Chest
Volume 146, Issue 5, November 2014, Pages 1347-1357
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Translating Basic Research Into Clinical Practice
Scientific Foundations of Allergen-Specific Immunotherapy for Allergic Disease

https://doi.org/10.1378/chest.14-0049Get rights and content

Allergen-specific immunotherapy (AIT) was described as a therapeutic option for the treatment of allergies > 100 years ago. It is based on administration of allergen extracts and leads to the development of clinical allergen tolerance in selected patients. According to current knowledge, AIT results in the restoration of immune tolerance toward the allergen of interest. It is mainly accompanied by the induction of regulatory and suppressive subsets of T and B cells, the production of IgG4 isotype allergen-specific blocking antibodies, and decreased inflammatory responses to allergens by effector cells in inflamed tissues. Currently, AIT is mainly applied subcutaneously or sublingually and is suitable for both children and adults for pollen, pet dander, house dust mite, and venom allergies. It not only affects rhinoconjunctival symptoms but also has documented short- and long-term benefits in asthma treatment. Clinically, a fast onset of tolerance is achieved during desensitization, with a tolerable amount of side effects. The disease modification effect leads to decreased disease severity, less drug usage, prevention of future allergen sensitizations, and a long-term curative effect. Increasing safety while maintaining or even augmenting efficiency is the main goal of research for novel vaccine development and improvement of treatment schemes in AIT. This article reviews the principles of allergen-specific immune tolerance development and the effects of AIT in the clinical context.

Section snippets

Immune Mechanisms of Allergic Inflammation

The profound understanding of allergic inflammation is a prerequisite to finding a well-targeted therapy. In the early days, approximately 30 years ago, the allergic inflammation was believed to be solely caused by an imbalance between the effector Th subsets, with Th2 dominance over Th1. Multiple mechanisms that involve all immune system and resident tissue cell responses have become slowly understood over the past decades. In the sensitization phase, the allergens are presented to naive T

Mechanisms of Immune Tolerance to Allergens and AIT: The Role of DCs, T and B Cells in AIT and High-Dose Allergen Exposure

Today, the development of allergy is viewed as the loss of peripheral immune tolerance to allergens, whereas AIT is involved in mechanisms that restore immune tolerance to allergens. IgE is produced but does not cause the disease any more. However, the IgE-to-IgG4 ratio shows a significant change because of the very early increase in allergen-specific IgG4 levels. AIT induces an abundance of allergen-specific and general changes in immune regulatory processes, and various cytokines and cell

AIT in Clinical Settings

A successful AIT starts with the correct identification of patients who are suitable candidates. Immunotherapy vaccines, in general, consist of a mixture of allergen components with a predominance of major allergens. Molecular diagnostics helps to identify individuals who are sensitized to minor allergens or to cross-reactive allergens and who, therefore, may show a different immune response to and clinical benefit from AIT.39 Many large multicenter trials have been published demonstrating that

Future Developments in AIT Vaccines

Safety is certainly an issue for the improvement of SCIT in particular. Although local reactions are apparent in SCIT, ranging from itchy skin to wheal formation in about 5% to 58%,67 they are more frequently encountered in SLIT, where symptoms such as oral itchiness and local swelling are present in > 80%.68 Systemic anaphylactic reactions are more often found in SCIT, with one in > 30,000 injections leading to anaphylaxis compared with only one in 100 million administrations leading to this

Research Needs to Improve AIT

Although attempts to improve AIT have already been made, several issues still need to be addressed in future studies. All steps from diagnosis to follow-up should be considered, starting with patient selection. So far, novel biomarkers and definitions of specific phenotypes are missing. Vaccines can be further improved by standardizing extracts for improved quality and defining their potency in an internationally accepted way. Safety and economic efficiency should be elucidated in various

Conclusions

AIT offers the opportunity to cure wide-spread disease across all continents while preventing the formation of new allergies. There is abundant evidence on clinical safety and efficacy of AIT and its mechanisms of action. Tregs and Bregs appear to be the key immunologic players in restoring tolerance in individuals treated with AIT by producing cytokines such as IL-10 and TGF-β. The skewing of the sole production of allergen-specific IgE toward the noninflammatory IgG4 antibodies is considered

Acknowledgments

Financial/nonfinancial disclosures:The authors have reported to CHEST the following conflicts: Dr Soyka serves on the advisory board of MEDA Pharma but receives no direct financial support. Rhinologic research of his department is supported by MEDA; but there is no conflict with this manuscript. Dr M. Akdis has received research grants from the Swiss National Science Foundation (2012-2015) and two European Union projects: MeDALL and Predicta. Dr C. A. Akdis has received research support from

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    FUNDING/SUPPORT:The authors' laboratories are supported by Swiss National Foundation [Grant 320030_140772] and the Christine Kühne-Center for Allergy Research and Education, European Seventh Framework Programme projects MeDALL: Mechanisms of the Development of Allergy [261357] and PREDICTA: Post-Infectious Immune Reprogramming and Its Association with Persistence and Chronicity of Respiratory Allergic Diseases [260895]. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

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