Novas perspectivas em imunoterapia: a importância das células dendríticas na imunoterapia alérgeno-específica / New perspectives in immunotherapy: the importance of dendritic cells in allergen-specific immunotherapy

A imunoterapia alérgeno-específica é o único tratamento capaz de alterar o curso natural da doença alérgica. Ensaios clínicos mostram que a imunoterapia é segura e eficaz para muitos pacientes. No entanto, ainda enfrenta problemas relacionados à eficácia, segurança, longa duração do tratamento e baixa adesão dos pacientes. Neste contexto, tem havido intensa pesquisa no desenvolvimento de adjuvantes com objetivo de aumentar a segurança, otimizar os esquemas de tratamento e melhorar a adesão dos pacientes. Alérgenos foram modificados (glicoconjugados) com carboidratos derivados de Saccharomyces cerevisae para aumentar sua captação e apresentação através dos receptores de carboidratos presentes nas células dendríticas, beneficiando-se da capacidade de atuarem na indução de tolerância para iniciar respostas imunes. À luz de novas evidências, essas células constituem alvo terapêutico chave para se obter uma resposta adequada à imunoterapia alérgeno-específica, com potencial de contribuição na inovação do campo da Imunoterapia.

Allergen-specific immunotherapy is the only treatment capable of altering the natural course of allergic disease. Clinical trials have shown that immunotherapy is safe and effective for many patients. However, it still faces problems related to efficacy, safety, long treatment duration and poor patient compliance. In this context, there has been intense research into the development of adjuvant treatments that increase safety, optimize treatment regimens, and improve patient compliance. Allergens were modified (glycoconjugated) with carbohydrates derived from Saccharomyces cerevisae to increase their uptake and presentation through carbohydrate receptors in dendritic cells, benefiting from their ability to induce tolerance and initiate immune response. In light of the new evidence, these cells are a key therapeutic target for adequate response to allergenspecific immunotherapy and can drive innovation in the field of immunotherapy.

Factors Associated with Adherence to Allergen Specific Subcutaneous Immunotherapy

PURPOSE: Allergen-specific immunotherapy (AIT) is known to be the only therapeutic modality to alter the natural course of allergic diseases. However, at least 3 years of treatment is recommended for achieving long-term disease modifying effect. This study aimed to investigate factors associated with immunotherapy non-adherence in real practice. MATERIALS AND METHODS: We retrospectively reviewed medical records of patients who were diagnosed with allergic rhinitis, asthma, or atopic dermatitis, and received AIT to common allergens such as house dust mite and/or pollens from January 2007 to August 2014. In this study, non-adherence was defined as not completing 3 years of AIT. RESULTS: Among 1162 patients enrolled, 228 (19.6%) failed to complete 3 years of AIT. In multivariate analysis, age less than 20 years [odds ratio (OR) 3.11, 95% confidence interval (CI) 1.70–5.69] and 20 to 40 years (OR 2.01, 95% CI 1.17–3.43), cluster build-up (OR 1.78, 95% CI 1.05–3.02) and ultra-rush build-up schedules (OR 5.46, 95% CI 2.40–12.43), and absence of visit to other departments in the same hospital (OR 1.87, 95% CI 1.05–3.32) were independently associated with immunotherapy non-adherence. Disease duration of 5–10 years was negatively associated with non-adherence compared to shorter disease duration of less than 5 years (OR 0.61, 95% CI 0.40–0.94). Although male sex and commercial product of AIT, Tyrosine S®, compared to Novo-Helisen® were non-adherent factors in univariate analysis, no statistical significances were identified in multivariate analysis. CONCLUSION: Various factors are associated with immunotherapy adherence affecting the utility of immunotherapy. Clinicians should be aware of factors associated with adherence to maximize the utility of allergen-specific subcutaneous immunotherapy.

