Mechanisms of allergen-specific immunotherapy: Multiple suppressor factors at work in immune tolerance to allergens
2014; Elsevier BV; Volume: 133; Issue: 3 Linguagem: Inglês
10.1016/j.jaci.2013.12.1088
ISSN1097-6825
AutoresMübeccel Akdiş, Cezmi A. Akdiş,
Tópico(s)Asthma and respiratory diseases
ResumoAllergen-specific immunotherapy (AIT) has been used for more than 100 years as a desensitizing therapy for IgE-mediated allergic diseases and represents a potentially curative way of treatment. The mechanisms of action of AIT include the induction of very early desensitization of mast cells and basophils; generation of regulatory T and regulatory B (Breg) cell responses; regulation of IgE and IgG4; decreases in numbers and activity of eosinophils and mast cells in mucosal allergic tissues; and decreases in the activity of basophils in circulation. Skewing of allergen-specific effector T and effector B cells to a regulatory phenotype appears as a key event in the course of AIT and normal immune response to allergens. Recently, inducible IL-10–secreting Breg cells were also demonstrated to contribute to allergen tolerance through suppression of effector T cells and selective induction of IgG4 isotype antibodies. Allergen-specific regulatory T and Breg cells orchestrate a general immunoregulatory activity, which can be summarized as suppression of cytokines from inflammatory dendritic cells; suppression of effector TH1, TH2, and TH17 cells; suppression of allergen-specific IgE and induction of IgG4; and suppression of migration of mast cells, basophils, eosinophils, and effector T cells to tissues. A detailed knowledge of the mechanisms of AIT is not only important in designing the prevention and treatment of allergic diseases but might also find applications in the treatment of autoimmune diseases, organ transplantation, chronic infection, and cancer. Allergen-specific immunotherapy (AIT) has been used for more than 100 years as a desensitizing therapy for IgE-mediated allergic diseases and represents a potentially curative way of treatment. The mechanisms of action of AIT include the induction of very early desensitization of mast cells and basophils; generation of regulatory T and regulatory B (Breg) cell responses; regulation of IgE and IgG4; decreases in numbers and activity of eosinophils and mast cells in mucosal allergic tissues; and decreases in the activity of basophils in circulation. Skewing of allergen-specific effector T and effector B cells to a regulatory phenotype appears as a key event in the course of AIT and normal immune response to allergens. Recently, inducible IL-10–secreting Breg cells were also demonstrated to contribute to allergen tolerance through suppression of effector T cells and selective induction of IgG4 isotype antibodies. Allergen-specific regulatory T and Breg cells orchestrate a general immunoregulatory activity, which can be summarized as suppression of cytokines from inflammatory dendritic cells; suppression of effector TH1, TH2, and TH17 cells; suppression of allergen-specific IgE and induction of IgG4; and suppression of migration of mast cells, basophils, eosinophils, and effector T cells to tissues. A detailed knowledge of the mechanisms of AIT is not only important in designing the prevention and treatment of allergic diseases but might also find applications in the treatment of autoimmune diseases, organ transplantation, chronic infection, and cancer. GlossaryCYTOTOXIC T LYMPHOCYTE ANTIGEN 4 (CTLA-4)Also known as CD152, CTLA-4 is expressed on activated T cells, is a member of the immunoglobulin superfamily, and contains an immunoreceptor tyrosine-based inhibition motif. CTLA-4 binds to B7 and limits T-cell activation. CTLA-4–deficient mice have lymphoproliferative disease.ENDOTYPESA definition of a disease subtype that is defined by the underlying pathobiology, as opposed to a phenotype, which is defined by the clinical characteristics. An example of an asthmatic endotype would be aspirin-exacerbated respiratory disease.GM-CSFGM-CSF stimulates stem cells to