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Scientific Foundations of Allergen-Specific Immunotherapy for Allergic DiseaseAllergen-Specific Immunotherapy for Allergies FREE TO VIEW

Michael B. Soyka, MD; Willem van de Veen, PhD; David Holzmann, MD; Mübeccel Akdis, MD, PhD; Cezmi A. Akdis, MD
Author and Funding Information

From the Swiss Institute of Allergy and Asthma Research Davos (Drs Soyka, van de Veen, M. Akdis, and C. A. Akdis), University of Zurich, Davos; Department of Otorhinolaryngology Head and Neck Surgery (Drs Soyka and Holzmann), University Hospital Zurich, Zurich; and Christine Kühne-Center for Allergy Research and Education (Dr C. A. Akdis), Davos, Switzerland.

CORRESPONDENCE TO: Cezmi A. Akdis, MD, Swiss Institute of Allergy and Asthma Research, Obere Str 22, 7270 Davos Platz, Switzerland; e-mail: akdisac@siaf.uzh.ch


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.


Chest. 2014;146(5):1347-1357. doi:10.1378/chest.14-0049
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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.

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Allergies are among the most common diseases worldwide, with rising disease prevalence and increasing rates of allergen sensitizations.1 Symptoms of allergic disorders affect both upper and lower airways as well as eyes, skin, GI organs, and the whole body in the case of anaphylaxis. Seasonal and perennial allergens mainly comprise proteins that can be inhaled, ingested, or taken up by many other routes and induce an IgE-mediated local or systemic inflammatory process. Common therapies target such symptoms as inflammation with the use of antihistamines, topical and systemic corticosteroids, mast cell stabilizers, leukotriene antagonists, β-adrenergic agonists, and monoclonal anti-IgE antibodies. Currently, only allergen-specific immunotherapy (AIT) provides a disease modification effect leading to cure2 in select patients and has proven to be effective for > 100 years. Despite that we are far from completely understanding the causes of allergic disease as well as the exact mode of action of AIT, the scientific community worldwide wants to understand the mechanisms of immune tolerance in the fields of allergies, autoimmunity, and organ transplantation. The mechanisms of action of AIT mechanisms have become increasingly clear in recent years.

Immune tolerance can be described as the adaptation of the immune system to external antigens or allergens. The ultimate goal for the therapy of immunologic diseases and conditions such as allergy, autoimmunity, and organ transplantation should be the induction of immune tolerance, a change in the immune response to specific antigens so that the discontinuation of the therapy results in continued long-lasting therapeutic benefits. It is, therefore, an active immune response to a particular epitope that leads to a clinical tolerance to allergens.

Mouse immune tolerance models have been well studied, and evidence has been obtained in adaptive transfer models on the role of T regulatory cells (Tregs) in allergen tolerance in mice.36 Direct evidence at the level of mouse studies, for obvious reasons, are more difficult to obtain from human immunology studies.

Three levels of evidence prove this concept in humans. In the first level, the relationship of clinical nonreactivity (allergen tolerance) to allergens and immune tolerance could be observed in two types of direct tissue analysis in humans. One was the investigation of skin late-phase responses, and the second was the investigation of nasal mucosa biopsy specimens in allergic rhinitis. The data showed a decrease in T helper (Th) 2 cells and eosinophils in both cases by AIT and a parallel increase in Tregs and their cytokines in these tissues.7,8 The same data were shown in T-cell epitope peptide immunotherapy.9 In addition, allergen tolerance in beekeepers was associated with similar mechanisms and decreased skin late-phase responses.10

The second level of evidence came from direct analysis of human peripheral blood cells without any further culture. This level was obtained for mechanisms of allergen tolerance in healthy beekeepers, who are exposed to a high dose of venom allergens, and during AIT. Allergen tetramer-positive CD4+ antigen-specific T cells were analyzed or cytokine-secreting cells were purified in these studies, and the data demonstrated that allergen-specific Treg levels increase in these clinical allergen tolerance models.10,11 The third level of evidence was obtained from cell cultures. In both allergen extract and peptide immunotherapies, peripheral T-cell tolerance was shown with the development of decreased T-cell reactivity to whole allergens and their T-cell epitope peptides.9,12

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 cells by dendritic cells (DCs), and a Th2 switch and clonal allergen-specific T-cell expansion occurs.13,14 Depending on the microenvironment and the nature of the allergen, either immune tolerance develops or IgE sensitization occurs. DCs express a variety of Toll-like receptors (TLRs), C-type lectin receptors, or scavenger receptors that are activated by the microenvironmental molecules around allergens and may contribute to allergic sensitization.14 In the early phase, upon recognition of an antigen, DCs migrate to lymphoid tissues and activate T-cell maturation and differentiation by antigen presentation and cytokine release. In airway exposure, primary sensitization occurs mainly throughout the Waldeyer ring, whereas later B-cell expansion after reexposure takes place in lymph nodes that drain the upper and lower airways.15 Today, evidence shows that IgE-producing plasma cells are also localized in the bone marrow. These cells have been suggested as the reason for long-term IgE memory to explain why reversal of IgE production within a short time is difficult.16 Through insufficiently understood mechanisms in humans, naive T cells transform into Th2 cells in the presence of thymic stromal lymphopoietin, IL-4, IL-25, and IL-33. Th2 cells then drive naive B cells to undergo immunoglobulin class switching to IgE and expansion of allergen-specific IgE-producing B cells and plasma cells. Specific IgE antibodies engage their specific receptors (FcεRI) on mast cells and basophils, which concludes the sensitization phase (Fig 1). Upon reexposure to the same allergen, the IgE on the surface of mast cells and basophils is cross-linked, leading to the degranulation of the cells and then to the liberation of vasoactive amines, such as histamine, lipid mediators, and cytokines, which are responsible for the type 1 hypersensitivity reaction. The attraction of other effector cells, particularly eosinophils and more Th2 cells, to allergic tissues aggravates these effects and promotes further tissue inflammation as observed in the late-phase reaction.

