International Consensus on Allergen Immunotherapy II: Mechanisms, standardization, and pharmacoeconomics
2016; Elsevier BV; Volume: 137; Issue: 2 Linguagem: Inglês
10.1016/j.jaci.2015.12.1300
ISSN1097-6825
AutoresMarek Jutel, Ioana Agache, С. Бонини, A. Wesley Burks, Moisés A. Calderón, Giorgio Walter Canonica, Linda Cox, Pascal Demoly, A.J. Frew, Robyn E. O’Hehir, Jörg Kleine‐Tebbe, Antonella Muraro, Gideon Lack, Désirée Larenas‐Linnemann, Michael Levin, Bryan Martin, Harald Nelson, Ruby Pawankar, Oliver Pfaar, Ronald van Ree, Hugh A. Sampson, James L. Sublett, Kazunari Sugita, George Du Toit, Thomas Werfel, Roy Gerth van Wijk, Luo Zhang, Mübeccel Akdiş, Cezmi A. Akdiş,
Tópico(s)Food Allergy and Anaphylaxis Research
ResumoThis article continues the comprehensive international consensus (ICON) statement on allergen immunotherapy (AIT). The initial article also recently appeared in the Journal. The conclusions below focus on key mechanisms of AIT-triggered tolerance, requirements in allergen standardization, AIT cost-effectiveness, and regulatory guidance. Potential barriers to and facilitators of the use of AIT are described in addition to future directions. International allergy specialists representing the European Academy of Allergy and Clinical Immunology; the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma and Immunology; and the World Allergy Organization critically reviewed the existing literature and prepared this summary of recommendations for best AIT practice. The authors contributed equally and reached consensus on the statements presented herein. This article continues the comprehensive international consensus (ICON) statement on allergen immunotherapy (AIT). The initial article also recently appeared in the Journal. The conclusions below focus on key mechanisms of AIT-triggered tolerance, requirements in allergen standardization, AIT cost-effectiveness, and regulatory guidance. Potential barriers to and facilitators of the use of AIT are described in addition to future directions. International allergy specialists representing the European Academy of Allergy and Clinical Immunology; the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma and Immunology; and the World Allergy Organization critically reviewed the existing literature and prepared this summary of recommendations for best AIT practice. The authors contributed equally and reached consensus on the statements presented herein. This article represents the second part of the international consensus (ICON) document on allergen immunotherapy (AIT), an effort of the International Collaboration in Asthma, Allergy and Immunology that includes the European Academy of Allergy and Clinical Immunology; the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma and Immunology; and the World Allergy Organization. There are other articles that outline international or national guidelines, positions, or consensus statements on the current knowledge on AIT. In this document we offer a critical appraisal of major evidence on AIT mechanisms, recommendations on allergen standardization (AS), regulatory issues, pharmacoeconomics, and barriers to and facilitators of future developments in AIT. The governing boards of the participating organizations approved the final draft. The allergen-specific immune response involves a series of complex mechanisms. These include the structural features and dose of allergen, the route and timing of its exposure, the existence of innate immune response stimulants within the allergen and micromilieu, and the genetic susceptibility of the host.1Akdis M. Akdis C.A. Mechanisms of allergen-specific immunotherapy: multiple suppressor factors at work in immune tolerance to allergens.J Allergy Clin Immunol. 