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Palomares F, Testera-Montes A, Aranda CJ, Alba-Linero C, Sáenz de Santa María-García R, Bentabol-Ramos G, Mayorga C, Torres MJ, Rondon C, Eguiluz-Gracia I. Allergen exposure boosts peripheral Th9 responses in patients with local allergic rhinitis. Int Forum Allergy Rhinol 2023; 13:2086-2091. [PMID: 37150905 DOI: 10.1002/alr.23175] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 04/24/2023] [Accepted: 04/27/2023] [Indexed: 05/09/2023]
Abstract
KEY POINTS Intranasal allergen exposure increases peripheral total Th2 and Th9 cells in patients with local allergic rhinitis (LAR). Peripheral T-cell response seems dominated by Th9 cells in patients with LAR, whereas Th2 responses prevail in patients with allergic rhinitis. Our results identify Th9 cells as potential therapeutic targets for patients with LAR.
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Affiliation(s)
- Francisca Palomares
- Allergy Research Group, Instituto de Investigación Biomédica de Málaga (IBIMA)-Plataforma BIONAND. RETICS Asma, Reacciones Adversas y Alergicas (ARADyAL), and RICORS "Enfermedades inflamatorias", Málaga, Spain
| | - Almudena Testera-Montes
- Allergy Research Group, Instituto de Investigación Biomédica de Málaga (IBIMA)-Plataforma BIONAND. RETICS Asma, Reacciones Adversas y Alergicas (ARADyAL), and RICORS "Enfermedades inflamatorias", Málaga, Spain
- Allergy Unit, Hospital Regional Universitario de Malaga, Malaga, Spain
| | - Carlos Jose Aranda
- Allergy Research Group, Instituto de Investigación Biomédica de Málaga (IBIMA)-Plataforma BIONAND. RETICS Asma, Reacciones Adversas y Alergicas (ARADyAL), and RICORS "Enfermedades inflamatorias", Málaga, Spain
| | - Carmen Alba-Linero
- Allergy Research Group, Instituto de Investigación Biomédica de Málaga (IBIMA)-Plataforma BIONAND. RETICS Asma, Reacciones Adversas y Alergicas (ARADyAL), and RICORS "Enfermedades inflamatorias", Málaga, Spain
- Ophthalmology Unit, Hospital Clinico Virgen de la Victoria, Malaga, Spain
- School of Medicine, Universidad de Málaga (UMA), Málaga, Spain
| | - Rocío Sáenz de Santa María-García
- Allergy Research Group, Instituto de Investigación Biomédica de Málaga (IBIMA)-Plataforma BIONAND. RETICS Asma, Reacciones Adversas y Alergicas (ARADyAL), and RICORS "Enfermedades inflamatorias", Málaga, Spain
- Allergy Unit, Hospital Regional Universitario de Malaga, Malaga, Spain
| | | | - Cristobalina Mayorga
- Allergy Research Group, Instituto de Investigación Biomédica de Málaga (IBIMA)-Plataforma BIONAND. RETICS Asma, Reacciones Adversas y Alergicas (ARADyAL), and RICORS "Enfermedades inflamatorias", Málaga, Spain
- Allergy Unit, Hospital Regional Universitario de Malaga, Malaga, Spain
| | - Maria Jose Torres
- Allergy Research Group, Instituto de Investigación Biomédica de Málaga (IBIMA)-Plataforma BIONAND. RETICS Asma, Reacciones Adversas y Alergicas (ARADyAL), and RICORS "Enfermedades inflamatorias", Málaga, Spain
- Allergy Unit, Hospital Regional Universitario de Malaga, Malaga, Spain
- School of Medicine, Universidad de Málaga (UMA), Málaga, Spain
| | - Carmen Rondon
- Allergy Research Group, Instituto de Investigación Biomédica de Málaga (IBIMA)-Plataforma BIONAND. RETICS Asma, Reacciones Adversas y Alergicas (ARADyAL), and RICORS "Enfermedades inflamatorias", Málaga, Spain
- Allergy Unit, Hospital Regional Universitario de Malaga, Malaga, Spain
| | - Ibon Eguiluz-Gracia
- Allergy Research Group, Instituto de Investigación Biomédica de Málaga (IBIMA)-Plataforma BIONAND. RETICS Asma, Reacciones Adversas y Alergicas (ARADyAL), and RICORS "Enfermedades inflamatorias", Málaga, Spain
- Allergy Unit, Hospital Regional Universitario de Malaga, Malaga, Spain
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Onodera A, Kokubo K, Okano M, Onoue M, Kiuchi M, Iwamura C, Iinuma T, Kimura MY, Ebihara N, Hanazawa T, Nakayama T, Hirahara K. Pathogenic helper T cells as the novel therapeutic targets for immune-mediated intractable diseases. Pharmacol Ther 2023; 247:108445. [PMID: 37201737 DOI: 10.1016/j.pharmthera.2023.108445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 05/11/2023] [Accepted: 05/15/2023] [Indexed: 05/20/2023]
Abstract
Allergic diseases arise from a complex interplay between immune system and environmental factors. A link between the pathogenesis of allergic diseases and type 2 immune responses has become evident, with conventional and pathogenic type 2 helper T (Th2) cells involved in both. Recently, there has been a significant development in therapeutic agents for allergic diseases: IL-5 and IL-5 receptor antagonists, Janus kinase (JAK) inhibitors, and sublingual immunotherapy (SLIT). Mepolizumab, an IL-5, and Benralizumab, an IL-5 receptor antagonist, modulate eosinophilic inflammation mediated by IL-5-producing Th2 cells. Delgocitinib shows that JAK-associated signaling is essential for the inflammatory reaction in atopic dermatitis, one of the common allergic diseases. SLIT has a significant effect on allergic rhinitis by reducing pathogenic Th2 cell numbers. More recently, novel molecules that are involved in pathogenic Th2 cell-mediated allergic diseases have been identified. These include calcitonin gene-related peptide (CGRP), reactive oxygen species (ROS) scavenging machinery regulated by the Txnip-Nrf2-Blvrb axis, and myosin light chain 9 (Myl9), which interacts with CD69. This review provides an updated view of the recent research on treatment of allergic diseases and their cause: conventional and pathogenic Th2 cells.
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Affiliation(s)
- Atsushi Onodera
- Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan; Institute for Advanced Academic Research, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Kota Kokubo
- Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Mikiko Okano
- Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Miki Onoue
- Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Masahiro Kiuchi
- Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Chiaki Iwamura
- Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Tomohisa Iinuma
- Department of Experimental Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Motoko Y Kimura
- Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan; Chiba University "Synergy Institute for Futuristic Mucosal Vaccine Research and Development (cSIMVa), Japan Initiative for World-leading Vaccine Research and Development Centers, Japan Agency for Medical Research and Development (AMED), Chiba, Japan
| | - Nobuyuki Ebihara
- Department of Ophthalmology, Juntendo University Urayasu Hospital, Chiba 279-0021, Japan
| | - Toyoyuki Hanazawa
- Department of Experimental Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Toshinori Nakayama
- Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan; AMED-CREST, AMED, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Kiyoshi Hirahara
- Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan; Chiba University "Synergy Institute for Futuristic Mucosal Vaccine Research and Development (cSIMVa), Japan Initiative for World-leading Vaccine Research and Development Centers, Japan Agency for Medical Research and Development (AMED), Chiba, Japan.