A Retrospective Study of Clinical Response Predictors in Subcutaneous Allergen Immunotherapy With House Dust Mites for Allergic Rhinitis

PURPOSE: House dust mites (HDM) are major allergens that cause allergic rhinitis (AR). Allergen-specific subcutaneous immunotherapy (SCIT) has been shown to be clinically beneficial in many clinical trials. Such trials, however, are not reflective of all patient populations. The aim of this study was to describe the efficacy and safety of SCIT in routine clinical practice in Korean adults with AR sensitized to HDM. METHODS: We reviewed medical records of 304 patients with AR treated at an allergy clinic of a tertiary hospital using SCIT with aluminum hydroxide-adsorbed allergen extract targeting HDM alone or with pollens for at least 1 year from 2000 to 2012. Patients with asthma were excluded. Rates of remission, defined as no further requirement of maintenance medication, over time were determined by means of life tables and extension of survival analysis. Specific immunoglobulin E (IgE) levels to HDM were categorized into 6 classes. RESULTS: The mean time until achieving remission was 4.9±0.1 years, and the cumulative incidence of remission from AR was 76.6%. Severe AR (odds ratio [OR], 0.40; 95% confidence interval [CI], 0.23-0.69; P=0.001), specific IgE levels to HDM ≥17.5 kU/L (OR, 1.85; 95% CI, 1.01-3.37; P=0.045), and duration of immunotherapy ≥3 years (OR, 7.37; 95% CI, 3.50-15.51; P<0.001) were identified as significant predictors of clinical remission during SCIT for patients with AR sensitized to HDM. Overall, 73 patients (24.0%) experienced adverse reactions to SCIT, and only 1 case of anaphylaxis (0.3%) developed. CONCLUSIONS: SCIT with HDM was found to be effective and safe for patients with AR. Specific IgE levels to HDM and a duration of SCIT ≥3 years may be predictors of clinical responses to SCIT in AR patients.

The International Study of the Allergic Rhinitis Survey: outcomes from 4 geographical regions

BACKGROUND: Allergic rhinitis (AR) is a global health problem and is characterised by one or more symptoms, including sneezing, itching, nasal congestion and rhinorrhea. OBJECTIVE: We investigated the features of AR and the physician's approach to the management of AR patients in four geographical regions. METHODS: In this cross-sectional study, a questionnaire survey concerning AR was completed by Honorary and Corresponding Members of the Italian Society of Rhinology from different countries among 4 world geographical regions—Asia, Europe, the Americas, and Africa. RESULTS: The prevalence of AR was reported to be 15%–25%. Children and adolescents, as well as young adults, were the age groups more affected by AR with comorbidities of asthma, sinusitis, conjunctivitis, and nasal polyposis. Nasal symptoms of AR were more intense in the spring (51.92%) and autumn (28.85%). The most common aero-allergens were pollen and mites (67.31%), animal dander and pollutants (23.08%), and fungal allergens (21.15%). Allergen-specific immunotherapy was prescribed for both perennial and seasonal allergens (32.69%) via sublingual swallow (46.15%) and subcutaneous (32.69%) routes. For the AR patients, the most prescribed drugs were intranasal corticosteroids (86.54%) and oral H₁-antihistamines (82.69%). CONCLUSION: A network of experts can improve our knowledge concerning AR epidemiology, and together with guidelines, could assist practitioners and otolaryngologists in standardising the diagnosis and treatment of AR.

Attaching importance to diagnosis and treatment of allergic conjunctivitis / 中华实验眼科杂志

Allergic conjunctivitis is one of the most common eye diseases,and its incidence is ever increasing every year.The disease has unbearable ocular symptoms and repeated attacks,which seriously affect the daily life and work of patients.Ophthalmologist has not paid enough attention for the diagnosis and treatment of allergic conjunctivitis.Ophthalmologists can give appropriate laboratory examinations in combination with the medical history and signs of patients with allergic conjunctivitis,so that patients can be fully and clearly diagnosed.While giving appropriate drug treatment,the patients can get appropriate desensitization treatment by defining allergens.Ophthalmologists should take full care of the allergic conjunctivitis,especially for allergen testing and allergen-specific immunotherapy,in their practices.