2014; 133: 621-631Abstract Full Text Full Text PDF PubMed Scopus (405) Google Scholar, 2Burks 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 (366) Google Scholar Effective AIT sequentially activates multiple mechanisms (Fig 1), ideally resulting in multifaceted clinical improvement. Depending on the AIT protocol, desensitization to allergen, allergen-specific immune tolerance, and suppression of allergic inflammation appear within hours. This is followed by allergen-specific regulatory T (Treg) and regulatory B (Breg) cell generation, regulation of allergen-specific IgE and IgG4, and establishment of immune tolerance (Fig 1, A). AIT in particular targets type II immune cells, including TH2 cells, type 2 innate lymphoid cells (ILC2), and type 2 cytotoxic T cells, which produce IL-4, IL-5, and IL-13, which induce mast cell, basophil, and eosinophil activation, as well as IgE antibody production (Fig 1, B).3Annunziato F. Romagnani C. Romagnani S. The 3 major types of innate and adaptive cell-mediated effector immunity.J Allergy Clin Immunol. 2015; 135: 626-635Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar, 4Agache I. Sugita K. Morita H. Akdis M. Akdis C.A. The complex type 2 endotype in allergy and asthma: from laboratory to bedside.Curr Allergy Asthma Rep. 2015; 15: 29Crossref PubMed Scopus (65) Google ScholarFig 1Cellular and molecular changes during AIT. A, Differentiation of naive T cells after allergen presentation in the presence of innate immune response substances that trigger pattern recognition receptors (PRR) and vitamins, monoamines that control cellular differentiation, and coexposed substances with the antigen and status of the cells and cytokines in the microenvironment is shown. Naive T cells can differentiate into TH1, TH2, TH9, TH17, and TH22 T cells. Based on their respective cytokine profiles, responses to chemokines, and interactions with other cells, these T-cell subsets can contribute to general inflammation. The increase in TH1 and Treg cell numbers plays a role in counterbalancing other effector cells. The balance between allergen-specific effector T cells (particularly TH2 cells) and IL-10–producing Treg cells is decisive for the development or suppression of allergic inflammation. Treg cells and their cytokines suppress TH2-type immune responses and contribute to the control of allergic diseases in several major ways. Similarly, induction of IL-10–producing Breg cells plays an essential role in suppression of IgE and induction of IgG4. B, The suppression of peripheral ILCs, especially ILC2s, might contribute to TH2 suppression and immunologic tolerance induced by AIT. iNKT, Invariant natural killer T; TSLP, thymic stromal lymphopoietin.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The literature indicates that administration of AIT leads to very early decreases in the susceptibility of mast cells and basophils to degranulation in spite of the presence of increased allergen-specific IgE levels.5Uermosi C. Zabel F. Manolova V. Bauer M. Beerli R.R. Senti G. et al.IgG-mediated down-regulation of IgE bound to mast cells: a potential novel mechanism of allergen-specific desensitization.Allergy. 2014; 69: 338-347Crossref PubMed Scopus (41) Google Scholar This effect appears to be similar to the one observed when these 2 immune cell types are rapidly desensitized in anaphylactic reactions to drugs.6Romano 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 (183) Google Scholar Several mechanisms have been proposed to explain why mast cells and basophils become unresponsive to environmental proteins even in the presence of specific IgE. A number of studies have investigated the involvement of basophils in the very early induction of allergen tolerance and the so-called desensitization effect of venom immunotherapy (VIT).7Novak 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 (102) Google Scholar, 8Shamji M.H. Layhadi J.A. Scadding G.W. Cheung D.K. Calderon M.A. Turka L.A. et al.Basophil expression of diamine oxidase: a novel biomarker of allergen immunotherapy response.J Allergy Clin Immunol. 2015; 135: 913-921.e9Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 9Santos A.F. James L.K. Bahnson H.T. Shamji M.H. Couto-Francisco N.C. Islam S. et al.IgG4 inhibits peanut-induced basophil and mast cell activation in peanut-tolerant children sensitized to peanut major allergens.J Allergy Clin Immunol. 