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Huang Z, Chu M, Chen X, Wang Z, Jiang L, Ma Y, Wang Y. Th2A cells: The pathogenic players in allergic diseases. Front Immunol 2022; 13:916778. [PMID: 36003397 PMCID: PMC9393262 DOI: 10.3389/fimmu.2022.916778] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 07/12/2022] [Indexed: 11/13/2022] Open
Abstract
Proallergic type 2 helper T (Th2A) cells are a subset of memory Th2 cells confined to atopic individuals, and they include all the allergen-specific Th2 cells. Recently, many studies have shown that Th2A cells characterized by CD3+ CD4+ HPGDS+ CRTH2+ CD161high ST2high CD49dhigh CD27low play a crucial role in allergic diseases, such as atopic dermatitis (AD), food allergy (FA), allergic rhinitis (AR), asthma, and eosinophilic esophagitis (EoE). In this review, we summarize the discovery, biomarkers, and biological properties of Th2A cells to gain new insights into the pathogenesis of allergic diseases.
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Affiliation(s)
- Ziyu Huang
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
- Department of Clinical Medicine, Mudanjiang Medical University, Mudanjiang, China
| | - Ming Chu
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
| | - Xi Chen
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
| | - Ziyuan Wang
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
| | - Lin Jiang
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
| | - Yinchao Ma
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
| | - Yuedan Wang
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
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Iinuma T, Kiuchi M, Hirahara K, Kurita J, Kokubo K, Yagyu H, Yoneda R, Arai T, Sonobe Y, Fukuyo M, Kaneda A, Yonekura S, Nakayama T, Okamoto Y, Hanazawa T. Single-cell immunoprofiling after immunotherapy for allergic rhinitis reveals functional suppression of pathogenic Th2 cells and clonal conversion. J Allergy Clin Immunol 2022; 150:850-860.e5. [PMID: 35863510 DOI: 10.1016/j.jaci.2022.06.024] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 06/22/2022] [Accepted: 06/29/2022] [Indexed: 10/17/2022]
Abstract
BACKGROUND Allergic rhinitis is a growing problem worldwide. Currently, the only treatment that can modify the disease is antigen-specific immunotherapy; however, its mechanism(s) of action is not fully understood. OBJECTIVE To comprehensively investigate the role and changes of antigen-specific T cells before and after sublingual immunotherapy (SLIT) for Japanese cedar pollinosis (JCP). METHODS We cultured PBMCs obtained both before and at 1 year after initiating SLIT and used a combination of single-cell RNA sequence and repertoire sequencing. To investigate biomarkers, we used PBMCs from patients participating a phase II/III trial of SLIT tablets for JCP and PBMCs from good and poor responders in outpatients. RESULTS Antigen-stimulated culturing after SLIT led to clonal expansion of Th2 and Treg cells, and most of these CD4+ T cells retained their CDR3 regions before and after treatment, indicating antigen-specific clonal responses and differentiation secondary to SLIT. However, SLIT reduced the number of clonal functional Th2 cells but increased the Trans-type Th2 cell population that expresses musculin (MSC), TGF-β, and IL-2. Trajectory analysis suggested that SLIT induced clonal differentiation of the Trans-type Th2 cells differentiated into Treg cells. Using real-time PCR, we found that the MSC levels increased in the active SLIT group and good responders after 1 year of treatment. CONCLUSION The combination of single-cell RNA sequencing and repertoire analysis helped reveal a part of the underlying mechanism-that SLIT promotes the expression of MSC on pathogenic Th2 cells and suppresses their function; MSC may be a potential biomarker of SLIT for allergic rhinitis.
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Affiliation(s)
- Tomohisa Iinuma
- Department of Otorhinolaryngology, Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Masahiro Kiuchi
- Department of Immunology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Kiyoshi Hirahara
- Department of Immunology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Junya Kurita
- Department of Otorhinolaryngology, Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Kota Kokubo
- Department of Immunology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hiroyuki Yagyu
- Department of Immunology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Riyo Yoneda
- Department of Otorhinolaryngology, Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Tomoyuki Arai
- Department of Otorhinolaryngology, Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yuri Sonobe
- Department of Immunology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Masaki Fukuyo
- Department of Molecular Oncology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Atsushi Kaneda
- Department of Molecular Oncology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Syuji Yonekura
- Department of Otorhinolaryngology, Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Toshinori Nakayama
- Department of Immunology, Chiba University Graduate School of Medicine, Chiba, Japan; AMED-CREST, AMED, Chiba, Japan
| | | | - Toyoyuki Hanazawa
- Department of Otorhinolaryngology, Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
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IFNG, FCER1A, PCDHB10 expression as a new potential marker of efficacy in grass pollen allergen-specific immunotherapy. Postepy Dermatol Alergol 2021; 38:665-672. [PMID: 34658711 PMCID: PMC8501422 DOI: 10.5114/ada.2021.108925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 04/01/2020] [Indexed: 11/17/2022] Open
Abstract
Introduction Allergen-specific immunotherapy (AIT) is the core treatment in allergic rhinitis and asthma. Although widely used, some patients do not benefit from treatment and there is no efficacy objective marker. Aim To define the profile of gene transcripts during the build-up phase of AIT and their comparison to the control group and then search for a viable efficacy marker in relation to patient symptoms. Material and methods AIT was administered in 22 patients allergic to grass pollen. Analysis of 15 selected transcript expression was performed in whole blood samples taken before AIT (sample A) and after reaching the maintenance dose (sample B). The control group included 25 healthy volunteers (sample C). The primary endpoint was Relative Quantification. The gene expression analysis was followed by clinical evaluation with the use of Allergy Control Score (ACS). Results Comparison between samples A and B of gene expression showed a significant increase in IFNG expression (p = 0.03). In relation to the control group, pretreatment samples from patients showed higher levels of AFAP1L1 (p = 0.006), COMMD8 (p = 0.001), PIK3CD (p = 0.027) and TWIST2 (p = 0.0003) in univariate analysis. A generalized linear regression model was built according to the Bayesian Information Criterion based on the IFNG, FCER1A and PCDHB10 expression pattern for prediction of the AIT outcome. The model showed a correlation in predicted and observed changes in ACS. Conclusions There is a significant change in the expression of IFNG during the build-up phase of AIT. The authors propose an in vitro model of AIT efficacy prediction for further validation.
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Pfaar O, Zieglmayer P. Allergen exposure chambers: implementation in clinical trials in allergen immunotherapy. Clin Transl Allergy 2020; 10:33. [PMID: 32742636 PMCID: PMC7388504 DOI: 10.1186/s13601-020-00336-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 06/19/2020] [Indexed: 12/13/2022] Open
Abstract
Allergen exposure chambers (AECs) have been developed for controlled allergen challenges of allergic patients mimicking natural exposure. As such, these facilities have been utilized e.g., for proof of concept, dose finding or the demonstration of onset of action and treatment effect sizes of antiallergic medication. Moreover, clinical effects of and immunological mechanisms in allergen immunotherapy (AIT) have been investigated in AECs. In Europe AIT products have to fulfill regulatory requirements for obtaining market authorization through Phase I to III clinical trials. Multiple Phase II (dose-range-finding or proof-of-concept) trials on AIT products have been performed in AECs. However, they are not accepted by regulatory bodies for pivotal (Phase III) trials and a more thorough technical and clinical validation is requested. Recently, a Position Paper of the European Academy of Allergy and Clinical Immunology (EAACI) has outlined unmet needs in further development of AECs. The following review aims to address some of these needs on the basis of recently published data in the first part, whereas the second part overviews published examples of most relevant Phase II trials in AIT performed in AEC facilities.