produce granulocytes and monocytes.IgG4IgG4 has been associated with the development of immune tolerance to antigens, including foods, and the ratio of specific IgE to IgG4 might be useful in the context of desensitization. IgG4 does not bind complement and blocks IgE binding to allergens.IL-5IL-5 promotes the survival, activation, and chemotaxis of eosinophils. Its receptor shares a common β chain with the IL-3 receptor.IL-6IL-6 is released by dendritic cells, primes for TH2 effector cells, and inhibits the suppressive functions of CD4+CD25+ Treg cells.IL-19, IL-20, IL-22, IL-24, IL-26All are members of the IL-10 family. IL-19 is produced by B cells and monocytes in response to GM-CSF and increases the production of IL-4 and IL-13. IL-20 is involved in cutaneous inflammation, such as that seen in patients with psoriasis, and produced by keratinocytes and monocytes. IL-22 is produced by activated T cells, as well as mast cells, and largely targets hepatocytes to induce acute-phase reactants. IL-24 is produced by monocytes, macrophages, and TH2 cells. It controls cell survival and proliferation through signal transducer and activator of transcription (STAT) 1 and STAT3. IL-24 plays important roles in wound healing, psoriasis, and cancer. IL-26 is expressed in certain herpesvirus-transformed T cells but not in primary stimulated T cells. IL-26 signals through IL-20 receptor 1 and IL-10 receptor 2.PROGRAMMED DEATH 1 (PD-1)A member of the CD28 family, PD-1 binds to its ligands, PD-L1 and PD-L2, to limit immune response development. PD-1 blockade with an mAb has recently been used in patients with B-cell lymphoma.RUNT-RELATED TRANSCRIPTION FACTOR (RUNX)A family of transcription factors that cause epigenetic changes for gene silencing or activation. For example, Runx3 inhibits IL-4 production in conjunction with T-box transcription factor (T-bet) in TH2 cells and increases IFN-γ production in TH1 cells.TH9A T-cell subset that is defined by the production of IL-9 and promoted in the presence of IL-4 and TGF-β1. IL-9 has a number of functions, including increased mucus production, in asthmatic patients.TH17TH17 cells are defined by IL-17A, IL-17F, IL-6, IL-21, IL-22, and TNF-α production and are involved in autoimmune diseases, such as inflammatory bowel disease. IL-23 increases IL-17 production and activates the transcription factor signal transducer and activator of transcription 3 to maintain a TH17 phenotype of CD4+ T cells. IL-17 in turn induces IL-1β and IL-6.TOLL-LIKE RECEPTOR (TLR)Essential members of the innate immune system, TLRs are pattern recognition receptors that bind both endogenous and exogenous ligands. TLR4 binds LPS from gram-negative bacteria, heat shock protein 6, and respiratory syncytial virus protein F. TLR7 and TLR8 bind single-stranded RNA and are important for antiviral defense, whereas TLR3 binds double-stranded RNA. TLR9 binds CpG.The Editors wish to acknowledge Seema S. Aceves, PhD, for preparing this glossary. Also known as CD152, CTLA-4 is expressed on activated T cells, is a member of the immunoglobulin superfamily, and contains an immunoreceptor tyrosine-based inhibition motif. CTLA-4 binds to B7 and limits T-cell activation. CTLA-4–deficient mice have lymphoproliferative disease. A definition of a disease subtype that is defined by the underlying pathobiology, as opposed to a phenotype, which is defined by the clinical characteristics. An example of an asthmatic endotype would be aspirin-exacerbated respiratory disease. GM-CSF stimulates stem cells to produce granulocytes and monocytes. IgG4 has been associated with the development of immune tolerance to antigens, including foods, and the ratio of specific IgE to IgG4 might be useful in the context of desensitization. IgG4 does not bind complement and blocks IgE binding to allergens. IL-5 promotes the survival, activation, and chemotaxis of eosinophils. Its receptor shares a common β chain with the IL-3 receptor. IL-6 is released by dendritic cells, primes for TH2 effector cells, and inhibits the suppressive functions