Figure Jump LinkFigure 1 –  Sensitization and effector phase in allergic reactions. In individuals with allergies, differentiation and clonal expansion of Th2 cells may occur in response to common environmental antigens. Cytokines such as IL-4 and IL-13 are produced that induce IgE class switching and expansion in naive B cells and further clonal expansion in IgE-expressing memory B cells. IL-5 induces eosinophil activation and survival. The cross-linking of mast cell and basophil surface FcεRI-bound IgE leads to the release of vasoactive amines, lipid mediators, cytokines, and chemokines and to the immediate symptoms of allergic disease, including pruritis, wheal and flare, nasal conjunctival discharge, angioedema, systemic anaphylaxis, and bronchoconstriction. DC = dendritic cell; Th = T helper; TLSP = thymic stromal lymphopoietin.Grahic Jump Location

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 subsets play central roles (Fig 2, Table 1). Tregs and B regulatory cells (Bregs) are key players in this context. Two broad populations of Tregs exist: naturally occurring Tregs and the inducible Tregs. Multiple suppressor factors also have been demonstrated to play a role. Suppressor cytokines, such as IL-10 and transforming growth factor-β (TGF-β)17; cell surface molecules, such as cytotoxic T-lymphocyte antigen-4 and programmed death ligand18; and adenylcyclase-activating receptors, such as histamine receptor 2,10 have been proposed in various human studies. Many of the effects of Tregs were shown to depend on the production of IL-10 and TGF-β, with several clinically relevant findings. For example, decreased numbers of allergen-specific IL-10-producing Tregs were found in patients with allergic rhinitis.19 An increase in IL-10 production by T cells during AIT has been demonstrated,17,20 and IL-10 holds the propensity to suppress antigen-presenting cells and inhibits the expression of various proinflammatory cytokines.21

Figure Jump LinkFigure 2 –  Allergen tolerance: changes in cells of allergic inflammation during allergen tolerance. AIT = allergen-specific immunotherapy; Breg = B regulatory cell; Treg = T regulatory cell. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location
Table Graphic Jump Location
TABLE 1 ]  Characteristics of Major Cytokines That Play a Role in the Mechanisms of AIT

AIT = allergen-specific immunotherapy; DC = dendritic cell; IFN-γ = interferon γ; mDC = myeloid dendritic cell; MHC-II = major histocompatibility complex class II; NK = natural killer; NKT = natural killer T; TGF-β = transforming growth factor-β; Th = T helper; Treg = T regulatory cell; TSLP = thymic stromal lymphopoietin.

In addition to Tregs, a significant increase in the frequency of IL-10-producing Bregs (so-called Br1 cells) specific for the major bee venom allergen phospholipase A2 (PLA) was observed in AIT.22 IL-10-producing Br1 cells specifically upregulate IgG4 production, and these cells may play a role in peripheral tolerance.22 The frequencies of PLA-specific Br1 cells in patients receiving AIT reach a level comparable to that observed in highly exposed healthy beekeepers. At the same time, a strong decrease in the ratio of circulating PLA-specific IgG4-to-IgE antibodies was observed. Br1 cells could potently suppress antigen-specific CD4+ T-cell proliferation and specifically upregulated IgG4 production. Thus, Br1 cells may play a role in the induction of peripheral tolerance through IL-10 production as well as through IgG4 production.22 In addition to the direct role of Br1 cells, Treg-derived IL-10 stimulates B cells to undergo class switching toward the production of IgG4 antibodies in the presence of IL-4, whereas IL-4 alone induces IgE production.23

IgG4 does not exist in mice and has evolved in primates. It is considered a tolerogenic antibody. Allergen-specific IgG4 competes with allergen-specific IgE with the same specificity for allergen binding, thus, preventing the release of mediators from mast cells and basophils with further possible formation of IgE-allergen-IgG4 complexes that bind to both FcεRIIb and FcεRI, inhibiting the IgE receptor. These effects have been summarized by Wachholz and Durham.24 IgG4 antibodies of various specificities can exchange their immunoglobulin heavy chain through a process referred to as Fab arm exchange. This process leads to the formation of bispecific, functionally monovalent IgG4 antibodies that are unable to cross-link allergens.25 Furthermore, IgG4 is unable to fix complements and has limited affinity for activating Fcγ receptors.26,27 AIT is known to induce a transient increase in serum IgE levels in the early course of treatment, despite its protective clinical efficacy. For this reason, the assessment of IgE levels does not help in the measurement of therapeutic efficacy. The allergen-specific IgE-to-IgG4 antibody ratio and particularly functional IgG4 blocking activity might be a better choice for monitoring because the IgE blocking activity of IgG4 has been demonstrated to correlate with clinical AIT outcome.28 The effects of Bregs and Tregs are summarized in Figure 3.

