Forms Of Allergen Immunotherapy Research Articles

New insights in the optimal diagnosis and management of food allergy.

Background: In recent years, food allergy has become a rising global epidemic, more so in Western countries. Although genetics may play a role in this increase, there are many other factors that have contributed to the upsurge. Recent research has shown that introducing allergenic foods to infants at an early age can reduce the risk of developing allergies to those foods. This is a substantial departure from traditional advice, which had recommended delaying the introduction of potential allergenic foods until a child was at least 1 year old and, in some cases, until the child was much older. Objective: The purpose of the present report is to review the epidemiology, mechanisms, and new prevention strategies for food allergies, and to discuss new treatment modalities associated with immune tolerance, which include the use of biologics as well as new forms of allergen immunotherapy (AIT) such as oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT), which have particular relevance for the allergist/immunologist. Results: Innovative developments in the treatment of food allergies have emerged through improved comprehension of immune tolerance and the induction of regulatory T (Treg) cells, the understanding of T-helper type 2 (Th2) cell-driven responses and their associated proinflammatory cytokine production, epitope mapping techniques, and the utilization of drugs such as monoclonal antibodies that target interleukin (IL) 4, IL-5, and IL-13 to disrupt Th2 cell-related pathways. In addition, there have been significant advancements in new forms AIT methods, which include OIT, SLIT, and EPIT. Conclusion: The present report reviews several of the many aspects of food allergy that have been impacted by this new knowledge and which have led to new insights for the optimal diagnosis and management of food allergy, and has had important implications for the diagnosis, treatment, prevention, and management of these conditions. The improved understanding of Treg-related mechanisms of immune tolerance and Th2 cell-driven responses associated with the production of proinflammatory cytokines associated with these responses, together with epitope mapping techniques, have played a crucial role in enhancing the diagnosis and management of food allergies. By identifying these variables, the allergist/immunologist is better equipped to tailor new diagnostic approaches and develop targeted therapies to significantly impact the lives of individuals affected by food allergies.

Allergen Immunotherapy: Current and Future Trends.

Allergen immunotherapy (AIT) is the sole disease-modifying treatment for allergic rhinitis; it prevents rhinitis from progressing to asthma and lowers medication use. AIT against mites, insect venom, and certain kinds of pollen is effective. The mechanism of action of AIT is based on inducing immunological tolerance characterized by increased IL-10, TGF-β, and IgG4 levels and Treg cell counts. However, AIT requires prolonged schemes of administration and is sometimes associated with adverse reactions. Over the last decade, novel forms of AIT have been developed, focused on better allergen identification, structural modifications to preserve epitopes for B or T cells, post-traductional alteration through chemical processes, and the addition of adjuvants. These modified allergens induce clinical-immunological effects similar to those mentioned above, increasing the tolerance to other related allergens but with fewer side effects. Clinical studies have shown that molecular AIT is efficient in treating grass and birch allergies. This article reviews the possibility of a new AIT to improve the treatment of allergic illness.

Current Practices in Prescribing Auto-Injectable Epinephrine during Immunotherapy amongst Otolaryngic Allergists

Purpose: Allergen immunotherapy (AIT) while usually safe, is not without risk. Both sublingual (SLIT) and subcutaneous immunotherapy (SCIT) have the potential for systemic reactions including anaphylaxis. Materials and Methods: A short survey was distributed to fellows of the American Academy of Otolaryngic Allergy (AAOA) (n = 553) in July of 2019 to determine current prescribing practices. Results: A total of 103/553 surveys were completed, giving a response rate of 18.6%. Prescribing patterns for SCIT showed 79.6% prescribed auto-injectable epinephrine (AIE) to all patients, 11.7% prescribed only to high risk patients, while 1.9% did not prescribe AIE at all. SLIT showed similar patterns with 71.8% prescribing AIE to all, 11.7% to high risk or letting patient choose, and 6.8% did not prescribe to anyone. Just under half of the physicians responded affirmatively to giving a written anaphylaxis plan to patients on immunotherapy. 48.5% physicians reported treating in-office anaphylaxis due to SCIT or skin testing in the past year, while 6% reported anaphylaxis due to SLIT. Conclusions: A majority of otolaryngic allergists are still prescribing AIE for both SCIT and SLIT. With the recent higher costs attributed to AIE as well as drug shortages, some physicians are risk-stratifying patients. While SCIT has a higher risk for treatment related systemic reactions, anaphylaxis does occur with SLIT, thus making it imperative to counsel patients on a clear anaphylaxis protocol in all forms of AIT.