Latest research topics on allergic asthma / 中国免疫学杂志

The prevalence of allergic asthma has been growing steadily worldwide including China.Complex genetic and envi-ronmental factors have been assumed to contribute to disease pathogenesis.Key players in the barrier system such as airway epithelia secret allergic mediators in response to allergen stimulation.The micro-environment composed of innate immune cells,e.g.,innate lymphoid cells,and various immune effector molecules is critical in regulating the production of cytokines/chemokines,which further impacts the cells in adaptive immunity.The revelation of the neuron-ILC2 axis confirms the importance of the cross-talk between the nervous system and local immune responses on the regulation of tissue homeostasis.Furthermore,accumulating data implicate the involvement of the epigenetics and microbiota in allergic diseases.The concept of endotype has improved personalized medicine that aims to select the most suitable patient for a therapy according to the patient-specific patterns of disease pathology.There is also a demand for more precise biomarkers that can identify the appropriate treatment recipient.Lastly,the validity of experimental animal models of allergic asthma may need to be re-evaluated.This review summarizes recent progress addressing these issues in our understanding of allergic pathology.

A Pilot Study of Intralymphatic Immunotherapy for House Dust Mite, Cat, and Dog Allergies

Several recent clinical trials reported that intralymphatic immunotherapy (ILIT) for some allergens, such as cat dander and pollen, induce tolerance more rapidly than conventional subcutaneous or sublingual immunotherapy, have a comparable duration of effect after only 3 injections, and do not provoke serious local or systemic reactions. However, the efficacy and safety of ILIT are using Dermatophagoides farinae (Df), Dermatophagoides pteronyssinus (Dp), and dog, which are indoor allergens that are commonly found globally, need to be evaluated. Furthermore, use of multiple allergens in ILIT should be investigated. We assessed the clinical efficacy and adverse effects of ILIT using aqueous Df, Dp, dog, and cat allergens or mixtures thereof in patients with allergic rhinitis. A total of 11 subjects with AR sensitized to Df, Dp, cat, and/or dog allergens received 3 intralymphatic inguinal injections of sensitized allergen extract (HollisterStier, New Orleans, LA, USA). Clinical parameters were assessed before ILIT, and 4 months and 1 year after the first injection. Rhinitis symptoms were alleviated and quality of life was improved 4 months after ILIT (P=0.012 and P=0.007, respectively), and these improvements lasted for 1 year after ILIT (P=0.047 and P=0.009, respectively). However, we observed 2 cases of anaphylaxis, one case of a moderate-to-severe systemic hypersensitivity reaction and the other case of a severe local reaction at the injection site after ILIT. In conclusion, ILIT can rapidly improve allergy symptoms and quality of life, and this effect lasts for 1 year. In hypersensitized patients, however, ILIT can provoke severe systemic and/or local hypersensitivity reactions when performed using aqueous allergen extracts.

Subcutaneous Immunotherapy for Allergic Asthma in a Single Center of Korea: Efficacy, Safety, and Clinical Response Predictors

Allergen-specific immunotherapy is the only causal treatment for allergic diseases. However, the efficacy of immunotherapy may vary around the world due to differences in climate, the nature of aero-allergens and their distribution. The aim of this study was to describe the effects of subcutaneous immunotherapy (SCIT) in Korean adults with allergic asthma (AA). As a retrospective cohort study, we reviewed medical records for 627 patients with AA in Korea who were sensitized to house dust mite (HDM) and/or pollens and who underwent SCIT with aluminum hydroxide adsorbed allergen extract from 2000 to 2012. Rates of remission, defined as no further requirement of maintenance medication, over time were determined by means of life tables and extension of survival analysis. Herein, 627 asthmatic patients achieved remission within a mean of 4.7 ± 0.2 years. The cumulative incidence rates of remission from AA were 86.9% upon treatment with SCIT. Baseline forced expiratory volume in the first second (FEV1) ≥ 80% (hazard ratio [HR], 3.10; 95% confidence interval [CI], 1.79–5.39; P < 0.001), and maintenance of immunotherapy for more than 3 years (HR, 1.82; 95% CI, 1.21–2.72; P = 0.004) were significant predictors of asthma remission during SCIT. In 284 patients on SCIT with HDM alone, initial specific immunoglobulin E (IgE) levels to Dermatophagoides pteronyssinus and Dermatophagoides farinae did not show significant difference between remission and non-remission group after adjusting demographic variables. In conclusion, SCIT was effective and safe treatment modality for patients with AA. Initial FEV1 ≥ 80% and immunotherapy more than 3 years were found to be associated with favorable clinical responses to SCIT.