Figure Jump LinkFigure 3 –  T and B regulatory cells contribute to allergen tolerance in several ways: suppression of effector Th1, Th2, Th9, Th17, and Th22 cells; suppression of allergen-specific IgE; induction of IgG4; and suppression of mast cells, basophils, and eosinophils. Br1 = IL-10-producing B regulatory cells; TGF = transforming growth factor. See Figure 2 legend for expansion of other abbreviations.Grahic Jump Location

TGF-β inhibits B-cell differentiation and the production of immunoglobulins, except for IgA, while promoting the formation of new Tregs from CD4+CD25. The main transcription factor of Th2 cells GATA3 is suppressed by TGF-β. Both subsets of Tregs have been shown to have direct cytolytic effects on other effector T cells in a granzyme- and perforin-dependent mechanism. Tregs interfere with the degranulation of mast cells by OX40-OX40 ligand interaction and inhibit costimulatory molecule (CD28) signaling on T cells.29,30

How immune tolerance to allergens is broken wherein patients may develop allergies after a certain age has been a long-standing question. The loss of immune tolerance does not simply include the formation of IgE; rather, it must be viewed as an inability of the immune system to suppress an overwhelming IgE-mediated response. The formation of IgE without clinical symptoms may indicate sensitization but not the development of relevant allergic disease. T-cell tolerance to allergens developed by AIT can be reversed by stimulation with certain cytokines, such as IL-1, IL-2, IL-6, and IL-15.12,31 In addition, the recent demonstration of the role of TLR4 and TLR8, but not TLR7 and TLR9, stimulation in breaking allergen tolerance supports the contribution of myeloid DC in the disruption and plasmocytoid DCs in the induction of allergen tolerance.31 This is in line with findings supporting the important roles of plasmocytoid DCs in the induction and maintenance of peripheral tolerance to food and inhalant allergens in human tonsils.32 The tonsils have been recently proposed as the target lymphoid organ of sublingual immunotherapy (SLIT), with the demonstration of allergen-specific Tregs in high percentages and direct in vivo generation of FoxP3+ Tregs. It should be noted that even after palatine tonsillectomy, the lingual tonsil, which contains plenty allergen-specific Tregs and plasmocytoid DCs, will stay as a lifelong immunologically active lymphoid organ.32

AIT also interferes with the innate immune system. IL-12-producing monocytes could be restored to numbers comparable with that in healthy individuals after rush immunotherapy in patients with cat and birch allergies.33 As a further mechanism of action of AIT, the cytokine production and proliferation of T cells is controlled by the T-cell/transmembrane immunoglobulin and mucin (TIM)-1 complex, which acts as a costimulatory signal. Th2 cells in individuals with allergies express TIM-1, and polymorphisms are known in atopic diseases, whereas the interaction of TIM-1 with the natural ligand TIM-4 is suppressed after AIT.34,35 Furthermore, downregulation of the costimulatory molecules CD80/CD86 on antigen-presenting cells has been observed during SLIT.36 Moreover, an upregulation of human β-defensins has been seen after AIT in patients with seasonal allergies.37

A normal immune response to high-dose allergen exposure is considered an efficient model to study the mechanisms of immune tolerance to allergens. Upon multiple beestings during the beekeeping season, allergen-specific T-cells downregulate their cytokine production and proliferate less, whereas the circulating ratio of IgE to IgG4 is 1,000 times higher in individuals with bee allergies compared with that of beekeepers.10,22 Similar to findings in beekeepers, elevated levels of specific IgG4 linked to IL-10 production were observed in children exposed to high doses of cat allergen.10,38

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 AIT has beneficial effects by changing the course of disease and restoring allergen-specific clinical tolerance (Table 2). Clinically, AIT affects all symptoms of allergic disorders, including the amelioration of asthma and allergic rhinoconjunctivitis, and inhibits the development of new sensitizations in the long term.5154

Table Graphic Jump Location
TABLE 2 ]  Results of Large-scale Clinical Trials and Systematic Reviews

AE = adverse event; AUC = area under the curve; DB-PCRT = double-blind placebo-controlled randomized trial; n/a = not available; PCT = placebo-controlled trial; SCIT = subcutaneous immunotherapy; SLIT = sublingual immunotherapy; SQ-U = standardized quality unit. See Table 1 legend for expansion of other abbreviation.