2015; 135: 1249-1256Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar Rapid upregulation of histamine type 2 receptors within the first 6 hours of the build-up phase of VIT was observed, which suppressed FcεRI-induced activation and mediator release of basophils,7Novak 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 (102) Google Scholar and histamine receptor 2 has strong immune regulatory activities on T cells, dendritic cells (DCs), and basophils.10Ferstl R. Frei R. Schiavi E. Konieczna P. Barcik W. Ziegler M. et al.Histamine receptor 2 is a key influence in immune responses to intestinal histamine-secreting microbes.J Allergy Clin Immunol. 2014; 134: 744-746.e3Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Overall, mast cells and basophils express many targets for future enhancement of the efficacy of AIT, as well as the development of novel biomarkers.11Harvima I.T. Levi-Schaffer F. Draber P. Friedman S. Polakovicova I. Gibbs B.F. et al.Molecular targets on mast cells and basophils for novel therapies.J Allergy Clin Immunol. 2014; 134: 530-544Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 12Kaczorowski M. Jutel M. Human T regulatory cells: on the way to cognition.Arch Immunol Ther Exp. 2013; 61: 229-236Crossref PubMed Scopus (13) Google Scholar AIT induces a major change in allergen-specific T-cell subsets. The proportion of IL-4–secreting TH2 cells decreases; meanwhile, IL-10–secreting inducible Treg cells specific for the same allergenic epitope increase in number and achieve function similar to the immune status observed in nonallergic healthy subjects. This appears to be one of the milestones in the development of peripheral tolerance to allergens.1Akdis M. Akdis C.A. Mechanisms of allergen-specific immunotherapy: multiple suppressor factors at work in immune tolerance to allergens.J Allergy Clin Immunol. 2014; 133: 621-631Abstract Full Text Full Text PDF PubMed Scopus (405) Google Scholar, 13Jutel M. Akdis C.A. Immunological mechanisms of allergen-specific immunotherapy.Allergy. 2011; 66: 725-732Crossref PubMed Scopus (195) Google Scholar A significant correlation exists between improvement of symptoms and the increase in inducible Treg cell numbers during immunotherapy.14Suarez-Fueyo A. Ramos T. Galan A. Jimeno L. Wurtzen P.A. Marin A. et al.Grass tablet sublingual immunotherapy downregulates the TH2 cytokine response followed by regulatory T-cell generation.J Allergy Clin Immunol. 2014; 133 (e1-2): 130-138Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 15Lou W. Wang C. Wang Y. Han D. Zhang L. Responses of CD4(+) CD25(+) Foxp3(+) and IL-10-secreting type I T regulatory cells to cluster-specific immunotherapy for allergic rhinitis in children.Pediatr Allergy Immunol. 2012; 23: 140-149Crossref PubMed Scopus (43) Google Scholar Inducible Treg cells are composed of 2 sets: forkhead box protein 3 (FOXP3)–adaptive Treg cells and FOXP3− but IL-10–producing type 1 regulatory cells.16Sugita K. Hanakawa S. Honda T. Kondoh G. Miyachi Y. Kabashima K. et al.Generation of Helios reporter mice and an evaluation of the suppressive capacity of Helios(+) regulatory T cells in vitro.Exp Dermatol. 2015; 24: 554-556Crossref PubMed Scopus (23) Google Scholar Studies investigating the role of different types of Treg cells during AIT have shown overlapping effects of different Treg cell subsets for the induction of T-cell tolerance.17Mobs C. Ipsen H. Mayer L. Slotosch C. Petersen A. Wurtzen P.A. et al.Birch pollen immunotherapy results in long-term loss of Bet v 1-specific TH2 responses, transient TR1 activation, and synthesis of IgE-blocking antibodies.J Allergy Clin Immunol. 2012; 130: 1108-1116.e6Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 18Radulovic S. Jacobson M.R. Durham S.R. Nouri-Aria K.T. Grass pollen immunotherapy induces Foxp3-expressing CD4+ CD25+ cells in the nasal mucosa.J Allergy Clin Immunol. 