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Affiliation(s)
- O Pfaar
- Department of Otorhinolaryngology, Head and Neck Surgery, Section of Rhinology and Allergy, University Hospital Marburg, Philipps-Universität Marburg, Marburg, Germany
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Luce S, Chinthrajah S, Lyu SC, Nadeau KC, Mascarell L. Th2A and Th17 cell frequencies and regulatory markers as follow-up biomarker candidates for successful multifood oral immunotherapy. Allergy 2020; 75:1513-1516. [PMID: 31930521 DOI: 10.1111/all.14180] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 12/17/2019] [Accepted: 12/08/2019] [Indexed: 01/10/2023]
Affiliation(s)
- Sonia Luce
- Research Department Stallergenes Greer Antony France
| | - Sharon Chinthrajah
- Sean N. Parker Center for Allergy and Asthma Research Stanford University Stanford CA USA
- Division of Pulmonary and Critical Care Medicine and Division of Allergy, Immunology and Rheumatology Stanford University Stanford CA USA
| | - Shu-Chen Lyu
- Sean N. Parker Center for Allergy and Asthma Research Stanford University Stanford CA USA
- Division of Pulmonary and Critical Care Medicine and Division of Allergy, Immunology and Rheumatology Stanford University Stanford CA USA
| | - Kari C. Nadeau
- Sean N. Parker Center for Allergy and Asthma Research Stanford University Stanford CA USA
- Division of Pulmonary and Critical Care Medicine and Division of Allergy, Immunology and Rheumatology Stanford University Stanford CA USA
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Digital Immune Gene Expression Profiling Discriminates Allergic Rhinitis Responders from Non-Responders to Probiotic Supplementation. Genes (Basel) 2019; 10:genes10110889. [PMID: 31690037 PMCID: PMC6896104 DOI: 10.3390/genes10110889] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 10/28/2019] [Accepted: 10/30/2019] [Indexed: 01/19/2023] Open
Abstract
Probiotic supplementation for eight weeks with a multi-strain probiotic by individuals with allergic rhinitis (AR) reduced overall symptom severity, the frequency of medication use and improved quality of life. The purported mechanism of action is modulation of the immune system. This analysis examined changes in systemic and mucosal immune gene expression in a subgroup of individuals, classified as either responders or non-responders based on improvement of AR symptoms in response to the probiotic supplement. Based on established criteria of a beneficial change in the mini-rhinoconjunctivitis quality of life questionnaire (mRQLQ), individuals with AR were classified as either responders or non-responders. Systemic and mucosal immune gene expression was assessed using nCounter PanCancer Immune Profiling (Nanostring Technologies, Seattle, WA, USA) kit on blood samples and a nasal lysate. There were 414 immune genes in the blood and 312 immune genes in the mucosal samples expressed above the limit of detection. Unsupervised hierarchical clustering of immune genes separated responders from non-responders in blood and mucosal samples at baseline and after supplementation, with key T-cell immune genes differentially expressed between the groups. Striking differences in biological processes and pathways were evident in nasal mucosa but not blood in responders compared to non-responders. These findings support the use of network approaches to understand probiotic-induced changes to the immune system.
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Guéguen C, Luce S, Lombardi V, Baron‐Bodo V, Moingeon P, Mascarell L. IL-10 mRNA levels in whole blood cells correlate with house dust mite allergen immunotherapy efficacy. Allergy 2019; 74:2223-2226. [PMID: 30793324 DOI: 10.1111/all.13751] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
| | - Sonia Luce
- Research Department Stallergenes Greer Antony France
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Bacher P, Scheffold A. The effect of regulatory T cells on tolerance to airborne allergens and allergen immunotherapy. J Allergy Clin Immunol 2019; 142:1697-1709. [PMID: 30527063 DOI: 10.1016/j.jaci.2018.10.016] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 10/16/2018] [Accepted: 10/19/2018] [Indexed: 12/16/2022]
Abstract
Forkhead box P3-positive regulatory T (Treg) cells are essential mediators of tolerance against self-antigens and harmless exogenous antigens. Treg cell deficiencies result in multiple autoimmune and allergic syndromes in neonates. How Treg cells affect conventional allergies against aeroantigens, which are restricted to a few specific proteins released from inhaled particles, remains controversial. The hallmarks of antigen-specific loss of tolerance are allergen-specific TH2 cells and IgE. However, difficulties in identifying the rare allergen-specific Treg cells have obscured the cellular basis of tolerance to aeroallergens, which is also a major obstacle for the rational design of novel and more efficient allergen-specific immunotherapies. Recent technological progress allowing characterization of allergen-specific effectors and Treg cells with minimal in vitro manipulation revealed their detailed contribution to tolerance. The data identified inhaled particles as immunodominant Treg cell targets in healthy and allergic subjects. Conversely, the supposed immunodominant major allergens being rapidly released from inhaled particles apparently do not actively induce tolerance but are ignored by the immune system. Here, the partially contradictory data on various allergen-specific T-cell types in healthy subjects, allergic patients, and patients undergoing allergen-specific immunotherapy are discussed and integrated into one model, postulating Treg cell-dependent and Treg cell-independent checkpoints of tolerance and allergy development.
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Affiliation(s)
- Petra Bacher
- Institute for Immunology, Christian-Albrechts-Universität zu Kiel, Kiel, Germany; Institute of Clinical Molecular Biology Christian-Albrechts Universität zu Kiel & Universitätsklinik Schleswig-Holstein, Kiel, Germany
| | - Alexander Scheffold
- Institute for Immunology, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
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Kitzmüller C, Jahn‐Schmid B, Kinaciyan T, Bohle B. Sublingual immunotherapy with recombinant Mal d 1 downregulates the allergen-specific Th2 response. Allergy 2019; 74:1579-1581. [PMID: 30887520 PMCID: PMC6767596 DOI: 10.1111/all.13779] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Claudia Kitzmüller
- Department of Pathophysiology and Allergy Research Center of Pathophysiology, Infectiology and Immunology Medical University of Vienna Vienna Austria
| | - Beatrice Jahn‐Schmid
- Department of Pathophysiology and Allergy Research Center of Pathophysiology, Infectiology and Immunology Medical University of Vienna Vienna Austria
| | - Tamar Kinaciyan
- Department of Dermatology Medical University of Vienna Vienna Austria
| | - Barbara Bohle
- Department of Pathophysiology and Allergy Research Center of Pathophysiology, Infectiology and Immunology Medical University of Vienna Vienna Austria
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Ihara F, Sakurai D, Okamoto Y. [The analysis of Th2 cell subsets in house dust mite allergic rhinitis patients after sublingual immunotherapy]. Nihon Yakurigaku Zasshi 2019; 154:12-16. [PMID: 31308344 DOI: 10.1254/fpj.154.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Th2 cells are well known to play important roles in allergic diseases including allergic rhinitis (AR). Meanwhile, the factors that induce and sustain the pathogenesis of AR remain unclear. The recent development of sublingual immunotherapy (SLIT) is expected to allow changes to the underlying pathogenesis of AR. However, the phenotype of the pathogenic Th2 cells (Tpath2) cells in house dust mite-induced AR (HDM-AR) and the relation between Tpath2 and SLIT efficacy have not been clarified. Therefore we analyzed the cytokine production and frequency of HDM-reactive T-cell subsets in peripheral blood mononuclear cells (PBMCs) using flow cytometry in 89 HDM-AR patients (placebo; n = 43 and HDM 300 IR; n = 46) who participated in a placebo-controlled study of SLIT with HDM tablets. All patients provided samples both before treatment as a baseline and at the end of the 52-week study. HDM-reactive IL-5+IL-13+CD27-CD161+CD4+ cells and ST2+CD45RO+CD4+ cells were observed in the PBMCs from each patient with HDM-AR; these cells significantly decreased after SLIT in the group treated with active tablets. HDM-reactive ST2+CD45RO+CD4+ cells were significantly lower in active-responders. In conclusion, HDM-reactive ST2+CD45RO+CD4+ cells or those combined with IL-5+IL-13+CD27-CD161+CD4+ cells may be useful as markers indicating the successful treatment of SLIT. These cells may play a crucial role in the pathogenesis of HDM-AR as Tpath2.