Various schedules are currently in use. Conventionally, the build-up phase involves injection of the allergen every 1 to 2 weeks until reaching the final dose after several months. Faster protocols have provided safe and efficient results as has been observed in rush, ultra-rush, and short-course regimens.55 The start of AIT may be chosen intraseasonally, preseasonally, or coseasonally. Two routes of administration are mainly in use worldwide—SLIT and subcutaneous immunotherapy (SCIT)—and are suitable for elderly patients and children. Both routes are effective in reducing symptom scores for seasonal and perennial allergens, increasing quality of life, and decreasing the need of other medication.2 Although SCIT appears to be superior to SLIT in grass pollen AIT, direct comparisons of both treatments are missing.56 Large meta-analyses have proven high efficacy of SCIT for seasonal allergies and asthma, with a favorable risk profile.49 SLIT appears to be less frequently associated with side effects compared with SCIT.

AIT is contraindicated in severe and uncontrolled bronchial asthma; therefore, clear inclusion criteria must be followed before starting this type of treatment. It is a prerequisite to establishing adequate pulmonary therapy and to obtaining an FEV1 > 70%. If this cannot be achieved by the use of standard asthma medication, systemic supplementation as described in the next section may decrease the risk of life-threatening asthma attacks elicited by AIT. Clinical AIT studies with an emphasis on asthma end points are scarce. In a large overview, the clinical efficacy of AIT was compared with topical steroids.48,57 The evidence of beneficial effects of AIT for the treatment of adults and children with allergic rhinitis with or without asthma suggests that AIT can favorably affect asthma. In children, sublingual AIT has been more extensively investigated than injection AIT. The severity and frequency of asthma exacerbations could be decreased by adequate AIT. AIT reduces the levels of objective parameters, such as exhaled nitric oxide, and increases peak expiratory flow in patients with allergic asthma.58 Adequately powered trials are needed to reinforce the evidence of AIT efficacy in asthma.

Performing AIT in children with allergic rhinoconjunctivitis could potentially prevent the development of asthma for up to 7 years after therapy.59 It has been demonstrated to be cost-effective in children by reducing and even saving other drug expenses.60 In addition, the need for systemic steroids can be reduced by the use of SCIT over 3 years in patients with allergic rhinitis.61 At the same time, quality of life can be improved significantly in patients with allergic rhinitis with or without asthma, leading to a reduction in annual sick days taken and, therefore, alleviating the financial burden of the disease.62

SCIT is considered the standard among all available AIT forms because its efficacy and long-term effects have been investigated thoroughly. SLIT, on the other hand, is emerging as the predominant therapy in many countries. SLIT requires much-higher allergen doses compared with SCIT to exert similar effects. Currently, SLIT is not recommended to treat venom allergies because adequate studies are still missing.63 Despite the reasonably fast onset of therapeutic effects in AIT, long-term therapy is required to obtain sustainable results. In pollen, house dust mite, and pet allergies, a duration of 3 years is usually sufficient, whereas hymenoptera venom AIT may require longer treatment periods.6466

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 complication in SLIT.69 No fatalities were recorded in a systematic review.70

AIT faces several problems related to limited efficacy, side effects, low patient adherence, and high costs.71 Standardizing the allergen extracts may improve the success rates, enabling better-customized treatment plans. Some novel ways of AIT are gaining popularity because their outcomes show noninferiority with a favorable risk/benefit profile. These approaches include the production of hybrids and chimeras of recombinant allergens,72 the use of T-cell epitope peptides, physical coupling of allergens to immune response modifiers,73 modifications such as fusion with modular antigen-translocator vaccines and hepatitis B vaccine pre-S antigen, and anti-human CR1 monoclonal antibody.7476 In addition, novel routes of vaccine administration, such as intra-lymph node and epicutaneous, represent other approaches.77,78 The coadministration of anti-IgE antibodies, such as omalizumab, may improve efficacy and decrease side effects.79

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 therapeutic approaches and regimens.2 The effects of AIT on the barrier function are yet to be defined because tight junctions as well as other junctional proteins might play a substantial role in all atopic diseases.80 Allergic rhinitis and nonallergic rhinitis show many similarities in their clinical appearances, whereas a huge gap exists in the pathophysiologic knowledge on nonallergic rhinitis and its endotypes.81 Potentially, AIT and acetylsalicylic acid desensitization could also play a distinct role in certain phenotypes of nonallergic rhinitis, which merits further investigation.82

An important unmet need in AIT is the identification and validation of biomarkers predictive of clinical response. In particular, an AIT responder endotype of asthma, allergic rhinitis, and atopic dermatitis with its biomarkers remains to be determined. Clinical trials, understandably, have selected patients with allergic sensitizations to particular antigens without further attempts to discern good from nonresponders. It is now believed that some large clinical trials may have been relatively unsuccessful because they were performed without attempting to classify patients with AIT into preidentified AIT responder subgroups.81,83 It seems essential to select AIT responder cases from the large pool of patients with asthma, allergic rhinitis, and even atopic dermatitis. The definition of an AIT-responsive endotype of allergic diseases and discovery of relevant biomarkers is urgently needed for patient selection and perhaps for the selection of the type of vaccine or route of application. The criteria for endotyping will most likely include clinical features along with molecular markers.