Application of allergen specific immunotherapy in children with allergic diseases / 国际儿科学杂志

Allergen specific immunotherapy(AIT) is a desensitization treatment for IgE-mediated allergic diseases.Combined with pharmacological therapy,AIT is used to treat allergic asthma,allergic rhinitis and atopic dermatitis caused by allergens that cannot be avoided.AIT is the only treatment modality that can alter the natural course of allergic disease.However,because of the lack of studies,there still exists controversy about the application of immunotherapy in children with allergic diseases.The mechanism ofAIT,its clinical efficacy and safety in children with allergic diseases are reviewed.

Effects of allergen-specific immunotherapy on FEV1 and airway responsiveness in patients with idiopathic asthma / 中国生化药物杂志

Objective To investigate the effect of allergen-specific immunotherapy on FEV1 and airway responsiveness in patients with idiopathic asthma.Methods 90 patients with idiopathic asthma from January 2013 to August 2015 in Deqing City People's Hospital were selected and randomly divided into control group and study group with 45 cases in each group.Control group were treated with anti-infection, relieving cough and eliminating phlegm, relieving spasm and relieving asthma, the study group was treated with allergen specific immunotherapy based on the control group, and a total of 3 months for a course of treatment.Blood samples were used to measure inflammatory mediators , airway sensitivity index, pulmonary function and airway responsiveness, at the same time, the clinical efficacy and complications were compared.Results Compared with before treatment, the levels of FVC, PEF, FEV1 and FEV1/FVC in the two groups increased, levels of AI, AO, T and WA decreased, levels of serum IL-4 decreased, levels of IL-10, IFN-γincreased, levels of serum IgE, SIgE, TIgE and EOS decreased, the difference was statistically significant (P<0.05), compared with the control group, the levels of FVC, PEF, FEV1 and FEV1/FVC in the study group were higher, the levels of AI, AO, T and WA were lower, serum IL-4 levels were lower after treatment, levesls of IL-10, IFN-γwere higher, levels of serum IgE, SIgE, TIgE and EOS were lower, the difference was statistically significant (P<0.05), and the effective rate in the control group (71.11%) was lower than the study group (88.89%), the difference was statistically significant(P <0.05).Conclusion Allergen-specific immunotherapy was effective for cough variant asthma, it can improve pulmonary function, inflammation and airway sensitivity.

Retrospective Analysis on the Effects of House Dust Mite Specific Immunotherapy for More Than 3 Years in Atopic Dermatitis

PURPOSE: In extrinsic atopic dermatitis (AD), house dust mites (HDM) play a role in eliciting or aggravating allergic lesions. The nature of skin inflammation in AD has raised a growing interest in allergen-specific immunotherapy (SIT). Thus, we assessed clinical improvement and laboratory parameters for evaluation of the benefit of long-term SIT. MATERIALS AND METHODS: A total of 217 AD patients who were treated with SIT for at least 3 years were retrospectively assessed, by using their investigator global assessment, pruritus scores, loss of sleep (LOS), total serum IgE, and eosinophil counts collected. Patients were additionally classified into subgroups according to age, initial AD severity and mono- or multi-sensitization to include different individual factors in the evaluation of SIT efficacy. Lastly, we compared laboratory data of good responders to SIT with that of poor responders to SIT. RESULTS: Improvement after SIT therapy was observed in 192 out of 217 patients (88.4%). Among these patients, 138 (63.5%) achieved excellent, near-complete or complete clinical remission. Significant reduction of pruritus, LOS, and the mean value of total serum IgE were observed (p0.05). CONCLUSION: We emphasize the usefulness of long-term HDM SIT as a disease-modifying therapy for AD.