of CD4+CD25+ Treg cells. All are members of the IL-10 family. IL-19 is produced by B cells and monocytes in response to GM-CSF and increases the production of IL-4 and IL-13. IL-20 is involved in cutaneous inflammation, such as that seen in patients with psoriasis, and produced by keratinocytes and monocytes. IL-22 is produced by activated T cells, as well as mast cells, and largely targets hepatocytes to induce acute-phase reactants. IL-24 is produced by monocytes, macrophages, and TH2 cells. It controls cell survival and proliferation through signal transducer and activator of transcription (STAT) 1 and STAT3. IL-24 plays important roles in wound healing, psoriasis, and cancer. IL-26 is expressed in certain herpesvirus-transformed T cells but not in primary stimulated T cells. IL-26 signals through IL-20 receptor 1 and IL-10 receptor 2. A member of the CD28 family, PD-1 binds to its ligands, PD-L1 and PD-L2, to limit immune response development. PD-1 blockade with an mAb has recently been used in patients with B-cell lymphoma. A family of transcription factors that cause epigenetic changes for gene silencing or activation. For example, Runx3 inhibits IL-4 production in conjunction with T-box transcription factor (T-bet) in TH2 cells and increases IFN-γ production in TH1 cells. A T-cell subset that is defined by the production of IL-9 and promoted in the presence of IL-4 and TGF-β1. IL-9 has a number of functions, including increased mucus production, in asthmatic patients. TH17 cells are defined by IL-17A, IL-17F, IL-6, IL-21, IL-22, and TNF-α production and are involved in autoimmune diseases, such as inflammatory bowel disease. IL-23 increases IL-17 production and activates the transcription factor signal transducer and activator of transcription 3 to maintain a TH17 phenotype of CD4+ T cells. IL-17 in turn induces IL-1β and IL-6. Essential members of the innate immune system, TLRs are pattern recognition receptors that bind both endogenous and exogenous ligands. TLR4 binds LPS from gram-negative bacteria, heat shock protein 6, and respiratory syncytial virus protein F. TLR7 and TLR8 bind single-stranded RNA and are important for antiviral defense, whereas TLR3 binds double-stranded RNA. TLR9 binds CpG. The Editors wish to acknowledge Seema S. Aceves, PhD, for preparing this glossary. Allergen-specific immunotherapy (AIT) is effective in reducing symptoms of allergic asthma and rhinitis, as well as venom-induced anaphylaxis. A key feature of AIT is to change the course of disease by altering the underlying pathology. Currently, 2 types of AIT are in clinical practice, subcutaneous immunotherapy and sublingual immunotherapy (SLIT), and several novel AIT approaches are being evaluated in clinical trials.1Burks A.W. Calderon M.A. Casale T. Cox L. Demoly P. Jutel M. et al.Update on allergy immunotherapy: American Academy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical Immunology/PRACTALL consensus report.J Allergy Clin Immunol. 2013; 131: 1288-1296.e3Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar, 2Calderon M.A. Casale T. Cox L. Akdis C.A. Burks A.W. Nelson H.S. et al.Allergen immunotherapy: a new semantic framework from the European Academy of Allergy and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL consensus report.Allergy. 2013; 68: 825-828Crossref PubMed Scopus (37) Google Scholar There is moderate-level evidence for the efficacy of specific immunotherapy against atopic dermatitis3Bae J.M. Choi Y.Y. Park C.O. Chung K.Y. Lee K.H. Efficacy of allergen-specific immunotherapy for atopic dermatitis: a systematic review and meta-analysis of randomized controlled trials.J Allergy Clin Immunol. 