One century of allergen-specific immunotherapy for respiratory allergy

Among the treatments available for respiratory allergy, which include allergen avoidance and pharmacotherapy, specific immunotherapy (SIT) is the only treatment able to not only act on the symptoms of allergy but also act on the causes. SIT is the practice of administering gradually increasing doses of the specific causative allergen to reduce the clinical reactivity of allergic subjects and was introduced one century ago. SIT remained an empirical treatment for more than 40 years, but the first controlled trial in 1954 paved the way for the scientific era. At present, SIT may be administered in two forms: subcutaneous (SCIT) and sublingual immunotherapy (SLIT). A large number of trials, globally analyzed in several meta-analyses, evaluated the efficacy and safety of SCIT and SLIT in allergic rhinitis and asthma. Current available data give solid evidence to the clinical efficacy of both SCIT and SLIT in allergic rhinitis and asthma. Providing the recommended doses and administration schedules are adhered to, the safety and tolerability are very good; however, adverse systemic reactions remain a drawback for SCIT. After one century of use, accumulating evidence surrounds SIT and the central role in the management of respiratory allergy.     

Allergen-specific immunotherapy: from therapeutic vaccines to prophylactic approaches

Immunoglobulin E-mediated allergies affect more than 25% of the population. Allergen exposure induces a variety of symptoms in allergic patients, which include rhinitis, conjunctivitis, asthma, dermatitis, food allergy and life-threatening systemic anaphylaxis. At present, allergen-specific immunotherapy (SIT), which is based on the administration of the disease-causing allergens, is the only disease-modifying treatment for allergy. Current therapeutic allergy vaccines are still prepared from relatively poorly defined allergen extracts. However, with the availability of the structures of the most common allergen molecules, it has become possible to produce well-defined recombinant and synthetic allergy vaccines that allow specific targeting of the mechanisms of allergic disease. Here we provide a summary of the development and mechanisms of SIT, and then review new forms of therapeutic vaccines that are based on recombinant and synthetic molecules. Finally, we discuss possible allergen-specific strategies for prevention of allergic disease.     

变应原突变体在支气管哮喘免疫治疗中的应用

特异性免疫治疗（SIT）是对明确了变应原的变态反应性疾病的一种有效的治疗方法。重组变应原及其衍生物的技术的进步大大提高了生产用于治疗变应性疾病的新型疫苗的能力。本文将就用定点突变技术获取的重组变应原突变体在支气管哮喘免疫治疗中的应用做一综述。     

The History of IgE: From Discovery to 2010

The discovery of IgE and the role of IgE-mediated inflammation gave clinical allergy a scientific backbone, and as a result, the reputation of the specialty allergy has increased considerably over the years. Allergy diagnosis was improved by assays for in vitro determination of the presence and concentration of IgE antibodies, and clinical knowledge also broadened, allowing better service for the increasing number of allergic individuals. Access to immune assays for allergens finally allowed characterization and standardization of allergen preparations used for diagnosis and allergen-specific immunotherapy. Improved basic molecular technologies have further increased our knowledge about the complex component composition of an allergen extract, introduced IgE-specific immunotherapy, and allowed the allergist to better handle even severe allergic reactions such as anaphylaxis.     

Biology of tree pollen allergens

More than 25% of the population suffer from type I allergy. Pollens from trees of the Fagales, Oleaceae, and Cupressaceae belong to the most potent and frequent allergen sources. During the past 15 years, the nature of the most important allergens has been identified by molecular biological techniques, and recombinant allergens equivalent to the natural allergens have been produced. These advances provide insight into the biological functions of important allergens and allow the development of novel forms of diagnosis and therapy. In this review, we focus on Fagales allergens to illustrate the impact of recombinant allergens on diagnosis and therapy. We discuss structural similarities as a molecular basis for crossreactivities and develop diagnostic concepts by using speciesspecific marker allergens as well as highly cross-reactive allergens. The identification of the allergen recognition profiles of patients with recombinant allergens allows a more precise selection of patients for available forms of allergy treatment. Moreover, we describe novel recombinant allergen-based forms of specific immunotherapy.     