2008; 121: 1467-1472.e1Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar Secretion of IL-10 and TGF-β and expression of cytotoxic T lymphocyte antigen 4 and programmed death 1 protein on T-cell surfaces are also important for the suppressor activity of inducible Treg cells. Additionally, the runt homology domain transcription factors 1 and 3 both have an effect on TGF-β–mediated FOXP3 expression of inducible Treg cells in human subjects. Various mechanisms can underlie AIT's induction of an allergen-specific Treg cell response.19Tsai Y.G. Lai J.C. Yang K.D. Hung C.H. Yeh Y.J. Lin C.Y. Enhanced CD46-induced regulatory T cells suppress allergic inflammation after Dermatophagoides pteronyssinus-specific immunotherapy.J Allergy Clin Immunol. 2014; 134: 1206-1209.e1Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 20Palomares O. Martin-Fontecha M. Lauener R. Traidl-Hoffmann C. Cavkaytar O. Akdis M. et al.Regulatory T cells and immune regulation of allergic diseases: roles of IL-10 and TGF-beta.Genes Immun. 2014; 15: 511-520Crossref PubMed Scopus (226) Google Scholar It has been recently suggested that the target organ and site of immune tolerance induction during sublingual immunotherapy (SLIT) might be the tonsils.21Palomares O. Rückert B. Jartti T. Kücüksezer U.C. Puhakka T. Gomez E. 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: 510-520Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar This could hold true even in patients with tonsillectomy because the procedure removes only the pharyngeal tonsils while preserving the lingual and palatine tonsils. Plasmacytoid DCs with a high percentage of Treg cells were colocalized in human palatine and lingual tonsils. The ability of plasmacytoid DCs of human tonsil cells to generate CD4+CD25+CD127−FOXP3+ functional Treg cells further supports the tolerogenic function of DCs.20Palomares O. Martin-Fontecha M. Lauener R. Traidl-Hoffmann C. Cavkaytar O. Akdis M. et al.Regulatory T cells and immune regulation of allergic diseases: roles of IL-10 and TGF-beta.Genes Immun. 2014; 15: 511-520Crossref PubMed Scopus (226) Google Scholar Similar to mechanisms of AIT, in high-dose antigen exposure of beekeepers, IL-10–secreting Treg cells inhibited proliferation of phospholipase A-specific effector T cells 7 days after the beginning of the bee venom season.22Meiler 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 (387) Google Scholar Blocking cytotoxic T lymphocyte antigen 4, programmed death 1, and IL-10 receptors inhibited this suppressive effect. Mouse models to mimic these effects are being developed, and prolonged desensitization schedules have been proposed to study immune tolerance–inducing activities.23Fox E.M. Torrero M.N. Evans H. Mitre E. Immunologic characterization of 3 murine regimens of allergen-specific immunotherapy.J Allergy Clin Immunol. 2015; 135 (e1-7): 1341-1351Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Another important recent study investigated the mechanisms underlying the way in which allergen tolerance can be broken in healthy subjects. The authors indicate stimulation of allergen-specific T cells with certain Toll-like receptors (TLRs), and proinflammatory cytokines can induce in vitro CD4+ T-cell proliferation in peripheral lymphocytes. In this context stimulation of myeloid DCs with IL-1β, IL-6, TLR4, and TLR8 breaks allergen-specific CD4+ T-cell tolerance.24Kucuksezer U.C. Palomares O. Ruckert B. Jartti T. Puhakka T. Nandy A. 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: 875-885Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar Viral infections might play a role in immune tolerance–breaking roles through the abovementioned or other molecular mechanisms. Infection of the respiratory epithelium with rhinovirus can antagonize tolerance to inhaled antigen through combined induction of thymic stromal lymphopoietin, IL-33, and OX40 ligand.25Mehta A.K. Duan W. Doerner A.M. Traves S.L. Broide D.H. Proud D. et al.Rhinovirus infection interferes with induction of tolerance to aeroantigens through OX40 ligand, thymic stromal lymphopoietin, and IL-33.J Allergy Clin Immunol. 