2013; 132: 110-117Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar and SLIT for the treatment of allergic rhinitis and asthma provided by recent meta-analyses.4Lin S.Y. Erekosima N. Kim J.M. Ramanathan M. Suarez-Cuervo C. Chelladurai Y. et al.Sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: a systematic review.JAMA. 2013; 309: 1278-1288Crossref PubMed Scopus (201) Google Scholar Dysregulated immune function plays an essential role in many IgE-mediated diseases, including asthma, atopic dermatitis, allergic rhinitis, food allergy, and venom allergy, as well as autoimmune diseases, organ transplantation, tumors, chronic infections, and successful pregnancy.5Berin M.C. Mayer L. Can we produce true tolerance in patients with food allergy?.J Allergy Clin Immunol. 2013; 131: 14-22Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 6Akdis C.A. Therapies for allergic inflammation: refining strategies to induce tolerance.Nat Med. 2012; 18: 736-749Crossref PubMed Scopus (244) Google Scholar Multiple mechanisms of immune regulation take place depending on the type, place, intensity, and chronicity of the immune response, as well as antigens/allergens, adjuvants, cytokines, or small molecules in the micromilieu. In addition, the type of tissue response plays an essential role in the thresholds for inflammation versus tolerance. The physiopathology of allergic diseases is complex and influenced by many factors, including genetic susceptibility, route of exposure, antigen/allergen dose, time of exposure, structural characteristics of the allergen/antigen, and coexposure with stimulators of innate immune response, such as infections or commensal bacteria. Allergens enter the body through the respiratory tract, gut, conjunctiva, injured skin, or insect stings, and most of the time, the result is induction of tolerance as a natural mechanism.5Berin M.C. Mayer L. Can we produce true tolerance in patients with food allergy?.J Allergy Clin Immunol. 2013; 131: 14-22Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 6Akdis C.A. Therapies for allergic inflammation: refining strategies to induce tolerance.Nat Med. 2012; 18: 736-749Crossref PubMed Scopus (244) Google Scholar, 7Akdis C.A. Allergy and hypersensitivity: mechanisms of allergic disease.Curr Opin Immunol. 2006; 18: 718-726Crossref PubMed Scopus (114) Google Scholar, 8Akdis M. Akdis A.C. Immune tolerance.in: Adkinson Jr., N.F. Bochner B.S. Burks A.W. Busse W.W. Holgate S.T. Lemanske Jr., R.F. Middleton’s allergy: principles and practice. 8th ed. Elsevier, Amsterdam2013Google Scholar Immune tolerance to allergens is characterized by establishment of long-term clinical tolerance.9Durham S.R. Emminger W. Kapp A. Colombo G. de Monchy J.G. Rak S. et al.Long-term clinical efficacy in grass pollen-induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet.J Allergy Clin Immunol. 2010; 125 (e1-7): 131-138Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar, 10Akdis M. Akdis C.A. Therapeutic manipulation of immune tolerance in allergic disease.Nat Rev Drug Discov. 2009; 8: 645-660Crossref PubMed Scopus (185) Google Scholar The mechanisms by which allergen tolerance is established in human subjects have been studied through various modes of AIT, as have the processes by which a healthy immune response develops during high dose of allergen exposure in beekeepers and cat owners.1Burks A.W. Calderon M.A. Casale T. Cox L. Demoly P. Jutel M. et al.Update on allergy immunotherapy: American Academy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical Immunology/PRACTALL consensus report.J Allergy Clin Immunol. 2013; 131: 1288-1296.e3Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar, 2Calderon M.A. Casale T. Cox L. Akdis C.A. Burks A.W. Nelson H.S. et al.Allergen immunotherapy: a new semantic framework from the European Academy of Allergy and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL consensus report.Allergy. 