特异性免疫治疗在特应性皮炎中的应用

特异性免疫治疗（SIT）是唯一可能改变变应性疾病自然病程的治疗方法，SIT对IgE介导的变应性鼻炎和变应性哮喘的疗效已经得到公认，但对特应性皮炎（AD）的应用价值却一直存在争论。造成这种争议的原因可能与不同研究所使用的变应原类别、治疗方案、治疗疗程、评价临床疗效的标准以及有无环境控制和所用对症药物之间的差别有关。本文对近年来有关SIT在AD中的应用进行综述。     

Components of plant-derived food allergens: Structure,diagnostics, and immunotherapy

A large number of plant-derived food allergen components have been identified to date. Although these allergens are diverse, they often share common structural features such as numerous disulfide bonds or oligomeric structures. Furthermore, some plant-derived food allergen components cross-react with pollen allergens. Since the relationship between allergen components and clinical symptoms has been well characterized, measurements of specific IgE to these components have become useful for the accurate clinical diagnosis and selection of optimal treatment methods for various allergy-related conditions including allergy caused by plant-derived foods. Herein, I have described the types and structures of different plant allergen components and outlined the diagnosis as well as treatment strategies, including those reported recently, for such substances. Furthermore, I have also highlighted the contribution of allergen components to this field.     

Evaluation of two grass pollen extracts for immunotherapy by serum determinations of specific IgE and IgG4 antibodies towards purified Timothy grass pollen allergens (Phl p 1, 2, 4, 5, 6, 7, 11, 12) in patients undergoing hyposensitization treatment

BackgroundThe diagnosis of allergic diseases with recombinant allergens allows us to detect antibodies specific for single allergens in extracts. The aim of the present study was to assess the early effect of grass pollen immunotherapy on IgE and IgG4 responses to eight purified grass pollen allergens in patients undergoing hyposensitization treatment.MethodsThe sera of 22 consecutive atopic individuals undergoing cluster regimen grass pollen immunotherapy were analyzed for IgE and IgG4 antibodies specific for grass pollen allergens (Phl p 1, 2, 4, 5, 6, 7, 11, 12). Two serum samples were taken, one before the start of therapy and one between 12 and 15 weeks after the first immunization. Immunotherapy was performed with two allergy vaccines comprising a standardized extract aluminum-adsorbed grass pollen mix and a standardized extract of grass pollen mix adsorbed onto calcium phosphate.ResultsOne treated patient showed a specific IgE conversion from negative (< 0.35 kUA/L) to positive in the capsulated hydrophilic carrier polymer (CAP) test for Phl p 2, 1 and 4 (1.89, 0.84 and 0.68 kUA/L, respectively). The sera of 10 of 11 patients treated with alluminum-adsorbed grass pollen extract showed a significant increase in specific IgG4 towards natural Timothy grass pollen extract and purified allergens, as well as significant IgG4 levels towards Phl p 1 (P = 0.000238) Phl p 2 (P = 0.000289), Phl p 4 (P = 0.000585), Phl p 5 (P = 0.000364), Phl p 6 (P = 0.000346) and Phl p 11 (P = 0.039623; Mann–Whitney U-test) 12 weeks after the onset of immunotherapy. The sera of seven of 11 subjects treated with calcium phospate-adsorbed grass pollen extract had significant IgG4 levels against Timothy pollen allergens, as well as significant IgG4 titers against Phl p 1 (P = 0.004703), Phl p 4 (P = 0.000282), Phl p 5 (P = 0.015480), Phl p 6 (P = 0.013012) and Phl p 11 (P = 0.005178). Patients treated with aluminum-adsorbed grass pollen extract had higher levels of IgG4 towards Phl p 2, 4 and 6 and natural Timothy grass extract compared with patients treated with calcium phosphate-adsorbed grass pollen extract. Both the alluminum-adsorbed and calcium phosphate-adsorbed grass pollen extract allergy vaccines induced significant titers of specific IgG4 towards Phleum pratense pollen extract (P = 0.008376 and 0.01148, respectively).ConclusionsThese results indicate that grass pollen immunotherapy elicits an array of antibody specificities that reflect the allergen content and the potency of allergen extracts; this could be of pivotal importance to define optimal allergen extract doses.     