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 highly important. There are multiple opportunities for improving therapy by making it more reliable, convenient, pleasant, and safe. The correct selection of the responder patient population with defined biomarkers remains an essential unmet need in clinical settings.

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 Novartis, PREDICTA, EU Research Network,​ ​the Swiss National Science Foundation, MeDALL, Global Allergy and Asthma European Network, and Christine Kuhne-Center for Allergy Research and Education​.​ Dr C. A. Akdis has served as a consultant for Actelion, Sanofi-Aventis, Stallergenes, and Allergopharma; is the past president of the European Academy of Allergy and Clinical Immunology; a fellow and interest group member for the American Academy of Allergy, Asthma & Immunology; a former committee member of the Global Allergy and Asthma European Network; and director of the Christine Kuhne-Center for Allergy Research and Education. Drs van de Veen and Holzmann have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

AIT

allergen-specific immunotherapy

Br1

IL-10-producing B regulatory

Breg

B regulatory cell

DC

dendritic cell

PLA

phospholipase A2

SCIT

subcutaneous immunotherapy

SLIT

sublingual immunotherapy

TGF-β

transforming growth factor-β

Th

T helper

TIM

transmembrane immunoglobulin and mucin

TLR

Toll-like receptor

Treg

T regulatory cell

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Schroeder HW Jr, Cavacini L. Structure and function of immunoglobulins. J Allergy Clin Immunol. 2010;125(2)(suppl 2):S41-S52. [CrossRef] [PubMed]
 
Aalberse RC, Schuurman J. IgG4 breaking the rules. Immunology. 2002;105(1):9-19. [CrossRef] [PubMed]
 
Shamji MH, Ljorring C, Francis JN, et al. Functional rather than immunoreactive levels of IgG(4) correlate closely with clinical response to grass pollen immunotherapy. Allergy. 2012;67(2):217-226. [CrossRef] [PubMed]
 
Gri G, Piconese S, Frossi B, et al. CD4+CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction. Immunity. 2008;29(5):771-781. [CrossRef] [PubMed]
 
Taylor A, Akdis M, Joss A, et al. IL-10 inhibits CD28 and ICOS costimulations of T cells via src homology 2 domain-containing protein tyrosine phosphatase 1. J Allergy Clin Immunol. 2007;120(1):76-83. [CrossRef] [PubMed]
 
Kücüksezer UC, Palomares O, Rückert B, et al. Triggering of specific Toll-like receptors and proinflammatory cytokines breaks allergen-specific T-cell tolerance in human tonsils and peripheral blood. J Allergy Clin Immunol. 2013;131(3):875-885. [CrossRef] [PubMed]
 
Palomares O, Rückert B, Jartti T, et al. Induction and maintenance of allergen-specific FOXP3+ Treg cells in human tonsils as potential first-line organs of oral tolerance. J Allergy Clin Immunol. 2012;129(2):510-520. [CrossRef] [PubMed]
 
Plewako H, Wosińska K, Arvidsson M, Björkander J, Håkansson L, Rak S. Production of interleukin-12 by monocytes and interferon-gamma by natural killer cells in allergic patients during rush immunotherapy. Ann Allergy Asthma Immunol. 2006;97(4):464-468. [CrossRef] [PubMed]
 
Lee J, Phong B, Egloff AM, Kane LP. TIM polymorphisms—genetics and function. Genes Immun. 2011;12(8):595-604. [CrossRef] [PubMed]
 
Zhao CQ, Li TL, He SH, et al. Specific immunotherapy suppresses Th2 responses via modulating TIM1/TIM4 interaction on dendritic cells. Allergy. 2010;65(8):986-995. [CrossRef] [PubMed]
 
Piconi S, Trabattoni D, Rainone V, et al. Immunological effects of sublingual immunotherapy: clinical efficacy is associated with modulation of programmed cell death ligand 1, IL-10, and IgG4. J Immunol. 2010;185(12):7723-7730. [CrossRef] [PubMed]
 
Bogefors J, Kvarnhammar AM, Cardell LO. Upregulated levels of human β-defensins in patients with seasonal allergic rhinitis after allergen-specific immunotherapy treatment. Int Forum Allergy Rhinol. 2013;3(2):99-103. [CrossRef] [PubMed]
 
Platts-Mills TA, Woodfolk JA. Allergens and their role in the allergic immune response. Immunol Rev. 2011;242(1):51-68. [CrossRef] [PubMed]
 
Valenta R, Twaroch T, Swoboda I. Component-resolved diagnosis to optimize allergen-specific immunotherapy in the Mediterranean area. J Investig Allergol Clin Immunol. 2007;17(suppl 1):36-40. [PubMed]
 
Creticos PS, Maloney J, Bernstein DI, et al. Randomized controlled trial of a ragweed allergy immunotherapy tablet in North American and European adults. J Allergy Clin Immunol. 2013;131(5):1342-1349. [CrossRef] [PubMed]
 
Durham SR, Emminger W, Kapp A, et al. SQ-standardized sublingual grass immunotherapy: confirmation of disease modification 2 years after 3 years of treatment in a randomized trial. J Allergy Clin Immunol. 2012;129(3):717-725. [CrossRef] [PubMed]
 