Cost-effectiveness of grass pollen allergen immunotherapy in adults.

Major scientific societies, such as the EAACI or the AAAAI, do not express any suggestion on which form of allergen immunotherapy (AIT) is to be preferred (subcutaneous immunotherapy, SCIT, vs sublingual immunotherapy, SLIT). This choice could depend on their relative pharmacoeconomic value. To assess the cost-effectiveness of AIT for grass pollen, administered as SCIT or SLIT. We created a Markovian Model, to evaluate, in a hypothetical cohort of adult patients suffering from moderate-to-severe rhino-conjunctivitis with or without allergic asthma, the cost-effectiveness of SLIT (tablets, Grazax® and Oralair® ) or SCIT (various currently available products, plus indirect nonmedical costs, such as travel and productivity costs) in addition to pharmacological therapy, assuming a 9-year horizon to capture AIT long-term effects. The incremental cost-effectiveness ratio (ICER) was calculated assuming pharmacological therapy as the reference comparator. In the base case, SCIT was slightly more expensive, but more effective than SLIT, being the most cost-effective option (ICER for SCIT, €11418; ICER for SLIT, €15212). ICERs greater than €120000 for both SCIT and SLIT were demonstrated in a scenario assuming that low treatment persistence rates, which are common in real-life, lead to absence of long-term AIT clinical benefit. Considering indirect nonmedical costs SLIT resulted more cost-effective than SCIT (ICER for SCIT, €17318; ICER for SLIT, €15212). In daily practice, AIT for grass pollens may be a cost-effective option only in patients with low discontinuation rates. SCIT, which is less affected by this limitation than SLIT, seems the most cost-effective AIT form.

Allergy immunotherapy in reducing healthcare cost.

To evaluate the cost-effectiveness of allergen immunotherapy (AIT) in the treatment of allergic rhinitis and asthma. Individual studies and systematic reviews that included information on AIT economic outcomes as compared with symptomatic drug treatment (SDT) were evaluated. One systematic review that included 14 studies concluded that subcutaneous and sublingual immunotherapy may be cost-effective compared with SDT from around 6 years. Another systematic review of 24 studies comparing economic outcomes of subcutaneous allergy immunotherapy and/or sublingual allergy immunotherapy with SDT found compelling evidence for cost-savings with both forms of AIT over SDT. There was no strong evidence indicating superior cost-efficacy of subcutaneous allergy immunotherapy or sublingual allergy immunotherapy over SDT in either of these systematic reviews. Individual studies have demonstrated AIT cost-savings as high as 80% compared with SDT. Significant cost-savings were reported as early as 3 months after AIT initiation. In some studies, cost-efficacy time-point was not established until after treatment discontinuation - presumably due to time required for the clinical benefits to outweigh the AIT treatment costs. Although some economic modeling studies included the costs of 'asthma prevented', the collective literature of AIT economics provides very little to no information about the cost benefits of the preventive aspect of AIT. Overall, individual studies and systematic reviews provide strong evidence for the cost-effectiveness of AIT over SDT. The magnitude of cost-efficacy is likely underestimated in that few studies consider the cost-savings due to AIT's long-term benefits or preventive effect.

Clinical contraindications to allergen immunotherapy: an EAACI position paper.