2013; 68: 825-828Crossref PubMed Scopus (37) Google Scholar, 11Meiler F. Zumkehr J. Klunker S. Ruckert B. Akdis C.A. Akdis M. In vivo switch to IL-10-secreting T regulatory cells in high dose allergen exposure.J Exp Med. 2008; 205: 2887-2898Crossref PubMed Scopus (405) Google Scholar, 12Platts-Mills T.A. Woodfolk J.A. Allergens and their role in the allergic immune response.Immunol Rev. 2011; 242: 51-68Crossref PubMed Scopus (96) Google Scholar, 13Jutel M. Van de Veen W. Agache I. Azkur K.A. Akdis M. Akdis C.A. Mechanisms of allergen-specific immunotherapy and novel ways for vaccine development.Allergol Int. 2013; 62: 425-433Crossref PubMed Scopus (55) Google Scholar Although many mechanisms are not fully elucidated, they include changes in the characteristics of allergen-specific memory T- and B-cell responses and the production of specific antibody isotypes to skew the immune response toward no inflammation, as well as decreased activation, tissue migration, and mediator release of mast cells, basophils, and eosinophils. After the discovery of TH1 and TH2 cell subsets in 1986, during the last 27 years, it is well understood that there is reciprocal regulation between individual TH cell subsets, such as TH1, TH2, TH9, TH17, and TH2214Akdis M. Palomares O. van de Veen W. van Splunter M. Akdis C.A. TH17 and TH22 cells: a confusion of antimicrobial response with tissue inflammation versus protection.J Allergy Clin Immunol. 2012; 129: 1438-1451Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 15Akdis M. Burgler S. Crameri R. Eiwegger T. Fujita H. Gomez E. et al.Interleukins, from 1 to 37, and interferon-gamma: receptors, functions, and roles in diseases.J Allergy Clin Immunol. 2011; 127 (e1-70): 701-721Abstract Full Text Full Text PDF PubMed Scopus (616) Google Scholar, 16Smarr C.B. Bryce P.J. Miller S.D. Antigen-specific tolerance in immunotherapy of Th2-associated allergic diseases.Crit Rev Immunol. 2013; 33: 389-414Crossref PubMed Scopus (42) Google Scholar; however, regulatory T (Treg) cells play a major role in the suppression of effector T-cell responses in different diseases.6Akdis C.A. Therapies for allergic inflammation: refining strategies to induce tolerance.Nat Med. 2012; 18: 736-749Crossref PubMed Scopus (244) Google Scholar, 10Akdis M. Akdis C.A. Therapeutic manipulation of immune tolerance in allergic disease.Nat Rev Drug Discov. 2009; 8: 645-660Crossref PubMed Scopus (185) Google Scholar Allergic diseases are complex disorders with several disease variants caused by different underlying cellular and molecular mechanisms. Although there are several clinically relevant phenotypes for rhinitis, asthma, atopic dermatitis, and even urticaria, these phenotypes do not necessarily provide any insight into the pathomechanisms that underpin the diseases. An important unmet need in patients with AIT is the identification and validation of biomarkers that are predictive of clinical response. It is now thought that some clinical trials might have been unsuccessful in the past because they were performed without attempting to classify patients with AIT into subgroups that are defined by a distinct pathophysiology, namely endotypes.17Lotvall J. Akdis C.A. Bacharier L.B. Bjermer L. Casale T.B. Custovic A. et al.Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome.J Allergy Clin Immunol. 2011; 127: 355-360Abstract Full Text Full Text PDF PubMed Scopus (923) Google Scholar, 18Akdis C.A. Bachert C. Cingi C. Dykewicz M.S. Hellings P.W. Naclerio R.M. 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: 1479-1490Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar It seems essential to select AIT responder cases from the big pool of patients with asthma, allergic rhinitis, and even atopic dermatitis. The definition of an AIT-responsive endotype of allergic diseases and relevant biomarkers is urgently needed for patient selection and maybe also even for the selection of the type of vaccine or route of application. Cellular and molecular events that take place during the course of AIT can be classified into 4 groups (Fig 1). Although there is significant variation between donors and protocols, decreases in mast cell and basophil activity and degranulation and the tendency for systemic anaphylaxis start to take place within hours when natural allergens are used. The second group of events are generation of allergen-specific Treg and regulatory B (Breg) cells and suppression of allergen-specific effector T-cell subsets. The third group of events include regulation of antibody isotypes demonstrating an