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Affiliation(s)
- Fumie Ihara
- Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, Chiba University.,Department of Medical Immunology, Graduate School of Medicine, Chiba University
| | - Daiju Sakurai
- Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, Chiba University
| | - Yoshitaka Okamoto
- Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, Chiba University
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Haruna T, Kariya S, Fujiwara T, Yuta A, Higaki T, Zhao P, Ogawa Y, Kanai K, Hirata Y, Oka A, Nishizaki K, Okano M. Role of whole saliva in the efficacy of sublingual immunotherapy in seasonal allergic rhinitis. Allergol Int 2019; 68:82-89. [PMID: 30166059 DOI: 10.1016/j.alit.2018.07.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 07/08/2018] [Accepted: 07/24/2018] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The development of methods to predict the clinical effectiveness of sublingual immunotherapy (SLIT) for allergic diseases is a crucial matter. We sought to determine whether whole saliva, which is the first body component that contacts allergen extracts during SLIT, is associated with the clinical effectiveness of SLIT in Japanese cedar pollinosis. METHODS Blood monocytes or monocytic THP-1 cells were cultured in the presence or absence of either whole saliva or pure saliva with or without treatments including filtration and blockade of TLR2 and/or TLR4 signaling. IL-10 levels in the supernatants were then measured. Whole saliva-induced IL-10 production by THP-1 cells was compared between asymptomatic and disease-onset patients during peak pollen dispersal after SLIT. RESULTS Both monocytes and THP-1 cells produced substantial amounts of IL-10 in response to whole saliva. IL-10 production was significantly reduced in response to pure saliva and 0.2 μm-filtered saliva. Simultaneous treatment with polymyxin B and TL2.1, a neutralizing antibody against TLR2, also reduced IL-10 production. IL-10 levels produced by THP-1 cells in response to whole saliva collected prior to SLIT were significantly higher in asymptomatic patients determined by symptom-medication scores than disease-onset patients following SLIT. Such differences were not seen in saliva collected 3 months after the initiation of SLIT or saliva collected during peak pollen dispersal. CONCLUSIONS Our results provide a basis for why the sublingual route is effective and preferable in allergen immunotherapy. Saliva-induced IL-10 levels produced by THP-1 cells may be a predictive marker for clinical remission after SLIT.
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Affiliation(s)
- Takenori Haruna
- Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shin Kariya
- Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Tazuko Fujiwara
- Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | | | - Takaya Higaki
- Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Pengfei Zhao
- Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | | | - Kengo Kanai
- Department Otorhinolaryngology-Head & Neck Surgery, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Yuji Hirata
- Department Otorhinolaryngology-Head & Neck Surgery, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Aiko Oka
- Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kazunori Nishizaki
- Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Mitsuhiro Okano
- Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; Department of Otorhinolaryngology, International University of Health and Welfare School of Medicine, Narita, Japan.
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Antigen-specific regulatory T-cell responses against aeroantigens and their role in allergy. Mucosal Immunol 2018; 11:1537-1550. [PMID: 29858582 DOI: 10.1038/s41385-018-0038-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 04/11/2018] [Accepted: 04/14/2018] [Indexed: 02/04/2023]
Abstract
The mucosal immune system of the respiratory tract is specialized to continuously monitor the external environment and to protect against invading pathogens, while maintaining tolerance to innocuous inhaled particles. Allergies result from a loss of tolerance against harmless antigens characterized by formation of allergen-specific Th2 cells and IgE. Tolerance is often described as a balance between harmful Th2 cells and various types of protective "regulatory" T cells. However, the identity of the protective T cells in healthy vs. allergic individuals or following successful allergen-specific therapy is controversially discussed. Recent technological progress enabling the identification of antigen-specific effector and regulatory T cells has significantly contributed to our understanding of tolerance. Here we discuss the experimental evidence for the various tolerance mechanisms described. We try to integrate the partially contradictory data into a new model proposing different mechanism of tolerance depending on the quality and quantity of the antigens as well as the way of antigen exposure. Understanding the basis of tolerance is essential for the rational design of novel and more efficient immunotherapies.
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Renand A, Shamji MH, Harris KM, Qin T, Wambre E, Scadding GW, Wurtzen PA, Till SJ, Togias A, Nepom GT, Kwok WW, Durham SR. Synchronous immune alterations mirror clinical response during allergen immunotherapy. J Allergy Clin Immunol 2018; 141:1750-1760.e1. [PMID: 29128670 PMCID: PMC5938141 DOI: 10.1016/j.jaci.2017.09.041] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 08/25/2017] [Accepted: 09/18/2017] [Indexed: 12/23/2022]
Abstract
BACKGROUND Three years of treatment with either sublingual or subcutaneous allergen immunotherapy has been shown to be effective and to induce long-term tolerance. The Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy (GRASS) trial demonstrated that 2 years of treatment through either route was effective in suppressing the response to nasal allergen challenge, although it was insufficient for inhibition 1 year after discontinuation. OBJECTIVE We sought to examine in the GRASS trial the time course of immunologic changes during 2 years of sublingual and subcutaneous immunotherapy and for 1 year after treatment discontinuation. METHODS We performed multimodal immunomonitoring to assess allergen-specific CD4 T-cell properties in parallel with analysis of local mucosal cytokine responses induced by nasal allergen exposure and humoral immune responses that included IgE-dependent basophil activation and measurement of serum inhibitory activity for allergen-IgE binding to B cells (IgE-facilitated allergen binding). RESULTS All 3 of these distinct arms of the immune response displayed significant and coordinate alterations during 2 years of allergen desensitization, followed by reversal at 3 years, reflecting a lack of a durable immunologic effect. Although frequencies of antigen-specific TH2 cells in peripheral blood determined by using HLA class II tetramer analysis most closely paralleled clinical outcomes, IgE antibody-dependent functional assays remained inhibited in part 1 year after discontinuation. CONCLUSION Two years of allergen immunotherapy were effective but insufficient for long-term tolerance. Allergen-specific TH2 cells most closely paralleled the transient clinical outcome, and it is likely that recurrence of the T-cell drivers of allergic immunity abrogated the potential for durable tolerance. On the other hand, the persistence of IgE blocking antibody 1 year after discontinuation might be an early indicator of a protolerogenic mechanism.