Frew AJ, Powell RJ, Corrigan CJ, Durham SR; UK Immunotherapy Study Group. Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2006;117(2):319-325. [CrossRef] [PubMed]
 
Tabar AI, Arroabarren E, Echechipia S, Garcia BE, Martin S, Alvarez-Puebla MJ. Three years of specific immunotherapy may be sufficient in house dust mite respiratory allergy. J Allergy Clin Immunol. 2011;127(1):57-63. [CrossRef] [PubMed]
 
Wahn U, Klimek L, Ploszczuk A, et al. High-dose sublingual immunotherapy with single-dose aqueous grass pollen extract in children is effective and safe: a double-blind, placebo-controlled study. J Allergy Clin Immunol. 2012;130(4):886-893. [CrossRef] [PubMed]
 
Patel D, Couroux P, Hickey P, et al. Fel d 1-derived peptide antigen desensitization shows a persistent treatment effect 1 year after the start of dosing: a randomized, placebo-controlled study. J Allergy Clin Immunol. 2013;131(1):103-109. [CrossRef] [PubMed]
 
Shaikh WA, Shaikh SW. A prospective study on the safety of sublingual immunotherapy in pregnancy. Allergy. 2012;67(6):741-743. [CrossRef] [PubMed]
 
Radulovic S, Wilson D, Calderon M, Durham S. Systematic reviews of sublingual immunotherapy (SLIT). Allergy. 2011;66(6):740-752. [CrossRef] [PubMed]
 
Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2010;;(8):CD001186.
 
Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database Syst Rev. 2007;;(1):CD001936.
 
Boyle RJ, Elremeli M, Hockenhull J, et al. Venom immunotherapy for preventing allergic reactions to insect stings. Cochrane Database Syst Rev. 2012;10:CD008838. [PubMed]
 
Eng PA, Borer-Reinhold M, Heijnen IA, Gnehm HP. Twelve-year follow-up after discontinuation of preseasonal grass pollen immunotherapy in childhood. Allergy. 2006;61(2):198-201. [CrossRef] [PubMed]
 
Möller C, Dreborg S, Ferdousi HA, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol. 2002;109(2):251-256. [CrossRef] [PubMed]
 
Pajno GB, Barberio G, De Luca F, Morabito L, Parmiani S. Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy. A six-year follow-up study. Clin Exp Allergy. 2001;31(9):1392-1397. [CrossRef] [PubMed]
 
Walker SM, Pajno GB, Lima MT, Wilson DR, Durham SR. Grass pollen immunotherapy for seasonal rhinitis and asthma: a randomized, controlled trial. J Allergy Clin Immunol. 2001;107(1):87-93. [CrossRef] [PubMed]
 
Calabria CW. Accelerated immunotherapy schedules. Curr Allergy Asthma Rep. 2013;13(4):389-398. [CrossRef] [PubMed]
 
Di Bona D, Plaia A, Leto-Barone MS, La Piana S, Di Lorenzo G. Efficacy of subcutaneous and sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: a meta-analysis-based comparison. J Allergy Clin Immunol. 2012;130(5):1097-1107. [CrossRef] [PubMed]
 
Shaikh WA. Immunotherapy vs inhaled budesonide in bronchial asthma: an open, parallel, comparative trial. Clin Exp Allergy. 1997;27(11):1279-1284. [CrossRef] [PubMed]
 
Compalati E, Braido F, Canonica GW. An update on allergen immunotherapy and asthma. Curr Opin Pulm Med. 2014;20(1):109-117. [CrossRef] [PubMed]
 
Jacobsen L, Niggemann B, Dreborg S, et al; PAT Investigator Group. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy. 2007;62(8):943-948. [CrossRef] [PubMed]
 
Reinhold T, Ostermann J, Thum-Oltmer S, Brüggenjürgen B. Influence of subcutaneous specific immunotherapy on drug costs in children suffering from allergic asthma. Clin Transl Allergy. 2013;3(1):30. [CrossRef] [PubMed]
 
Aasbjerg K, Torp-Pedersen C, Backer V. Specific immunotherapy can greatly reduce the need for systemic steroids in allergic rhinitis. Allergy. 2012;67(11):1423-1429. [CrossRef] [PubMed]
 
Petersen KD, Kronborg C, Larsen JN, Dahl R, Gyrd-Hansen D. Patient related outcomes in a real life prospective follow up study: allergen immunotherapy increase quality of life and reduce sick days. World Allergy Organ J. 2013;6(1):15. [CrossRef] [PubMed]
 
Ruëff F, Bilò MB, Jutel M, Mosbech H, Müller U, Przybilla B; Interest Group on Hymenoptera Venom Allergy of the European Academy of Allergology and Clinical Immunology. Sublingual immunotherapy with venom is not recommended for patients with Hymenoptera venom allergy. J Allergy Clin Immunol. 2009;123(1):272-273. [CrossRef] [PubMed]
 
Durham SR, Walker SM, Varga EM, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med. 1999;341(7):468-475. [CrossRef] [PubMed]
 