Overview of Serological-Specific IgE Antibody Testing in Children

Allergic diseases are among the most common chronic conditions in the pediatric population. Allergy diagnostic testing is an important part of the evaluation/management of allergic patients because the history may not be precise enough to identify the specific allergen sensitivity. In addition to providing information about specific sensitivities, allergy diagnostic tests have some predictive value in terms of future risk of developing an allergic condition and the severity/persistence of the allergic disease. The two most commonly used methods of confirming allergen sensitization are skin testing and measurement of serum-specific IgE. Both methods have similar diagnostic value in terms of sensitivity and specificity, with both parameters varying with the clinical scenario and allergen tested. Currently, there are three US Food and Drug Administration–cleared, serum-specific IgE assays used in the United States. The three assays report comparable analytic sensitivity, with the coefficients of variation of the precision, reproducibility, and linearity being less than 15%. However, comparative studies have demonstrated significant inter-assay variability, suggesting that they detect different populations of IgE antibody in human sera or do not measure the same antibodies with the same efficiency. Current specific IgE assays utilize allergen extract reagents. Testing with these reagents may identify sensitivity to clinically irrelevant allergens. This diagnostic limitation has spurred the development of molecular diagnostic tests, also referred to as component-resolved diagnostics, which utilize purified native or recombinant allergens to detect IgE sensitivity to individual allergen molecules. These advancements in serum IgE testing may enhance the precision of allergy diagnostic testing, which may decrease the need for oral food challenges and improve the specificity of allergen immunotherapy.     

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过敏性鼻炎是体外环境中的过敏原作用于特应性个体(atopy)后出现IgE介导的鼻腔黏膜Th2免疫反应占优的过敏性炎症,与下呼吸道关系密切。在社会群体中的患病率较高,已成为耳鼻咽喉头颈外科门诊的主要疾病。过敏原特异性免疫治疗是惟一可能通过免疫调节机制改变过敏性疾病自然进程的治疗方式,在过敏性鼻炎治疗体系中占有特殊重要的地位。     

Hidden allergic factors in the etiology of asthma

Increasing evidence from case control surveys, population studies and allergen avoidance studies suggest inhalant allergy plays an important role in the etiology of asthma. Recent studies in hospital emergency rooms have compared the prevalence of serum IgE antibodies to common allergens (mite, cat, cockroach, rye grass and ragweed pollen) in patients admitted with acute asthma attacks and in unselected age-matched control subjects. These studies, carried out in central Virginia and northern California, showed a highly increased prevalence of IgE antibodies to inhaled allergens among asthmatic patients, and suggest that the development of allergen specific IgE antibody responses is a major risk factor for emergency room admission with asthma. Presentation at the emergency room appeared to be related to patients' exposure to specific allergens: in central Virginia, in the fall, dust mite was the predominant allergy, whereas in northern California, in May-June, most asthmatic patients (greater than 90 percent) were allergic to rye grass. New immunoassay technology, based on the use of monoclonl antibodies, has been developed to measure the quantities of "indoor" allergens (mite, cat, cockroach) in asthmatic patients' houses. It is now possible to propose tentative levels of mite allergens which should be considered both as a risk for IgE antibody sensitization (2micrograms allergen/g dust) and as a risk for acute asthma attacks (10micrograms allergen/g dust). Future management of asthma will require analysis of indoor allergens and the development of efficient allergen avoidance procedures. Further research is necessary to investigate the relationship between airborne allergen levels, particle size and the precipitation of asthma attacks and also to investigate immunologic mechanisms which may cause bronchial hyperreactivity.     