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Affiliation(s)
- Amedee Renand
- Benaroya Research Institute at Virginia Mason, Seattle, Wash
| | - Mohamed H Shamji
- Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Section of Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London, United Kingdom; MRC and Asthma UK, Centre in Allergic Mechanisms of Asthma, London, United Kingdom
| | | | | | - Erik Wambre
- Benaroya Research Institute at Virginia Mason, Seattle, Wash
| | - Guy W Scadding
- Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Section of Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | | | - Stephen J Till
- Asthma, Allergy and Lung Biology, School of Immunology & Microbial Sciences, King's College London, London, United Kingdom; MRC and Asthma UK, Centre in Allergic Mechanisms of Asthma, London, United Kingdom
| | - Alkis Togias
- National Institute of Allergy and Infectious Diseases, Bethesda, Md
| | - Gerald T Nepom
- Benaroya Research Institute at Virginia Mason, Seattle, Wash; Immune Tolerance Network, Bethesda, Md
| | - William W Kwok
- Benaroya Research Institute at Virginia Mason, Seattle, Wash
| | - Stephen R Durham
- Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Section of Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London, United Kingdom; MRC and Asthma UK, Centre in Allergic Mechanisms of Asthma, London, United Kingdom.
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16
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Wambre E, Bajzik V, DeLong JH, O'Brien K, Nguyen QA, Speake C, Gersuk VH, DeBerg HA, Whalen E, Ni C, Farrington M, Jeong D, Robinson D, Linsley PS, Vickery BP, Kwok WW. A phenotypically and functionally distinct human T H2 cell subpopulation is associated with allergic disorders. Sci Transl Med 2017; 9:eaam9171. [PMID: 28768806 PMCID: PMC5987220 DOI: 10.1126/scitranslmed.aam9171] [Citation(s) in RCA: 286] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Revised: 02/03/2017] [Accepted: 05/31/2017] [Indexed: 12/13/2022]
Abstract
Allergen-specific type 2 helper T (TH2) cells play a central role in initiating and orchestrating the allergic and asthmatic inflammatory response pathways. One major factor limiting the use of such atopic disease-causing T cells as both therapeutic targets and clinically useful biomarkers is the lack of an accepted methodology to identify and differentiate these cells from overall nonpathogenic TH2 cell types. We have described a subset of human memory TH2 cells confined to atopic individuals that includes all allergen-specific TH2 cells. These cells are terminally differentiated CD4+ T cells (CD27- and CD45RB-) characterized by coexpression of CRTH2, CD49d, and CD161 and exhibit numerous functional attributes distinct from conventional TH2 cells. Hence, we have denoted these cells with this stable allergic disease-related phenotype as the TH2A cell subset. Transcriptome analysis further revealed a distinct pathway in the initiation of pathogenic responses to allergen, and elimination of these cells is indicative of clinical responses induced by immunotherapy. Together, these findings identify a human TH2 cell signature in allergic diseases that could be used for response-monitoring and designing appropriate immunomodulatory strategies.
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Affiliation(s)
- Erik Wambre
- Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA.
| | - Veronique Bajzik
- Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA
| | - Jonathan H DeLong
- Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA
| | - Kimberly O'Brien
- Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA
| | - Quynh-Anh Nguyen
- Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA
| | - Cate Speake
- Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA
| | - Vivian H Gersuk
- Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA
| | - Hannah A DeBerg
- Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA
| | - Elizabeth Whalen
- Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA
| | - Chester Ni
- Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA
| | | | - David Jeong
- Virginia Mason Medical Center, Seattle, WA 98101, USA
| | | | - Peter S Linsley
- Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA
| | | | - William W Kwok
- Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA
- Department of Immunology, University of Washington, Seattle, WA 98195, USA
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17
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Shamji MH, Kappen JH, Akdis M, Jensen-Jarolim E, Knol EF, Kleine-Tebbe J, Bohle B, Chaker AM, Till SJ, Valenta R, Poulsen LK, Calderon MA, Demoly P, Pfaar O, Jacobsen L, Durham SR, Schmidt-Weber CB. Biomarkers for monitoring clinical efficacy of allergen immunotherapy for allergic rhinoconjunctivitis and allergic asthma: an EAACI Position Paper. Allergy 2017; 72:1156-1173. [PMID: 28152201 DOI: 10.1111/all.13138] [Citation(s) in RCA: 239] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Allergen immunotherapy (AIT) is an effective treatment for allergic rhinoconjunctivitis (AR) with or without asthma. It is important to note that due to the complex interaction between patient, allergy triggers, symptomatology and vaccines used for AIT, some patients do not respond optimally to the treatment. Furthermore, there are no validated or generally accepted candidate biomarkers that are predictive of the clinical response to AIT. Clinical management of patients receiving AIT and efficacy in randomised controlled trials for drug development could be enhanced by predictive biomarkers. METHOD The EAACI taskforce reviewed all candidate biomarkers used in clinical trials of AR patients with/without asthma in a literature review. Biomarkers were grouped into seven domains: (i) IgE (total IgE, specific IgE and sIgE/Total IgE ratio), (ii) IgG-subclasses (sIgG1, sIgG4 including SIgE/IgG4 ratio), (iii) Serum inhibitory activity for IgE (IgE-FAB and IgE-BF), (iv) Basophil activation, (v) Cytokines and Chemokines, (vi) Cellular markers (T regulatory cells, B regulatory cells and dendritic cells) and (vii) In vivo biomarkers (including provocation tests?). RESULTS All biomarkers were reviewed in the light of their potential advantages as well as their respective drawbacks. Unmet needs and specific recommendations on all seven domains were addressed. CONCLUSIONS It is recommended to explore the use of allergen-specific IgG4 as a biomarker for compliance. sIgE/tIgE and IgE-FAB are considered as potential surrogate candidate biomarkers. Cytokine/chemokines and cellular reponses provided insight into the mechanisms of AIT. More studies for confirmation and interpretation of the possible association with the clinical response to AIT are needed.