2016; 137: 278-288Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar The phenotypic expression of Breg cells plays a role in allergic disease. Distinct from IL-10–secreting DCs, IL-10–secreting allergen-specific Breg cells were shown to exist in bee venom–tolerant beekeepers and patients with bee venom allergy who had undergone VIT.26van 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 (435) Google Scholar They were characterized as CD73−CD25+CD71+ B cells, with a suppressive function on antigen-specific CD4+ T cells and the capacity to produce specifically IgG4. This work is supported by data showing that IL-10 overexpression in human B cells is sufficient to induce a regulatory role of B cells.27Stanic B. van de Veen W. Wirz O.F. Ruckert B. Morita H. Sollner S. et al.IL-10-overexpressing B cells regulate innate and adaptive immune responses.J Allergy Clin Immunol. 2015; 135: 771-780.e8Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar In addition to the direct role of Breg cells, Treg cell–derived IL-10 stimulates B cells to undergo class-switching toward production of IgG antibodies in the presence of IL-4, whereas IL-4 alone induces IgE production.28Meiler F. Klunker S. Zimmermann M. Akdis C.A. Akdis M. Distinct regulation of IgE, IgG4 and IgA by T regulatory cells and toll-like receptors.Allergy. 2008; 63: 1455-1463Crossref PubMed Scopus (244) Google Scholar Human B cells can regulate CD4+ T-cell plasticity to create flexibility in the effector T-cell response.29de Wit J. Jorritsma T. Makuch M. Remmerswaal E.B. Klaasse Bos H. Souwer Y. et al.Human B cells promote T-cell plasticity to optimize antibody response by inducing coexpression of T(H)1/T(FH) signatures.J Allergy Clin Immunol. 2015; 135: 1053-1060Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar As 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. There is further possible formation of IgE-allergen-IgG4 complexes that bind to both the FcγRIIb and FcεRI, inhibiting the IgE receptor.30Wachholz P.A. Durham S.R. Mechanisms of immunotherapy: IgG revisited.Curr Opin Allergy Clin Immunol. 2004; 4: 313-318Crossref PubMed Scopus (167) Google Scholar IgG4 antibodies of different 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.31van der Neut Kolfschoten M. Schuurman J. Losen M. Bleeker W.K. Martinez-Martinez P. Vermeulen E. et al.Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange.Science. 2007; 317: 1554-1557Crossref PubMed Scopus (735) Google Scholar Furthermore, IgG4 is unable to fix complement and has limited affinity for activating Fcγ receptors.32Aalberse R.C. Schuurman J. IgG4 breaking the rules.Immunology. 2002; 105: 9-19Crossref PubMed Scopus (371) Google Scholar AIT is known to induce a transient increase in serum IgE levels in the early course of treatment, despite its protective clinical efficacy. The ratio of allergen-specific IgE to functional IgG4 antibody might be useful in monitoring AIT because the IgE blocking activity of IgG4 appears to correlate with clinical AIT outcome.33Shamji M.H. Ljorring C. Francis J.N. Calderon M.A. Larche M. Kimber I. et al.Functional rather than immunoreactive levels of IgG4 correlate closely with clinical response to grass pollen immunotherapy.Allergy. 2012; 67: 217-226Crossref PubMed Scopus (218) Google Scholar, 34Focke-Tejkl M. Weber M. Niespodziana K. Neubauer A. Huber H. Henning R. et al.Development and characterization of a recombinant, hypoallergenic, peptide-based vaccine for grass pollen allergy.J Allergy Clin Immunol. 2015; 135 (e1-11): 1207-1217Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar ILC2s play a role in allergic responses through secretion of IL-5 and IL-13, and ILC2s can be studied in human peripheral blood.3Annunziato F. Romagnani C. Romagnani S. The 3 major types of innate and adaptive cell-mediated effector immunity.J Allergy Clin Immunol. 