Molecular Approach to Allergy Diagnosis and Therapy

Presently, allergy diagnosis and therapy procedures are undergoing a transition phase in which allergen extracts are being step-by-step replaced by molecule-based products. The new developments will allow clinicians to obtain detailed information on sensitization patterns, more accurate interpretation of allergic symptoms, and thus improved patients' management. In this respect, recombinant technology has been applied to develop this new generation of molecule-based allergy products. The use of recombinant allergens allows full validation of identity, quantity, homogeneity, structure, aggregation, solubility, stability, IgE-binding and the biologic potency of the products. In contrast, such parameters are extremely difficult to assay and standardize for extract-based products. In addition to the possibility of bulk production of wild type molecules for diagnostic purposes, recombinant technology opened the possibility of developing safer and more efficacious products for allergy therapy. A number of molecule-based hypoallergenic preparations have already been successfully evaluated in clinical trials, bringing forward the next generation of allergy vaccines. In this contribution, we review the latest developments in allergen characterization, molecule-based allergy diagnosis, and the application of recombinant allergens in therapeutic setups. A comprehensive overview of clinical trials using recombinant allergens as well as synthetic peptides is presented.

Molecular Approach to Allergy Diagnosis and Therapy

Presently, allergy diagnosis and therapy procedures are undergoing a transition phase in which allergen extracts are being step-by-step replaced by molecule-based products. The new developments will allow clinicians to obtain detailed information on sensitization patterns, more accurate interpretation of allergic symptoms, and thus improved patients' management. In this respect, recombinant technology has been applied to develop this new generation of molecule-based allergy products. The use of recombinant allergens allows full validation of identity, quantity, homogeneity, structure, aggregation, solubility, stability, IgE-binding and the biologic potency of the products. In contrast, such parameters are extremely difficult to assay and standardize for extract-based products. In addition to the possibility of bulk production of wild type molecules for diagnostic purposes, recombinant technology opened the possibility of developing safer and more efficacious products for allergy therapy. A number of molecule-based hypoallergenic preparations have already been successfully evaluated in clinical trials, bringing forward the next generation of allergy vaccines. In this contribution, we review the latest developments in allergen characterization, molecule-based allergy diagnosis, and the application of recombinant allergens in therapeutic setups. A comprehensive overview of clinical trials using recombinant allergens as well as synthetic peptides is presented.

Alérgenos recombinantes: papel no diagnóstico e na imunoterapia alérgeno-específica / Recombinant allergens: role in diagnosis and in allergen-specific immunotherapy

Nos últimos 30 anos tem havido um avanço notável na identificação, purificação e expressão recombinante de alérgenos relevantes das mais variadas fontes, incluindo ácaros, insetos, mamíferos, polens, alimentos, fungos, látex e outras fontes. Estes avanços resultaram na utilização crescente de alérgenos purificados, naturais ou recombinantes, para melhorar o diagnóstico de alergia pelos métodos que dispomos, incluindo os testes cutâneos de hipersensibilidade imediata, e os métodos in vitro para medida de anticorpos IgE específicos, como ImmunoCAP, ImmunoCAP-ISAC, ELISA e MARIA. Mais recentemente, o uso de alérgenos recombinantes de pólen de bétula (rBet v 1) e de gramas (coquetel de 5 alérgenos) em imunoterapia foi relatado como seguro e eficaz, com resultados comparáveis aos obtidos usando extratos naturais, em pacientes com rinoconjuntivite alérgicos a polens. No presente artigo, apresentamos revisão atualizada do uso de alérgenos recombinantes em diagnóstico de alergia e em imunoterapia alérgeno-específica, incluindo novas estratégias de imunoterapia. Focalizamos na avaliação crítica de estudos que investigaram sensibilidade, especificidade, reatividade cruzada e valor prognóstico de métodos diagnósticos com uso de alérgenos recombinantes versus extratos naturais; nas recomendações atuais para o uso destes novos métodos na prática clínica; e na revisão de estudos clínicos com imunoterapia usando alérgenos recombinantes realizados até o momento.

Over the past 30 years, a great deal of progress has been made in the identification, purification,and recombinant expression of relevant allergens from various sources, including mites, insects,mammals, pollens, foods, fungi, latex, and other sources. These new developments have resultedin an increasing use of purified allergens, either natural or recombinant, to improve the diagnosisof allergy via the methods currently available, including skin tests and in vitro tests for measuringspecific IgE antibodies, e.g., ImmunoCAP, ImmunoCAP-ISAC, ELISA, and MARIA. More recently,the use of recombinant allergens from birch pollen (rBet v 1) and from grass pollen (a cocktailof five allergens) in immunotherapy has been reported to be safe and effective, with resultscomparable to those obtained with natural extracts in patients with rhino-conjunctivitis due topollen allergy. In the present article, we present an up-to-date review on the use of recombinantallergens in the diagnosis of allergy and in allergen-specific immunotherapy, including newstrategies for immunotherapy. We focus on the critical analysis of studies that have investigatedsensitivity, specificity, cross-reactivity, and the prognostic value of diagnostic methods that includerecombinant allergens versus natural extracts; on current recommendations for the use of thesenew methods in clinical practice; and on the review of clinical studies using immunotherapy withrecombinant allergens performed to date.