Tabar AI, Arroabarren E, Echechipia S, Garcia BE, Martin S, Alvarez-Puebla MJ. Three years of specific immunotherapy may be sufficient in house dust mite respiratory allergy. J Allergy Clin Immunol. 2011;127(1):57-63. [CrossRef] [PubMed]
 
Bonifazi F, Jutel M, Biló BM, Birnbaum J, Muller U; EAACI Interest Group on Insect Venom Hypersensitivity. Prevention and treatment of hymenoptera venom allergy: guidelines for clinical practice. Allergy. 2005;60(12):1459-1470. [CrossRef] [PubMed]
 
Erekosima N, Suarez-Cuervo C, Ramanathan M, et al. Effectiveness of subcutaneous immunotherapy for allergic rhinoconjunctivitis and asthma: a systematic review. Laryngoscope. 2014;124(3):616-627. [CrossRef] [PubMed]
 
Passalacqua G, Baena-Cagnani CE, Bousquet J, et al. Grading local side effects of sublingual immunotherapy for respiratory allergy: speaking the same language. J Allergy Clin Immunol. 2013;132(1):93-98. [CrossRef] [PubMed]
 
Calderón MA, Simons FE, Malling HJ, Lockey RF, Moingeon P, Demoly P. Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile. Allergy. 2012;67(3):302-311. [CrossRef] [PubMed]
 
Dretzke J, Meadows A, Novielli N, Huissoon A, Fry-Smith A, Meads C. Subcutaneous and sublingual immunotherapy for seasonal allergic rhinitis: a systematic review and indirect comparison. J Allergy Clin Immunol. 2013;131(5):1361-1366. [CrossRef] [PubMed]
 
Kiel MA, Roder E, Gerth van Wijk R, Al MJ, Hop WC, Rutten-van Molken MP. Real-life compliance and persistence among users of subcutaneous and sublingual allergen immunotherapy. J Allergy Clin Immunol. 2013;132(2):353-360. [CrossRef] [PubMed]
 
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Creticos PS, Schroeder JT, Hamilton RG, et al; Immune Tolerance Network Group. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med. 2006;355(14):1445-1455. [CrossRef] [PubMed]
 
Niespodziana K, Focke-Tejkl M, Linhart B, et al. A hypoallergenic cat vaccine based on Fel d 1-derived peptides fused to hepatitis B PreS. J Allergy Clin Immunol. 2011;127(6):1562-1570. [CrossRef] [PubMed]
 
Martínez-Gómez JM, Johansen P, Rose H, et al. Targeting the MHC class II pathway of antigen presentation enhances immunogenicity and safety of allergen immunotherapy. Allergy. 2009;64(1):172-178. [CrossRef] [PubMed]
 
Kerekov N, Michova A, Muhtarova M, et al. Suppression of allergen-specific B lymphocytes by chimeric protein-engineered antibodies. Immunobiology. 2014;219(1):45-52. [CrossRef] [PubMed]
 
Senti G, Crameri R, Kuster D, et al. Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections. J Allergy Clin Immunol. 2012;129(5):1290-1296. [CrossRef] [PubMed]
 
Senti G, von Moos S, Tay F, et al. Epicutaneous allergen-specific immunotherapy ameliorates grass pollen-induced rhinoconjunctivitis: A double-blind, placebo-controlled dose escalation study. J Allergy Clin Immunol. 2012;129(1):128-135. [CrossRef] [PubMed]
 
Schneider LC, Rachid R, LeBovidge J, Blood E, Mittal M, Umetsu DT. A pilot study of omalizumab to facilitate rapid oral desensitization in high-risk peanut-allergic patients. J Allergy Clin Immunol. 2013;132(6):1368-1374. [CrossRef] [PubMed]
 
Trautmann A, Altznauer F, Akdis M, et al. The differential fate of cadherins during T-cell-induced keratinocyte apoptosis leads to spongiosis in eczematous dermatitis. J Invest Dermatol. 2001;117(4):927-934. [CrossRef] [PubMed]
 
Akdis CA, Bachert C, Cingi C, et al. Endotypes and phenotypes of chronic rhinosinusitis: a PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2013;131(6):1479-1490. [CrossRef] [PubMed]
 
Bousquet J, Fokkens W, Burney P, et al. Important research questions in allergy and related diseases: nonallergic rhinitis: a GA2LEN paper. Allergy. 2008;63(7):842-853. [CrossRef] [PubMed]
 