2015; 135: 626-635Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar, 4Agache I. Sugita K. Morita H. Akdis M. Akdis C.A. The complex type 2 endotype in allergy and asthma: from laboratory to bedside.Curr Allergy Asthma Rep. 2015; 15: 29Crossref PubMed Scopus (65) Google Scholar ILC2s might have a role in the development of adaptive type 2 responses to local, but not systemic, antigen exposure.35Gold M.J. Antignano F. Halim T.Y. Hirota J.A. Blanchet M.R. Zaph C. et al.Group 2 innate lymphoid cells facilitate sensitization to local, but not systemic, TH2-inducing allergen exposures.J Allergy Clin Immunol. 2014; 133: 1142-1148Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar ILC2s can also be demonstrated in induced sputum in children.36Nagakumar P. Denney L. Fleming L. Bush A. Lloyd C.M. Saglani S. Type 2 innate lymphoid cells in induced sputum from children with severe asthma.J Allergy Clin Immunol. 2016; 137: 624-626Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar AIT has been shown to regulate ILCs, and seasonal increases in peripheral ILC2 numbers are inhibited by subcutaneous grass pollen immunotherapy.37Lao-Araya M. Steveling E. Scadding G.W. Durham S.R. Shamji M.H. Seasonal increases in peripheral innate lymphoid type 2 cells are inhibited by subcutaneous grass pollen immunotherapy.J Allergy Clin Immunol. 2014; 134: 1193-1195.e4Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar Circulating ILC2 responses are increased in asthmatic patients but not in those with allergic rhinitis.38Bartemes K.R. Kephart G.M. Fox S.J. Kita H. Enhanced innate type 2 immune response in peripheral blood from patients with asthma.J Allergy Clin Immunol. 2014; 134: 671-678.e4Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar For further information, see Box 1 and Fig 2.Box 1Effective AIT triggers multiple mechanisms, which are sequentially activated (Fig 2)AIT-induced immune tolerance controls:•the acute phase of the allergic reaction and•chronic events leading to inflammation and remodeling. AIT-induced immune tolerance controls:•the acute phase of the allergic reaction and•chronic events leading to inflammation and remodeling. AS is a prerequisite to providing reagents for the diagnosis of and allergen-specific intervention in atopic diseases. Established methods for AS measure potency, ensure consistency in composition, and demonstrate stability. Molecular technologies have accelerated the characterization of allergen preparations, providing optimal reagents for advanced AS.39Chapman M.D. Briza P. Molecular approaches to allergen standardization.Curr Allergy Asthma Rep. 2012; 12: 478-484Crossref PubMed Scopus (25) Google Scholar European manufacturers use in-house reference preparations (IHRPs) and create their own allergen extract units accordingly.40Larenas-Linnemann D. Cox L.S. Immunotherapy and Allergy Diagnostics Committee of the American Academy of Allergy, Asthma and ImmunologyEuropean allergen extract units and potency: review of available information.Ann Allergy Asthma Immunol. 2008; 100: 137-145Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar The European Medicines Agency (EMA) recently adopted a guideline on production and quality of allergen products (http://www.gmp-compliance.org/guidemgr/files/GUIDELINE ON ALLERGEN PRODUCTS PRODUCTION AND QUALITY ISSUES.PDF). Homologous allergens are now based on sequence identity among allergenic proteins rather than taxonomic relationships between allergen sources. This guideline complements existing documents for development and marketing authorization (MA) of products for AIT in Europe. The US Food and Drug Administration provides guidance for US manufacturers. Vaccines standardized for potency in the United States include Hymenoptera venoms (5 species), cat hair and pelt, dust mites (Dermatophagoides farinae and Dermatophagoides pteronyssinus), and pollen from 8 grass species and short ragweed. For each standardized extract, reference materials from the Center of Biologics Evaluation and Research are used to determine potency, forming the basis of IHRP calibration. The Nordic method, which is commonly used in Europe, considers 10,000 biologically standardized units/mL to be equivalent to