early increase in specific IgE levels, which later decrease, and an early and continuous increase in specific IgG4 levels. The fourth group of events take place after several months, with decreases in tissue mast cells and eosinophils and release of their mediators. It is accompanied by a decrease in type I skin test reactivity. Multiple cell types in the blood and affected organs show changes and contribute to allergen-specific immune tolerance development (Table I). All of these events are discussed below, with a special focus on Treg and Breg cells and their suppressive functions. AIT represents one of the most forward promising areas for better understanding of antigen-specific immune responses and immune tolerance development in human subjects. However, there still remains much to be investigated (see Box 1).Table IRoles of different cells in the development of allergen toleranceT cellsDecreased allergen-induced proliferation (PBMCs)Induction of allergen-specific TR1 cells (PBMCs and nasal biopsies in allergic rhinitis)Increased FOXP3 expression (PBMCs and T cells)Increased secretion of IL-10 and TGF-β (PBMCs and nasal biopsies in allergic rhinitis)Suppression of TH2 cells and cytokines (PBMCs)Decreased T-cell numbers in LPRs (skin LPRs)Increased FOXP3 expression (nasal biopsies in allergic rhinitis)B cellsInduction of allergen-specific IL-10–secreting BR1 cellsEarly increased and late decreased specific IgE production (serum)Increased specific IgG4 production (serum)Increased specific IgA production (serum)Suppressed IgE-facilitated antigen presentation (blood and cell lines)DCsSuppressed IgE-facilitated antigen presentation (blood)EosinophilsReduction of tissue numbers (allergic rhinitis)Decrease in mediator release (nose and blood)Mast cellsReduction of tissue numbers (allergic rhinitis)Decrease in mediator release (allergic rhinitis)Decrease in proinflammatory cytokine production (allergic rhinitis)BasophilsDecrease in mediator release (blood)Decrease in proinflammatory cytokine production (blood)Increased HR2 levels with suppressive effects on degranulation and cytokine production (blood) Open table in a new tab Box 1What is unknown in the mechanisms of AIT•Molecular mechanisms of Treg and Breg cell generation in vivo•Adjuvants that promote Treg and Breg cells in vivo•Lifespan of AIT-induced Treg and Breg cells in vivo•Relationship of resident tissue cells with AIT-induced immune tolerance•Early biomarkers and predictors for the success of immunotherapy•Local events in the microenvironment during SLIT•Identifying the optimal allergen dose and mechanisms of high-dose and low-dose AIT•Mechanisms of long-term maintenance of allergen tolerance•Is boosting needed for long-term effect? What should be the optimum time?•Mechanisms of inducing high-affinity IgG4 and low-affinity IgE antibodies •Molecular mechanisms of Treg and Breg cell generation in vivo•Adjuvants that promote Treg and Breg cells in vivo•Lifespan of AIT-induced Treg and Breg cells in vivo•Relationship of resident tissue cells with AIT-induced immune tolerance•Early biomarkers and predictors for the success of immunotherapy•Local events in the microenvironment during SLIT•Identifying the optimal allergen dose and mechanisms of high-dose and low-dose AIT•Mechanisms of long-term maintenance of allergen tolerance•Is boosting needed for long-term effect? What should be the optimum time?•Mechanisms of inducing high-affinity IgG4 and low-affinity IgE antibodies Several mechanisms have been proposed to explain why mast cells and basophils become unresponsive to environmental proteins, even in the presence of specific IgE. Notably, after the first injection of AIT, very early decreases in the susceptibility of mast cells and basophils to degranulation and in systemic anaphylaxis can be observed, even though all the treated subjects have high quantities of specific IgE. This effect occurs when 3-dimensional structure-intact allergens are used. Although the underlying molecular pathways remain to be elucidated, this effect seems similar to the one observed when these 2 immune cell types are rapidly desensitized during anaphylactic reactions to drugs.19Romano A. Torres M.J. Castells M. Sanz M.L. Blanca M. Diagnosis and management of drug hypersensitivity reactions.J Allergy Clin Immunol. 