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Affiliation(s)
- M. H. Shamji
- Allergy and Clinical Immunology; National Heart and Lung Institute; Imperial College London; London UK
- MRC & Asthma UK Centre in Allergic Mechanisms of Asthma; London UK
- Allergy and Clinical Immunology; Immunomodulation and Tolerance Group; Imperial College London; London UK
| | - J. H. Kappen
- Allergy and Clinical Immunology; National Heart and Lung Institute; Imperial College London; London UK
- MRC & Asthma UK Centre in Allergic Mechanisms of Asthma; London UK
- Allergy and Clinical Immunology; Immunomodulation and Tolerance Group; Imperial College London; London UK
- Department of Pulmonology; STZ Centre of Excellence for Asthma & COPD; Sint Franciscus Vlietland Group; Rotterdam The Netherlands
| | - M. Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF); University of Zürich; Davos Switzerland
| | - E. Jensen-Jarolim
- Department of Pathophysiology and Allergy Research; Center of Pathophysiology, Infectiology and Immunology; Medical University Vienna; Vienna Austria
- The interuniversity Messerli Research Institute; University of Veterinary Medicine Vienna; Medical University Vienna; Vienna Austria
| | - E. F. Knol
- Departments Immunology and Dermatology/Allergology; University Medical Center Utrecht; Utrecht The Netherlands
| | - J. Kleine-Tebbe
- Allergy & Asthma Center Westend; Outpatient Clinic and Research Center Hanf, Ackermann & Kleine-Tebbe; Berlin Germany
| | - B. Bohle
- Department of Pathophysiology and Allergy Research; Medical University of Vienna; Vienna Austria
| | - A. M. Chaker
- Center of Allergy and Environment (ZAUM); Technische Universität and Helmholtz Center Munich; Munich Germany
- Department of Otolaryngology; Allergy Section; Klinikum rechts der Isar; Technische Universität; Munich Germany
| | - S. J. Till
- Division of Asthma, Allergy and Lung Biology; King's College London; London UK
- Department of Allergy; Guy's and St. Thomas’ NHS Foundation Trust; London UK
| | - R. Valenta
- Division of Immunopathology; Department of Pathophysiology and Allergy Research; Center for Pathophysiology, Infectiology and Immunology; Medical University of Vienna; Vienna Austria
| | - L. K. Poulsen
- Allergy Clinic; Copenhagen University Hospital at Gentofte; Copenhagen Denmark
| | - M. A. Calderon
- Allergy and Clinical Immunology; National Heart and Lung Institute; Imperial College London; London UK
- MRC & Asthma UK Centre in Allergic Mechanisms of Asthma; London UK
- Allergy and Clinical Immunology; Immunomodulation and Tolerance Group; Imperial College London; London UK
| | - P. Demoly
- Division of Allergy; Department of Pulmonology; Arnaud de Villeneuve Hospital; University Hospital of Montpellier and Sorbonne University; Paris France
| | - O. Pfaar
- Department of Otorhinolaryngology; Head and Neck Surgery; Universitätsmedizin Mannheim; Medical Faculty Mannheim; Heidelberg University; Mannheim Germany
- Center for Rhinology and Allergology; Wiesbaden Germany
| | - L. Jacobsen
- Allergy Learning and Consulting; Copenhagen Denmark
| | - S. R. Durham
- Allergy and Clinical Immunology; National Heart and Lung Institute; Imperial College London; London UK
- MRC & Asthma UK Centre in Allergic Mechanisms of Asthma; London UK
- Allergy and Clinical Immunology; Immunomodulation and Tolerance Group; Imperial College London; London UK
| | - C. B. Schmidt-Weber
- Center of Allergy and Environment (ZAUM); Technische Universität and Helmholtz Center Munich; Munich Germany
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18
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Lawrence MG, Steinke JW, Borish L. Basic science for the clinician: Mechanisms of sublingual and subcutaneous immunotherapy. Ann Allergy Asthma Immunol 2017; 117:138-42. [PMID: 27499541 DOI: 10.1016/j.anai.2016.06.027] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 06/18/2016] [Accepted: 06/27/2016] [Indexed: 12/31/2022]
Abstract
OBJECTIVE To discuss the general immunologic changes that occur during immunotherapy, focusing on the differences between subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). DATA SOURCES PubMed literature review. STUDY SELECTIONS Articles pertaining to SCIT and SLIT, with specific emphasis on those that included immune mechanistic studies. RESULTS Both SCIT and SLIT are characterized by the induction of regulatory B and T cells, decreased allergen-specific T-cell proliferation, a shift from a TH2 to TH1 cytokine milieu and from an IgE to an IgG4/IgA antibody response. These changes are accompanied by clinical improvement in symptoms. CONCLUSION Immunotherapy using allergen extracts administered via both subcutaneous and sublingual approaches have demonstrated efficacy in the treatment of allergic rhinoconjunctivitis and other allergic conditions. There are subtle differences between the approaches, and understanding these differences may help clinicians select a preferred route of therapy for particular patients or allergens, depending on the immune response that is being targeted.
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Affiliation(s)
- Monica G Lawrence
- Asthma and Allergic Disease Center, University of Virginia Health System, Charlottesville, Virginia; Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
| | - John W Steinke
- Asthma and Allergic Disease Center, University of Virginia Health System, Charlottesville, Virginia; Department of Medicine, University of Virginia Health System, Charlottesville, Virginia; Carter Immunology Center, University of Virginia Health System, Charlottesville, Virginia
| | - Larry Borish
- Asthma and Allergic Disease Center, University of Virginia Health System, Charlottesville, Virginia; Department of Medicine, University of Virginia Health System, Charlottesville, Virginia; Carter Immunology Center, University of Virginia Health System, Charlottesville, Virginia; Department of Microbiology, University of Virginia Health System, Charlottesville, Virginia.
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19
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Rust BJ, Wambre E. Human Immune Monitoring Techniques during Food Allergen Immunotherapy. Curr Allergy Asthma Rep 2017; 17:22. [PMID: 28361386 DOI: 10.1007/s11882-017-0689-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2023]
Abstract
PURPOSE OF REVIEW Encouraging results from recent food allergen immunotherapy clinical trials indicate that the immune system plays an essential role in peripheral tolerance to food allergen. Thus, the monitoring of changes in immune responses and their possible correlation with clinical outcome in allergic patients receiving immunotherapies could theoretically serve as surrogate markers and be harnessed as rationale for food allergen immunotherapy development. RECENT FINDINGS A shift towards antigen specificity in recent assays has provided a solid foundation for the elucidation of cellular mechanisms involved in food allergen immunotherapy as well as the tracking of allergen-specific immune cells. In this review, we overview the current challenges and technologies used in immune monitoring during immunotherapy in allergic patients with a focus on cell-mediated immunity. We also discuss critical steps involved in some of the cellular immune assays utilized in clinical trials.
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Affiliation(s)
- Blake J Rust
- Department of Translational Immunology, Benaroya Research Institute, Seattle, WA, USA
| | - Erik Wambre
- Department of Translational Immunology, Benaroya Research Institute, Seattle, WA, USA.
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20
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Wang CM, Chang CB, Chan MW, Wen ZH, Wu SF. Dust mite allergen-specific immunotherapy increases IL4 DNA methylation and induces Der p-specific T cell tolerance in children with allergic asthma. Cell Mol Immunol 2017; 15:963-972. [PMID: 28603280 DOI: 10.1038/cmi.2017.26] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Revised: 03/25/2017] [Accepted: 03/25/2017] [Indexed: 12/23/2022] Open
Abstract
Allergen-specific immunotherapy (allergen-SIT) is a highly effective treatment for children with allergic asthma (AA), an immune-mediated chronic disease leading to bronchial muscle hypertrophy and airway obstruction in response to specific allergens. T helper cells and secreted cytokines play important roles in the pathogenesis of asthma, and epigenetic modulation controls genes important for T cell development and cytokine expression. This study evaluated T helper cell-secreted cytokines and DNA methylation patterns in children treated with Dermatophagoides pteronyssinus (Der p) allergen-SIT. Our results showed that after Der p challenge, peripheral blood mononuclear cells (PBMCs) from the SIT group, compared with the non-SIT AA group, produced lower levels of IL-4, IL-5 and IL-2. The SIT group, compared with the AA group, exhibited decreased sensitivity to the Der p allergen, concurrent with IL-4 down-modulation due to increased promoter DNA methylation, as estimated in PBMCs. Our results showed that SIT decreased IL-4 and IL-5, and inhibited T cell proliferation, by inhibiting IL-2 production after the specific allergen challenge. These results suggest that decreased IL-2 production and increased IL-4 cytokine promoter methylation is a potential mechanism of Der p-specific allergen desensitization immunotherapy.