Clinical indications for allergen immunotherapy (AIT) in respiratory and Hymenoptera venom allergy are well established; however, clinical contraindications to AIT are not always well documented. There are some discrepancies when classifying clinical contraindications for different forms of AIT as 'absolute' or 'relative'. EAACI Task Force on 'Contraindications to AIT' was created to evaluate and review current literature on clinical contraindications, and to update recommendations for both sublingual and subcutaneous AIT for respiratory and venom immunotherapy. An extensive review of the literature was performed on the use of AIT in asthma, autoimmune disorders, malignant neoplasias, cardiovascular diseases, acquired immunodeficiencies and other chronic diseases (including mental disorders), in patients treated with β-blockers, ACE inhibitors or monoamine oxidase inhibitors, in children under 5years of age, during pregnancy and in patients with poor compliance. Each topic was addressed by the following three questions: (1) Are there any negative effects of AIT on this concomitant condition/disease? (2) Are more frequent or more severe AIT-related side-effects expected? and (3) Is AIT expected to be less efficacious? The evidence, for the evaluation of these clinical conditions as contraindications, was limited, and most of the conclusions were based on case reports. Based on an extended literature research, recommendations for each medical condition assessed are provided. The final decision on the administration of AIT should be based on individual evaluation of any medical condition and a risk/benefit assessment for each patient.

Clinical considerations in the use of sublingual immunotherapy for allergic rhinitis.

Allergen immunotherapy (AIT) has been in practice for more than 100 years. However, research in novel routes and delivery methods of immunotherapy to treat allergic rhinitis (AR) and conjunctivitis has only recently occurred in the United States, where the predominant form of AIT provided is largely via a subcutaneous immunotherapy (SCIT) route. AIT may prevent new sensitizations, improve symptoms, decrease medication usage, and prevent allergic asthma. Although AIT is the only potentially curative treatment for AR, access and adherence continue to be problematic. Only a fraction of eligible patients actually undergo treatment, and attrition rates are high. An obvious limitation of SCIT includes the requirement of regular injections to be provided in the physician's office due to the potential for anaphylaxis. Sublingual immunotherapy (SLIT) for home administration has been investigated as a potential alternative to address this limitation of SCIT. A literature review was performed including the current findings from randomized clinical trials and meta-analyses with a discussion of the most recent evidence for the efficacy, safety, and dosing of allergen SLIT. The current data suggest that SLIT is effective for treatment of seasonal allergies, can potentially prevent asthma, and has a favorable safety profile. Head-to-head studies, however, are few, and comparative effectiveness still remains to be answered. Optimal treatment algorithms for SLIT have not yet been established, with wide variation in dosage selection and schedules. Similarly to SCIT, only a few allergens such as ragweed and grass pollen have been found to be effective in large clinical trials. Recent data indicate that SLIT is an effective treatment modality for seasonal AR, improve quality of life, and can potentially prevent asthma but head-to head studies comparing SLIT to SCIT are needed.

Reducing and managing systemic reactions to immunotherapy

To identify and discuss recent articles pertaining to the reduction and management of systemic reactions to allergen immunotherapy (AIT). Fatal reactions to AIT may be declining. Screening asthma patients before AIT and dose adjustment during pollen season may contribute to lower systemic reaction rates. Cluster build-up protocols with multiallergen subcutaneous immunotherapy (SCIT) may lead to an increased risk of systemic reactions compared with cluster build-up protocols with single-allergen SCIT. Sublingual immunotherapy (SLIT) studies confirm the low rates of systemic reactions using this method, including for rapid build-up schedules. Studies of newer forms of AIT (intralymphatic, epicutaneous, recombinant allergens) have too few patients to form confident systemic reaction risk estimates. High-grade delayed systemic reactions to AIT may be less frequent than previously reported. Recent studies increase confidence in risk estimates for systemic reactions to AIT, suggest useful strategies to predict systemic reactions to AIT, and offer strategies to prevent systemic reactions.