Mechanisms of immune tolerance to allergens in children / 소아과

Because the prevalence of allergic diseases has significantly increased in recent years, understanding the causes and mechanisms of these disorders is of high importance, and intense investigations are ongoing. Current knowledge pinpoints immune tolerance mechanisms as indispensable for healthy immune response to allergens in daily life. It is evident that development and maintenance of allergens-pecific T cell tolerance is of vital importance for a healthy immune response to allergens. Such tolerance can be gained spontaneously by dose-dependent exposures to allergens in nature or by allergen-specific immunotherapy. Allergen-specific immunotherapy induces regulatory T cells with the capacity to secrete interleukin-10 and transforming growth factor-beta, limits activation of effector cells of allergic inflammation (such as mast cells and basophils), and switches antibody isotype from IgE to the noninflammatory type IgG4. Although allergen-specific immunotherapy is the only method of tolerance induction in allergic individuals, several factors, such as long duration of treatment, compliance problems, and life-threatening side effects, have limited widespread applicability of this immunomodulatory treatment. To overcome these limitations, current research focuses on the introduction of allergens in more efficient and safer ways. Defining the endotypes and phenotypes of allergic diseases might provide the ability to select ideal patients, and novel biomarkers might ensure new custom-tailored therapy modalities.

Ambiente y estilo de vida en la prevención del asma en el niño: [revisión] / Environment and lifestyle in the prevention of asthma in children: [review]

Se ha planteado que el manejo del niño con antecedentes familiares de atopia que no ha presentado asma, debe incluir medidas de Prevención Primaria que lo puedan proteger de desarrollar esta condición. En los estudios realizados a este respecto, se ha evaluado la influencia de factores dietéticos, ambientales e infecciosos que pudieran tener impacto en la historia natural de la enfermedad. En este artículo se evalúa la evidencia disponible acerca de cada intervención, a fin de dar al médico Pediatra y de Atención Primaria herramientas para hacer recomendaciones apropiadas para los padres.

It has been suggested that the management of children at risk for developing asthma should include Primary Prevention measures in order to protect them against the development of this condition. In the published studies to date, the influence of dietary, environmental, and infectious factors involved has been assessed. In this article, we review the available evidence on each intervention, and give some tools to the Pediatrician and Primary Care Physician to make appropriate recommendations for parents.

Late Local Urticaria as a Long-term Sequela of Allergen-Specific Immunotherapy

Local reaction to allergen-specific immunotherapy (SIT) usually appears within 30 minutes, but cases with exercise-induced urticaria at the SIT site 2-3 weeks after the last allergen injection have been reported. A 28-year-old man was treated with house dust mite-SIT for 5 years, due to asthma when he was an 11-year-old boy. On a treadmill exercise test for 50 minutes, erythema, swelling, and pruritus occurred at the SIT site, which lasted for one hour. There was no evidence of complement activation, and the skin biopsy specimens showed no apparent difference between the lesion and normal sites in the distribution of inflammatory cells and in mast cell degranulation. However, the morphine, but not the histamine, skin test responses were increased after the exercise. There must be a remaining long-term sequela of the SIT, including an increased releasability of mast cells, even after more than 10 years.

Investingation of immune mechanism of only house dust mite Allergen-specific immunotherapy for allergic rhinitis / 重庆医科大学学报

0.05).Conclution:The NHD house can modulate a imbalanced status of Th1/Th2 cells,Some common antigens are contained in both the dermatophagoides pteronyssinus and other allergens:pollen,fungus,et al,which are able to combine with the specific antibodies in serum.This study provides a theoretical basis for the allergen-specific immunotherapy for allergic rhinitis.