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Affiliation(s)
- Chuang-Ming Wang
- Department of Pediatrics, Ditmanson Medical Foundation Chia-Yi Christian Hospital, 60002, Chia-Yi, Taiwan, China.,Department of Nursing, Chang Gung University of Science and Technology, 61363, Chia-Yi, Taiwan, China
| | - Chia-Bin Chang
- Department of Life Science and Institute of Molecular Biology, National Chung-Cheng University, 62102, Chia-Yi, Taiwan, China
| | - Michael Wy Chan
- Department of Life Science and Institute of Molecular Biology, National Chung-Cheng University, 62102, Chia-Yi, Taiwan, China
| | - Zhi-Hong Wen
- Department of Marine Biotechnology and Resources, Asia-Pacific Ocean Research Center, National Sun Yat-Sen University, 80424, Kaohsiung, Taiwan, China
| | - Shu-Fen Wu
- Department of Life Science and Institute of Molecular Biology, National Chung-Cheng University, 62102, Chia-Yi, Taiwan, China.
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21
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Update on Biomarkers to Predict Responders to Allergen Immunotherapy. CURRENT TREATMENT OPTIONS IN ALLERGY 2017. [DOI: 10.1007/s40521-017-0113-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Würtzen PA, Gupta S, Brand S, Andersen PS. Grass pollen immunotherapy: where are we now. Immunotherapy 2016; 8:399-411. [PMID: 26973122 DOI: 10.2217/imt.16.1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
During allergen immunotherapy (AIT), the allergic patient is exposed to the disease-inducing antigens (allergens) in order to induce clinical and immunological tolerance and obtain disease modification. Large trials of grass AIT with highly standardized subcutaneous and sublingual tablet vaccines have been conducted to document the clinical effect. Induction of blocking antibodies as well as changes in the balance between T-cell phenotypes, including induction of regulatory T-cell subtypes, have been demonstrated for both treatment types. These observations increase the understanding of the immunological mechanism behind the clinical effect and may make it possible to use the immunological changes as biomarkers of clinical effect. The current review describes the recent mechanistic findings for subcutaneous immunotherapy and sublingual immunotherapy/tablet treatment and discusses how the observed immunological changes translate into a scientific foundation for the observed clinical effects of grass pollen immunotherapy and lead to new treatment strategies for grass AIT.
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Affiliation(s)
- Peter A Würtzen
- Department of Immunology, Global Research, ALK, Hørsholm, Denmark
| | - Shashank Gupta
- Department of Immunology, Global Research, ALK, Hørsholm, Denmark
| | - Stephanie Brand
- Department of Immunology, Global Research, ALK, Hørsholm, Denmark
| | - Peter S Andersen
- Department of Immunology, Global Research, ALK, Hørsholm, Denmark
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Abstract
Biomarkers (BMKs) are biological parameters that can be measured to predict or monitor disease severity or treatment efficacy. The induction of regulatory dendritic cells (DCs) concomitantly with a downregulation of proallergic DC2s (ie, DCs supporting the differentiation of T-helper lymphocyte type 2 cells) in the blood of patients allergic to grass pollen has been correlated with the early onset of allergen immunotherapy efficacy. The combined use of omics technologies to compare biological samples from clinical responders and nonresponders is being implemented in the context of nonhypothesis-driven approaches. Such comprehensive "panoromic" strategies help identify completely novel candidate BMKs, to be subsequently validated as companion diagnostics in large-scale clinical trials.
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Affiliation(s)
- Philippe Moingeon
- Research and Development, Stallergenes SA, 6 Rue Alexis de Tocqueville, Antony Cedex 92183, France.
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24
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Abstract
PURPOSE OF REVIEW The aims of this review are to discuss the impact of chronic high-dose allergen exposure on allergen-specific CD4(+) T-cell subset during allergen-specific immunotherapy (AIT) and discuss recent advances supporting novel mechanisms for desensitization and tolerance induction during AIT. (Figure is included in full-text article.) RECENT FINDINGS New technologies for direct molecular and cellular analysis have now provided an unprecedented opportunity to compare the functions and phenotypes of allergen-specific T cells at a single cell level, both in the context of disease and clinical intervention. Recent studies have demonstrated that AIT may restore tolerance by transiently inducing interleukin (IL)-10 producing T cells followed by selective deletion of allergen-specific TH2 cell subset. SUMMARY With antigen-specific TH2 cells at the core of the allergic process in atopic individuals, the duration and dose of antigen exposure can be the driving force behind current AIT protocol. Mechanisms modulating allergen-specific CD4(+) T-cell responses may include autocrine IL-10 production to limit excessive TH2 cell effector responses, T-cell exhaustion, and preferential proallergic TH2 cell deletion allowing concurrent downregulating T-cell responses to emerge. Administration of AIT in the context of immune modulating strategies able to induce counter-regulatory immune response may lead to improved AIT with durable clinical benefit.
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25
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Nomura T, Suzuki M, Yokota M, Nakamura Y, Ozeki K, Ito Y, Tsuge I, Saitoh S. Effect of Japanese cedar-specific sublingual immunotherapy on allergen-specific TH2 cell counts in blood. Ann Allergy Asthma Immunol 2016; 117:72-78.e4. [PMID: 27156747 DOI: 10.1016/j.anai.2016.04.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 03/20/2016] [Accepted: 04/08/2016] [Indexed: 12/26/2022]
Abstract
BACKGROUND The contribution of antigen-specific TH cells in peripheral blood to immunologic mechanisms underlying sublingual immunotherapy (SLIT) remains unclear, partly because of the lack of a standardized method for the analysis of this rare lymphocyte subset. OBJECTIVE To clarify the role of antigen-specific TH cells during SLIT using a sensitive method analyzing activation marker CD154-positive TH cells with multicolor flow cytometry. METHODS We assessed antigen-specific TH cells using multicolor flow cytometry based on the expression of the activation marker CD154 and intracellular cytokines in patients with Japanese cedar pollinosis receiving SLIT at baseline and during the first pollen season after the initiation of SLIT. RESULTS A total of 18 patients between 12 and 44 years of age were enrolled in the present study. Of these, 8 patients received SLIT (SLIT group) and 10 patients received symptomatic treatment only (control group). Although seasonal pollen exposure significantly increased the number of Japanese cedar-specific interleukin 5- and interleukin 4-producing TH cells in the control group (P < .01 for both), SLIT ameliorated this increase in the SLIT group (P = .64 and P = .84, respectively). CONCLUSION The present study indicates that allergen-specific TH2 cells in peripheral blood are involved in mechanisms underlying SLIT. The analysis of antigen-specific TH cells using multicolor flow cytometry based on the expression of the activation marker CD154 represents a sensitive and relatively simple, standardized method for monitoring peripheral antigen-specific TH cells during allergen-specific immunotherapy.