The influence of different application forms of allergen immunotherapy on the level of allergen specific IgG antibodies in patients with grass pollen allergy

The influence of different application forms of allergen immunotherapy on the level of allergen specific IgG antibodies in patients with grass pollen allergy

The effects of grass pollen allergoid immunotherapy on clinical and immunological parameters in children with allergic rhinitis

Allergoid immunotherapy is a new form of allergen immunotherapy allowing safe administration of high allergen doses. There is limited information on the effects of allergoid immunotherapy in children with allergic rhinitis. To investigate the immunological and clinical effects of allergoid immunotherapy in children with allergic rhinitis due to grass pollen allergy. Children with allergic rhinitis were assigned to allergoid immunotherapy (n = 27) or control (n = 26, no immunotherapy) groups. Children in the immunotherapy group received seven injections of grass pollen allergoid immunotherapy before grass pollen season and continued to receive maintenance immunotherapy for 27 months. All patients were offered a pharmacotherapy regimen to be used on demand during the pollen seasons. Clinical and laboratory parameters were compared between the immunotherapy and control groups. The rhinoconjunctivitis symptom-medication score and asthma symptom score were lower in the immunotherapy group after 1 yr of maintenance immunotherapy (p < 0.01 for both). Skin test reactivity and nasal reactivity as determined by nasal provocation testing for grass pollen were significantly decreased after 1 yr of immunotherapy (p < 0.001 for both). The seasonal increase in bronchial reactivity and nasal lavage eosinophil cationic protein levels were prevented after the first year of immunotherapy (p < 0.05 for both). The seasonal increase in immunoglobulin (Ig)E decreased (p < 0.05) and grass-specific IgG, IgG(1) and IgG(4) increased significantly already at the end of the seven-injection build-up therapy (p < 0.001, for all). Interleukin (IL)-4 levels in the culture supernatants showed a steady decline from baseline at first and second year of immunotherapy (p < 0.001) but remained unchanged in the control group. Allergoid immunotherapy is an effective method in the treatment of grass pollen-induced allergic rhinitis in children and prevents the seasonal increase in bronchial hyper-reactivity. Changes in specific IgE and IgG levels and decreased IL-4 production in peripheral blood mononuclear cell culture supernatants may account for the observed clinical effects.

Impaired secretion of interleukin-4 and interleukin-13 by allergen-specific T cells correlates with defective nuclear expression of NF-AT2 and jun B: relevance to immunotherapy.

Allergen immunotherapy (IT) is a successful treatment associated with decreased Th2 cytokine production by allergen-specific T cells. We have previously demonstrated (Faith et al., J Immunol 1997; 159:53-57) that inhibition of Th2 cytokine production in vitro correlates with impaired tyrosine kinase activity through the TCR. The transcription factor complex, nuclear factor of activated T cells (NF-AT), which regulates Th2 cytokine production is controlled by the activity of tyrosine kinases. To address whether decreased Th2 cytokine production by allergen-specific CD4+ T cells following IT is correlated with altered translocation and nuclear expression of the NF-AT family member, NF-AT2, and the activator protein 1 (AP1) component of NF-AT, jun B. T cell lines specific for insect venom phospholipase A2 (PLA) were derived from patients prior to and during conventional venom IT. Nuclear expressions of NF-AT and jun B were assessed following stimulation through the TCR. Th1 and Th2 cytokine and IL-10 production by insect venom-specific T cells were also determined. Results were compared with a well-established model system in which anergy was induced in cloned, allergen-specific Th2 cells. Impaired translocation and decreased expression of NF-AT2 and jun B were detected in PLA-specific T cell lines derived from bee venom-allergic individuals following 16 weeks treatment compared to pre-treatment. These results correlated with significantly reduced production of IL-4 and IL-13 and significantly increased production of IFN-gamma and IL-10 by PLA-specific T cells. Impaired IL-4 and IL-13 production also correlated with defective nuclear expression of NF-AT2/jun B in cloned, anergic allergen-specific Th2 cells. These results suggested that optimal production of IL-4 and IL-13 by allergen-specific T cells is dependent on the nuclear expression of NF-AT2 and jun B. Thus, specific inhibition of NF-AT2/jun B might be an option in novel and improved forms of allergen IT.