Efficacy of immunotherapy in the treatment of asthma

Specific immunotherapy consists of the administration of allergen extracts to patients with allergic disease to achieve clinical tolerance to the causative allergens. Currently, it is the only etiologic treatment for respiratory allergy. A World Health Organization opinion paper published in 1997 defines immunotherapy as "the only form of treatment able to modify the natural course of allergic diseases". In patients with allergic rhinitis, several studies suggest that immunotherapy can modify the natural history of respiratory allergy by preventing the development of asthma in children with this disease. Numerous studies demonstrate its efficacy in IgE-mediated asthma and particularly in mild-to-moderate asthma. When complete avoidance of the allergen cannot be achieved with measures that allow the patient to lead a normal life, pharmacological treatment can help to control symptoms, but symptoms immediately return when treatment is interrupted. However, asthma care can be improved by allergen-specific treatment; immunotherapy may shift the immune response from an allergic pattern toward a more protective response, producing persistent improvement with reduction of symptoms and the need for pharmacological treatment. Numerous comparative studies with specific immunotherapy vs. placebo or pharmacological treatment have demonstrated the efficacy of this treatment and its advantages in control of the disease. Specific immunotherapy induces favorable clinical, biological and functional modifications in the course of allergic asthma. Significant improvement in clinical manifestations has been demonstrated, even with levels of allergen exposure higher than those at the beginning of treatment. This improvement is associated with a reduced need for antiinflammatory and bronchodilator treatment. Moreover, specific bronchial reactivity shows a clear improvement with disappearance of delayed response and a clear increase in the threshold for immediate response to the allergen. Reduction in nonspecific bronchial hyperreactivity and improvement in exercise-induced asthma are also observed. Several studies recommend an optimal duration of specific immunotherapy for allergic asthma of between 3 and 5 years to achieve maximal therapeutic efficacy. A direct relationship between treatment duration and the persistence of its effects has been observed. Moreover, the treatment is more effective when started early. The possible adverse effects related to systemic reactions should be borne in mind. Although these effects are infrequent, maximal precautions should be taken when administering this treatment. Immunotherapy is contraindicated in cases of severe asthma, heart disease, autoimmune disease and associated severe neoplastic processes. However, all the beneficial effects of immunotherapy are conditioned by an accurate and early etiological diagnosis confirming the causative allergen. The availability of high-quality allergen extracts is essential to obtain the desired effect. Inappropriate patient selection for this treatment is the main cause of its failure. The integral treatment of allergic asthma includes environmental measures, patient education, pharmacological treatment and, whenever possible, immunotherapy.     

Allergen-specific IgE in circulating immune complexes in patients with inhalant allergy undergoing specific immunotherapy.

Specific immunotherapy (SIT) has been used worldwide since it was introduced near the beginning of this century. Although this mode of therapy has been known for over 80 years, its mechanism of action is still not definitely clear. The problem of the presence of allergen-specific IgE in IgE-containing circulating immune complexes of patients with inhalant allergy has been mentioned in the literature. However, there are no data concerning specific immunotherapy. The aim of our study was to evaluate the influence of SIT in patients with inhalant allergy on allergen-specific IgE in serum and in IgE circulating immune complexes. A total of 112 subjects with allergic rhinitis (57 with grass pollen allergy and 55 sensitive to house dust mites Dermatophagoides pteronyssinus) were included in the study. SIT was administered to 29 patients suffering from pollinosis and 27 patients sensitive to house dust mites. The remaining patients were treated with an H2-receptor antagonist only. The decrease of allergen-specific IgE concentration in IgE circulating immune complexes was parallel to the analogous changes in the serum only in the patients with pollinosis. Immunotherapy of house dust mite-sensitive patients caused a much slower decrease of allergen-specific IgE in circulating immune complexes than in serum. The binding index of allergen-specific IgE in circulating immune complexes increased during the course of the treatment. No significant associations were found between the immunological indices studied and clinical score of the disease activity.     