an allergen dose that elicits a wheal equal (in square millimeters) to that elicited by 10 mg/mL histamine dihydrochloride. In vivo testing consists of titrated skin prick tests with 5-fold allergen dilutions averaged in at least 20 moderately to highly sensitized allergic subjects. The intradermal dilution for the 50-mm sum of erythema that determines bioequivalent allergy units (ID50EAL) method is used in the United States.41Turkeltaub P.C. Biological standardization based on quantitative skin testing—the ID50 EAL method (intradermal dilution for 50 mm sum of erythema diameters determines the allergy unit).Arb Paul Ehrlich Inst Georg Speyer Haus Ferdinand Blum Inst Frankf A M. 1987; : 169-173PubMed Google Scholar The dilution of extract that on average produces a 50-mm induration (sum of lengths and width [D50]) is assigned an arbitrary potency of 10,000 bioequivalent allergen units (BAU)/mL. Extracts with a mean D50 of 14, which falls between the 13th and 15th 3-fold serial dilution of the reference extract, are arbitrarily assigned the value of 100,000 BAU/mL. An extract with a mean D50 falling between the 11th and 13th dilutions is labeled 10,000 BAU/mL. Various qualitative and quantitative biochemical methods provide information on extract composition.42Kaul S. May S. Luttkopf D. Vieths S. Regulatory environment for allergen-specific immunotherapy.Allergy. 2011; 66: 753-764Crossref PubMed Scopus (51) Google Scholar Newer methods, such as mass spectrometry, can be expensive and technically challenging but can offer extremely powerful approaches for analysis of allergenic proteins, including detection of isoforms. Total potency is measured by IgE-binding inhibition or effector (ie, basophil) cell assays. Manufacturers usually combine different methods for AS and establish various in-process control measures for robust and reproducible allergen extract production. A World Health Organization/International Union of Immunological Societies–initiated and European Union (EU)–funded (FP5) project for the Development of Certified Reference Materials for Allergenic Products and Validation of Methods for their Quantification established comprehensive information on purified or recombinant forms of important major allergens (Bet v 1, Phl p 1, Phl p 5, Ole e 1, Der p 1, Der p 2, Der f 1, and Der f 2) and explored immunoassays for their quantification.43van Ree R. Chapman M.D. Ferreira F. Vieths S. Bryan D. Cromwell O. et al.The CREATE project: development of certified reference materials for allergenic products and validation of methods for their quantification.Allergy. 2008; 63: 310-326Crossref PubMed Scopus (170) Google Scholar, 44Chapman M.D. Ferreira F. Villalba M. Cromwell O. Bryan D. Becker W.M. et al.The European Union CREATE project: a model for international standardization of allergy diagnostics and vaccines.J Allergy Clin Immunol. 2008; 122: 882-889.e2Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar A follow-up project, which was supported by the Biological Standardization Program (BSP) of the European Directorate for the Quality of Medicines, performed a proficiency trial (BSP090) for ELISAs of Bet v 1 and Phl p 5a.45Kaul S. Dehus O. Zimmer J. Vieths S. Validation of major allergen references and ELISAs—current state of the BSP090 project.Arb Paul Ehrlich Inst Bundesinstitut Impfstoffe Biomed Arzneim Langen Hess. 2013; 97: 45-53PubMed Google Scholar, 46Vieths S. Barber D. Chapman M. Costanzo A. Daas A. Fiebig H. et al.Establishment of recombinant major allergens Bet v. 1 and Phl p 5a as Ph. Eur. reference standards and validation of ELISA methods for their measurement. Results from feasibility studies.Pharmeur Bio Sci Notes. 2012; 2012: 118-134PubMed Google Scholar, 47Neske F. Schorner C. Buchheit K.H. Costanzo A. Hanschmann K.M. Himly M. et al.BSP090–the follow-up to CREATE.Arb Paul Ehrlich Inst Bundesinstitut Impfstoffe Biomed Arzneim Langen Hess. 2009; 96: 12-20PubMed Google Scholar After approval by the European Pha
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