy in allergic rhinitis and asthma.

Clinical and immunologic tolerance are hallmarks of successful allergen immunotherapy (AIT). Clinical benefits such as reduced symptoms, pharmacotherapy intake and improvement of quality of life persist following cessation of treatment. Successful AIT is associated with suppression of allergic inflammatory cells such as mast cells, eosinophils and basophils in target organs. Furthermore, AIT down-regulates type 2 innate lymphoid cells and allergen-specific type 2 T-helper (Th2) cells. The immunologic tolerant state following AIT is associated with the induction of distinct phenotypes of regulatory T-cells (T-regs) including interleukin (IL)-10-, IL-35- and transforming growth factor (TGF)-β- producing T-regs and FoxP3+ T-regs. B-cell responses, including the induction of IL-10+ regulatory B-cells (B-regs) and the production of IgG4-associated blocking antibodies are also induced following successful AIT. These events are associated with the suppression of antigen-specific Th2 responses and delayed immune deviation in favour of Th1 type responses. Insight into the mechanisms of AIT has allowed identification of novel biomarkers with potential to predict the clinical response to AIT and also novel therapeutic strategies for more effective and safer AIT.

Present and future of allergen immunotherapy for allergic diseases

Current pharmacological therapies for allergic diseases can improve clinical symptoms but cannot change their long-term clinical course. There is an unmet need for a curative treatment for allergic diseases. Allergen immunotherapy (AIT) is the practice of administering increasing doses of clinically relevant allergens to an allergic subject to reduce the clinical symptoms associated with subsequent exposure to the allergen. AIT is clinically effective for allergic asthma, allergic rhinitis, venom-induced anaphylaxis, and atopic dermatitis. AIT can change the natural course of allergic diseases and induce allergen-specific immune tolerance. In current clinical practice, AIT is delivered either subcutaneously or sublingually. Both subcutaneous and sublingual AIT have long-term therapeutic efficacy after of 3-5 years of treatment. The development of safer and more effective AIT strategies is needed. Conclusion: AIT is a disease-modifying therapy for allergic diseases. Future development of AIT should be directed toward achieving long-term clinical remission in patients with allergic diseases by the safe and effective induction of immune tolerance.

Serum-Specific IgE and Allergen Immunotherapy in Allergic Children

Allergen immunotherapy (AIT) is indicated in IgE-mediated respiratory allergy. Recently, it has been reported that serum-specific IgE (sIgE) levels >10 kU/l may predict AIT efficacy in adults with allergic rhinitis. The aim of the present preliminary study was to investigate whether this cut-off could also be associated with perception of effective AIT in children with allergic asthma and/or rhinitis due to house dust mites (HDM). A total of 31 allergic children (17 males; mean age of 12.5 years) with levels of serum sIgE to HDM >10 kU/l were evaluated. Eight allergic children (five males; mean age of 13.4 years) with levels of serum sIgE to HDM <10 kU/l were considered as control. All patients were treated with sublingual immunotherapy for 3 years with HDM allergen extract. Children's perception of AIT efficacy was assessed by visual analog scale (VAS), considering both symptom severity and drug use. Responder patients were defined with >6 VAS. Severity of nasal symptoms was assessed by nasal VAS, and asthma control was evaluated by asthma control test; both were considered before and after AIT. All children (but one) with sIgE >10 kU/l perceived AIT efficacy, whereas only one child with sIgE <10 kU/l perceived AIT benefit (p < 0.001). There was a strong relationship between perception of AIT efficacy by VAS and serum sIgE levels (r = 0.615; p < 0.001). Also, nasal VAS and asthma control tests significantly improved only in children with sIgE >10 kU/l (p < 0.001 for both). Allergen-sIgE assessment before AIT prescription might represent a useful tool to individuate potential responders.

New directions in immunotherapy.

Allergen immunotherapy (AIT) is effective in reducing the clinical symptoms associated with allergic rhinitis, asthma and venom-induced anaphylaxis. Subcutaneous (SCIT) and sublingual immunotherapy (SLIT) with unmodified allergen extracts are the most widely prescribed AIT regimens. The efficacy of these 2 routes appears comparable, but the safety profile with SLIT is more favorable allowing for home administration and requiring less patient time. However, both require that the treatment is taken regularly over several years, e.g., monthly in a supervised medical setting with SCIT and daily at home with SLIT. Despite the difference in treatment settings, poor adherence has been reported with both routes. Emerging evidence suggests that AIT may be effective in other allergic conditions such as atopic dermatitis, venom sting-induced large local reactions, and food allergy. Research with oral immunotherapy (OIT) for food allergies suggest that many patients can be desensitized during treatment, but questions remain about whether this can produce long term tolerance. Further studies are needed to identify appropriate patients and treatment regimens with these conditions. Efforts to develop safer and more effective AIT for inhalant allergies have led to investigations with modified allergens and alternate routes. Intralymphatic (ILIT) has been shown to produce long-lasting clinical benefits after three injections comparable to a 3-year course of SCIT. Epicutaneous (EPIT) has demonstrated promising results for food and inhalant allergies. Vaccine modifications, such as T cell epitopes or the use of viral-like particles as an adjuvant, have been shown to provide sustained clinical benefits after a relatively short course of treatment compared to the currently available AIT treatments, SLIT and SCIT. These newer approaches may increase the utilization and adherence to AIT because the multi-year treatment requirement of currently available AIT is a likely deterrent for initiating and adhering to treatment.

Immunotherapy in the Age of Anti-IgE

Recent results of allergen immunotherapy research have continued to validate efficacy and have also demonstrated a truly preventive aspect for this treatment. This review summarizes the basic principles of effective allergen immunotherapy and highlights some of the advances that have been published in the past year. These studies show that allergen immunotherapy, when done appropriately and properly, not only causes a decrease in symptoms and use of medication as well as an improved quality of life, but that the progression of disease from allergic rhinitis to asthma is substantially decreased and the development of new allergies is diminished. In addition, laboratory studies continue to demonstrate significant changes in the immune system with a shift in the immune pathway from TH2 toward a TH1 response. The impact of anti-IgE as a therapeutic agent with allergen immunotherapy is also be reviewed.