“ARIA”: Global guidelines and new forms of allergen immunotherapy

“ARIA”: Global guidelines and new forms of allergen immunotherapy

Recombinant allergens for diagnosis and therapy of allergic disease

Many of the problems associated with using natural allergenic products for allergy diagnosis and treatment can be overcome with use of genetically engineered recombinant allergens. Over the past 10 years, the most important allergens from mites, pollens, animal dander, insects, and foods have been cloned, sequenced, and expressed. In many cases the three-dimensional allergen structure has been determined and B-cell and T-cell epitopes have been mapped. These studies show that allergens have diverse biologic functions (they may be enzymes, enzyme inhibitors, lipocalins, or structural proteins) and that as a rule the allergen function is unrelated to its ability to cause IgE antibody responses. High-level expression systems have been developed to produce recombinant allergens in bacteria, yeast, or insect cells. Recombinant allergens show comparable IgE antibody binding to their natural counterparts (where available) and show excellent reactivity on skin testing and in in vitro diagnostic tests. Cocktails of recombinant allergens can be formulated with predetermined and uniform allergen levels, which could replace natural allergens and result in the development of innovative, patient-based tests for allergy diagnosis. Recombinant allergens also offer the exciting possibility of developing new forms of allergen immunotherapy, including the use of hypoallergens, allergens coupled to IgE suppressive adjuvants, and peptide-based therapies. The production of recombinant allergens as defined molecular entities makes it feasible to consider the possibility of developing prophylactic allergen vaccines. The introduction of recombinant allergens in research and in clinical trials should lead to significant improvements in allergy diagnosis and treatment. (J Allergy Clin Immunol 2000;106:409-18.)

Recombinant allergen fragments as candidate preparations for allergen immunotherapy

Background: Lately, renewed interest has arisen in the new forms of allergen immunotherapy because they may offer alternatives for drug treatment. Objective: The purpose of this study was to develop a well-characterized preparation of the main respiratory cow dander allergen, Bos d 2, with attenuated allergenic activity. Methods: The immunologic characteristics of Bos d 2 preparations were studied by indirect IgE ELISA, ELISA inhibition, Western blotting, histamine release, skin prick tests, and the proliferation tests of allergen-specific T-cell clones. Results: The complete recombinant Bos d 2 was observed to bind effectively, IgE of cow-allergic patients in indirect ELISA. In other experiments, the IgE-binding capacity of recombinant Bos d 2 proved to be lower compared with native Bos d 2. When the two overlapping recombinant fragments of Bos d 2 (corresponding amino acids 1-131 and 81-172, respectively) covering the whole molecule were compared with the complete recombinant Bos d 2 with several methods, only a low level of residual reactivity was observed. For example, recombinant fragments could not bind antibody at all in ELISA inhibition tests retaining, however, some reactivity in skin prick tests. In contrast, the fragments were able to stimulate vigorously Bos d 2-specific T-cell clones. Conclusion: The approach we have taken may offer a simple and reproducible way to produce hypoallergenic preparations for immunotherapy, circumventing simultaneously some of the problems of other experimental methods such as individual T-cell epitope recognition in peptide-based immunotherapy. (J Allergy Clin Immunol 1997;100:721-7.)

Modified allergen immunotherapy: effect on immunoglobulin E production.

New forms of allergen immunotherapy are proposed employing modified allergens that induce T-cell responses without associated increased IgE-related responses. Synthetic polyelectrolytes attached to an analyte amy modulate T- and B-cell function, producing effective desensitization and altering immunoglobulin production dependent on the physico-chemical nature of the carrier molecule.