2011; 127: S67-S73Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar Anaphylaxis is associated with the release of inflammatory mediators from both mast cells and basophils, and successful hyposensitization alters the magnitude of mediator release.20Eberlein-Konig B. Ullmann S. Thomas P. Przybilla B. Tryptase and histamine release due to a sting challenge in bee venom allergic patients treated successfully or unsuccessfully with hyposensitization.Clin Exp Allergy. 1995; 25: 704-712Crossref PubMed Scopus (57) Google Scholar The release of these inflammatory mediators in low quantities, less than the required dose for systemic anaphylaxis, might affect the subsequent threshold of activation of mast cells and basophils.20Eberlein-Konig B. Ullmann S. Thomas P. Przybilla B. Tryptase and histamine release due to a sting challenge in bee venom allergic patients treated successfully or unsuccessfully with hyposensitization.Clin Exp Allergy. 1995; 25: 704-712Crossref PubMed Scopus (57) Google Scholar, 21Plewako H. Wosinska K. Arvidsson M. Bjorkander J. Skov P.S. Hakansson L. et al.Basophil interleukin 4 and interleukin 13 production is suppressed during the early phase of rush immunotherapy.Int Arch Allergy Immunol. 2006; 141: 346-353Crossref PubMed Scopus (53) Google Scholar The investigation of histamine receptor (HR) expression on basophils of patients undergoing venom immunotherapy (VIT) demonstrated that selective suppression of basophils mediated by H2R might be highly relevant for the very early induction of allergen tolerance and the so-called desensitization effect of VIT. Rapid upregulation of H2R within the first 6 hours of the build-up phase of VIT was observed. H2R strongly suppressed FcεRI-induced activation and mediator release of basophils, including histamine and sulfidoleukotrienes, as well as cytokine production in vitro.22Novak N. Mete N. Bussmann C. Maintz L. Bieber T. Akdis M. et al.Early suppression of basophil activation during allergen-specific immunotherapy by histamine receptor 2.J Allergy Clin Immunol. 2012; 130: 1153-1158Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar It is now generally appreciated that peripheral T-cell tolerance is essential for a normal immune response and successful immunotherapy of allergic disorders (Fig 2).23James L.K. Shamji M.H. Walker S.M. Wilson D.R. Wachholz P.A. Francis J.N. et al.Long-term tolerance after allergen immunotherapy is accompanied by selective persistence of blocking antibodies.J Allergy Clin Immunol. 2011; 127 (e1-5): 509-516Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar Although multiple factors contribute, the tolerant state of specific cells essentially results from increased IL-10 secretion.24Akdis C.A. Blesken T. Akdis M. Wuthrich B. Blaser K. 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Blaser K. et al.Regulation of T cells and cytokines by the interleukin-10 (IL-10)-family cytokines IL-19, IL-20, IL-22, IL-24 and IL-26.Eur J Immunol. 2006; 36: 380-388Crossref PubMed Scopus (124) Google Scholar IL-10 particularly originates from activated and antigen-specific Treg and Breg cell populations and increases during AIT and natural allergen exposure.28van de Veen W. Stanic B. Yaman G. Wawrzyniak M. Sollner S. Akdis D.G. et al.IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses.J Allergy Clin Immunol. 2013; 131: 1204-1212Abstract Full Text Full Text PDF PubMed Scopus (482) Google Scholar, 29Jutel M. Pichler W.J. Skrbic D. Urwyler A. Dahinden C. Müller U.R. Bee venom immunotherapy results in decrease of IL-4 and IL-5 and increase of IFN-g secretion in specific allergen stimulated T cell cultures.J Immunol. 1995; 154: 4178-4194Google Scholar, 30Jutel M. Akdis M. Budak F. Aebischer-Casaulta C. Wrzyszcz M. 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