Regulatory cells in allergen-specific immunotherapy

Allergen-specific immunotherapy (SIT) is currently the best available curative treatment in allergies and has been used for the treatment of patients for the past 100 years. The formation of a Th2 cell predominant inflammation in addition to production of allergen-specific IgE, the attraction of proinflammatory cells and the degranulation of effector cells, such as mast cells, are essential mechanisms in allergy development. Tregs aim to diminish these effects by IL-10- and TGF-β-mediated anti-inflammatory reactions and therefore are one of the main targets in SIT. The induction of allergen tolerance is the key to successful SIT. With a special focus on Tregs, this review aims to clarify what is currently known about allergy development and the mode of action in allergen-SIT, which helps to develop further therapeutic strategies in the fight against allergic diseases.     

Allergen-derived T cell peptides in immunotherapy

The incidence of allergic diseases has continued to rise during the last 30 years. A combination of genetic and environmental factors is likely to be responsible for the increased prevalence of both allergic and autoimmune diseases. Whilst the majority of approaches towards treatment are palliative, specific allergen immunotherapy (SIT) is an approach that has been proven to be efficacious and disease-modifying. However, as a result of interaction between allergen-specific IgE and conformational B cell epitopes on the surface of the allergen molecule, SIT is associated with adverse reactions during treatment. One strategy developed to reduce IgE-mediated adverse events whilst maintaining clinical efficacy has been to treat subjects with short peptide sequences corresponding to T cell epitopes of the allergen. The size and the monomeric nature of peptides have allowed relatively large doses of antigen to be delivered in soluble form. Treatment with peptides has been shown to improve clinical surrogate measurements of disease, to modify the immune response to allergen and to improve patients’ perception of disease. This review will summarise results achieved in recent years with peptide immunotherapy and discuss the mechanisms that may be responsible for efficacy.     

Recombinant allergens for immunotherapy.

Many of the problems associated with using natural allergenic products for allergy diagnosis and treatment can be overcome using 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. Allergens have diverse biological functions (they may be enzymes, enzyme inhibitors, lipocalins, or structural proteins). High-level expression systems have been developed to produce recombinant allergens in bacteria, yeast, or insect cells. Recombinant allergens show comparable immunoglobulin E (IgE) antibody binding to natural allergens and show excellent reactivity on skin testing and in in vitro diagnostic tests. Recombinant allergens will enable innovative new strategies for allergen immunotherapy to be developed. These include peptide-based vaccines, engineered hypoallergens with reduced reactivity for IgE antibodies, nucleotide-conjugated vaccines that promote Th1 responses, and the possibility of developing prophylactic allergen vaccines.     

Overview of Component Resolved Diagnostics

Component-resolved diagnostics (CRD) utilize purified native or recombinant allergens to detect IgE sensitivity to individual allergen molecules and have become of growing importance in clinical investigation of IgE-mediated allergies. This overview updates current developments of CRD, including multiarray test systems. Cross-reactions between allergens of known allergen families (i.e. to Bet v 1 homologues) are emphasised. In pollinosis as well as in allergy to hymenoptera venoms or to food, CRD allows to some extent discrimination between clinically significant and irrelevant sIgE results and the establishing of sensitisation patterns with particular prognostic outcomes (i.e. sensitisations to storage proteins which correlate with clinically severe reactions in peanut allergy). Further promising improvements in diagnostics are expected from additional, not yet commercially available, recombinant allergen diagnostics identifying particular molecules of risk. Overall, CRD may decrease the need for provocation testing and may also improve the specificity of allergen-specific immunotherapy.     

Vaccines and Immunomodulatory Therapies for Food Allergy

The apparent increase in food allergy prevalence has led to a surge in the amount of clinical and basic science research dedicated to the field. At the current time, allergen avoidance remains the cornerstone of treatment; however, recent clinical trials investigating various forms of immunotherapy have opened doors to the possible future application of an active treatment strategy in everyday practice. In addition, improvements in molecular biology have allowed researchers to purify, clone, and modify allergens, thus laying the groundwork for research on vaccines using modified proteins of decreased allergenicity. Finally, various allergen-nonspecific immunomodulatory therapies are also being investigated as a means to alter the immune response to food allergens. With these emerging therapeutic strategies, it is hoped that practitioners will have options in caring for their food-allergic patients in the near future.