Lötvall J, Akdis CA, Bacharier LB, et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011;127(2):355-360. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Sensitization and effector phase in allergic reactions. In individuals with allergies, differentiation and clonal expansion of Th2 cells may occur in response to common environmental antigens. Cytokines such as IL-4 and IL-13 are produced that induce IgE class switching and expansion in naive B cells and further clonal expansion in IgE-expressing memory B cells. IL-5 induces eosinophil activation and survival. The cross-linking of mast cell and basophil surface FcεRI-bound IgE leads to the release of vasoactive amines, lipid mediators, cytokines, and chemokines and to the immediate symptoms of allergic disease, including pruritis, wheal and flare, nasal conjunctival discharge, angioedema, systemic anaphylaxis, and bronchoconstriction. DC = dendritic cell; Th = T helper; TLSP = thymic stromal lymphopoietin.Grahic Jump Location
Figure Jump LinkFigure 2 –  Allergen tolerance: changes in cells of allergic inflammation during allergen tolerance. AIT = allergen-specific immunotherapy; Breg = B regulatory cell; Treg = T regulatory cell. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location
Figure Jump LinkFigure 3 –  T and B regulatory cells contribute to allergen tolerance in several ways: suppression of effector Th1, Th2, Th9, Th17, and Th22 cells; suppression of allergen-specific IgE; induction of IgG4; and suppression of mast cells, basophils, and eosinophils. Br1 = IL-10-producing B regulatory cells; TGF = transforming growth factor. See Figure 2 legend for expansion of other abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Characteristics of Major Cytokines That Play a Role in the Mechanisms of AIT

AIT = allergen-specific immunotherapy; DC = dendritic cell; IFN-γ = interferon γ; mDC = myeloid dendritic cell; MHC-II = major histocompatibility complex class II; NK = natural killer; NKT = natural killer T; TGF-β = transforming growth factor-β; Th = T helper; Treg = T regulatory cell; TSLP = thymic stromal lymphopoietin.

Table Graphic Jump Location
TABLE 2 ]  Results of Large-scale Clinical Trials and Systematic Reviews

AE = adverse event; AUC = area under the curve; DB-PCRT = double-blind placebo-controlled randomized trial; n/a = not available; PCT = placebo-controlled trial; SCIT = subcutaneous immunotherapy; SLIT = sublingual immunotherapy; SQ-U = standardized quality unit. See Table 1 legend for expansion of other abbreviation.

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Aalberse RC, Schuurman J. IgG4 breaking the rules. Immunology. 2002;105(1):9-19. [CrossRef] [PubMed]
 
Shamji MH, Ljorring C, Francis JN, et al. Functional rather than immunoreactive levels of IgG(4) correlate closely with clinical response to grass pollen immunotherapy. Allergy. 2012;67(2):217-226. [CrossRef] [PubMed]
 
Gri G, Piconese S, Frossi B, et al. CD4+CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction. Immunity. 2008;29(5):771-781. [CrossRef] [PubMed]
 
Taylor A, Akdis M, Joss A, et al. IL-10 inhibits CD28 and ICOS costimulations of T cells via src homology 2 domain-containing protein tyrosine phosphatase 1. J Allergy Clin Immunol. 2007;120(1):76-83. [CrossRef] [PubMed]
 
Kücüksezer UC, Palomares O, Rückert B, et al. Triggering of specific Toll-like receptors and proinflammatory cytokines breaks allergen-specific T-cell tolerance in human tonsils and peripheral blood. J Allergy Clin Immunol. 2013;131(3):875-885. [CrossRef] [PubMed]
 
Palomares O, Rückert B, Jartti T, et al. Induction and maintenance of allergen-specific FOXP3+ Treg cells in human tonsils as potential first-line organs of oral tolerance. J Allergy Clin Immunol. 2012;129(2):510-520. [CrossRef] [PubMed]
 
Plewako H, Wosińska K, Arvidsson M, Björkander J, Håkansson L, Rak S. Production of interleukin-12 by monocytes and interferon-gamma by natural killer cells in allergic patients during rush immunotherapy. Ann Allergy Asthma Immunol. 2006;97(4):464-468. [CrossRef] [PubMed]
 
Lee J, Phong B, Egloff AM, Kane LP. TIM polymorphisms—genetics and function. Genes Immun. 2011;12(8):595-604. [CrossRef] [PubMed]
 
Zhao CQ, Li TL, He SH, et al. Specific immunotherapy suppresses Th2 responses via modulating TIM1/TIM4 interaction on dendritic cells. Allergy. 2010;65(8):986-995. [CrossRef] [PubMed]
 
Piconi S, Trabattoni D, Rainone V, et al. Immunological effects of sublingual immunotherapy: clinical efficacy is associated with modulation of programmed cell death ligand 1, IL-10, and IgG4. J Immunol. 2010;185(12):7723-7730. [CrossRef] [PubMed]
 
Bogefors J, Kvarnhammar AM, Cardell LO. Upregulated levels of human β-defensins in patients with seasonal allergic rhinitis after allergen-specific immunotherapy treatment. Int Forum Allergy Rhinol. 2013;3(2):99-103. [CrossRef] [PubMed]
 
Platts-Mills TA, Woodfolk JA. Allergens and their role in the allergic immune response. Immunol Rev. 2011;242(1):51-68. [CrossRef] [PubMed]
 
Valenta R, Twaroch T, Swoboda I. Component-resolved diagnosis to optimize allergen-specific immunotherapy in the Mediterranean area. J Investig Allergol Clin Immunol. 2007;17(suppl 1):36-40. [PubMed]
 
Creticos PS, Maloney J, Bernstein DI, et al. Randomized controlled trial of a ragweed allergy immunotherapy tablet in North American and European adults. J Allergy Clin Immunol. 2013;131(5):1342-1349. [CrossRef] [PubMed]
 
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