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Affiliation(s)
- Takayasu Nomura
- Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.
| | - Motohiko Suzuki
- Department of Otorhinolaryngology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Makoto Yokota
- Department of Otorhinolaryngology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Yoshihisa Nakamura
- Department of Otorhinolaryngology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Kazuyoshi Ozeki
- Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Yasuhiko Ito
- Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Ikuya Tsuge
- Department of Pediatrics, School of Medicine, Fujita Health University, Toyoake, Japan
| | - Shinji Saitoh
- Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
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Gueguen C, Bouley J, Moussu H, Luce S, Duchateau M, Chamot-Rooke J, Pallardy M, Lombardi V, Nony E, Baron-Bodo V, Mascarell L, Moingeon P. Changes in markers associated with dendritic cells driving the differentiation of either TH2 cells or regulatory T cells correlate with clinical benefit during allergen immunotherapy. J Allergy Clin Immunol 2015; 137:545-58. [PMID: 26522402 DOI: 10.1016/j.jaci.2015.09.015] [Citation(s) in RCA: 91] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 08/27/2015] [Accepted: 09/11/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Regulatory dendritic cell (DC) markers, such as C1Q, are upregulated in PBMCs of patients with grass pollen allergy exhibiting clinical benefit during allergen immunotherapy (AIT). OBJECTIVES We sought to define markers differentially expressed in human monocyte-derived DCs differentiated toward a proallergic (DCs driving the differentiation of TH2 cells [DC2s]) phenotype and investigate whether changes in such markers in the blood correlate with AIT efficacy. METHODS Transcriptomes and proteomes of monocyte-derived DCs polarized toward DCs driving the differentiation of TH1 cells (DC1s), DC2s, or DCs driving the differentiation of regulatory T cells (DCreg cells) profiles were compared by using genome-wide cDNA microarrays and label-free quantitative proteomics, respectively. Markers differentially regulated in DC2s and DCreg cells were assessed by means of quantitative PCR in PBMCs from 80 patients with grass pollen allergy before and after 2 or 4 months of sublingual AIT in parallel with rhinoconjunctivitis symptom scores. RESULTS We identified 20 and 26 new genes/proteins overexpressed in DC2s and DCreg cells, respectively. At an individual patient level, DC2-associated markers, such as CD141, GATA3, OX40 ligand, and receptor-interacting serine/threonine-protein kinase 4 (RIPK4), were downregulated after a 4-month sublingual AIT course concomitantly with an upregulation of DCreg cell-associated markers, including complement C1q subcomponent subunit A (C1QA), FcγRIIIA, ferritin light chain (FTL), and solute carrier organic anion transporter family member 2B1 (SLCO2B1), in the blood of clinical responders as opposed to nonresponders. Changes in such markers were better correlated with clinical benefit than alterations of allergen-specific CD4(+) T-cell or IgG responses. CONCLUSIONS A combination of 5 markers predominantly expressed by blood DCs (ie, C1Q and CD141) or shared with lymphoid cells (ie, FcγRIIIA, GATA3, and RIPK4) reflecting changes in the balance of regulatory/proallergic responses in peripheral blood can be used as early as after 2 months to monitor the early onset of AIT efficacy.
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Affiliation(s)
- Claire Gueguen
- Research and Pharmaceutical Development, Stallergenes, Antony, France
| | - Julien Bouley
- Research and Pharmaceutical Development, Stallergenes, Antony, France
| | - Hélène Moussu
- Research and Pharmaceutical Development, Stallergenes, Antony, France
| | - Sonia Luce
- Research and Pharmaceutical Development, Stallergenes, Antony, France
| | - Magalie Duchateau
- Unité de Spectrométrie de Masse Structurale et Protéomique, Institut Pasteur, Paris, France
| | - Julia Chamot-Rooke
- Unité de Spectrométrie de Masse Structurale et Protéomique, Institut Pasteur, Paris, France
| | - Marc Pallardy
- Université Paris-Sud, INSERM UMR 996, Faculté de Pharmacie, Châtenay-Malabry, France
| | - Vincent Lombardi
- Research and Pharmaceutical Development, Stallergenes, Antony, France
| | - Emmanuel Nony
- Research and Pharmaceutical Development, Stallergenes, Antony, France
| | | | - Laurent Mascarell
- Research and Pharmaceutical Development, Stallergenes, Antony, France
| | - Philippe Moingeon
- Research and Pharmaceutical Development, Stallergenes, Antony, France.
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New technologies for monitoring human antigen-specific T cells and regulatory T cells by flow-cytometry. Curr Opin Pharmacol 2015; 23:17-24. [DOI: 10.1016/j.coph.2015.04.005] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Accepted: 04/24/2015] [Indexed: 11/24/2022]
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Rösner-Friese K, Kaul S, Vieths S, Pfaar O. Environmental exposure chambers in allergen immunotherapy trials: Current status and clinical validation needs. J Allergy Clin Immunol 2014; 135:636-43. [PMID: 25528360 DOI: 10.1016/j.jaci.2014.10.045] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Revised: 09/24/2014] [Accepted: 10/31/2014] [Indexed: 11/17/2022]
Abstract
As required by the European Medicines Agency and the US Food and Drug Administration for pivotal trials involving allergen immunotherapy (AIT) products, clinical efficacy assessment is currently based on double-blind, placebo-controlled field studies with natural allergen exposure during the allergen season. However, this study design is associated with several drawbacks, such as the high variability of allergen exposure in different trial sites or seasons and the presence of confounding environmental factors. On the contrary, environmental exposure chambers (EECs) aim to operate with a stable and reproducible allergen exposure under highly standardized environmental conditions. Technical validation parameters for different EECs worldwide have been published by several groups. However, full clinical validation of EEC study outcomes is required for their classification as an appropriate alternative to natural allergen exposure for AIT product efficacy assessment. Some clinical validation parameters have already been addressed for EEC units. The reliability of provoked symptoms in repeated EEC sessions is high, but the predictive power of EEC settings for the clinical response on natural exposure and the impact of seasonal priming on test results still have to be validated systematically, as does the inter-EEC variability. Thus the authors recommend a continued in-depth validation of EECs to exploit the potential of this technology for future AIT product development.
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Affiliation(s)
- Karen Rösner-Friese
- Division of Allergology, Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Langen, Germany
| | - Susanne Kaul
- Division of Allergology, Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Langen, Germany.
| | - Stefan Vieths
- Division of Allergology, Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Langen, Germany
| | - Oliver Pfaar
- Center for Rhinology and Allergology Wiesbaden and the Department of Otorhinolaryngology, Head and Neck Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
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Szépfalusi Z, Bannert C, Ronceray L, Mayer E, Hassler M, Wissmann E, Dehlink E, Gruber S, Graf A, Lupinek C, Valenta R, Eiwegger T, Urbanek R. Preventive sublingual immunotherapy in preschool children: first evidence for safety and pro-tolerogenic effects. Pediatr Allergy Immunol 2014; 25:788-95. [PMID: 25406682 PMCID: PMC6597351 DOI: 10.1111/pai.12310] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/14/2014] [Indexed: 11/30/2022]
Abstract
BACKGROUND Prevention of new IgE sensitizations has been described during allergen-specific immunotherapy. However, prospective data using a preventive approach in very young children who would benefit most are missing. We initiated a prospective pilot study investigating the safety, immunomodulatory, and sensitization-preventive effect of sublingual immunotherapy (SLIT) in mono/oligoclonally sensitized, clinically asymptomatic children 2-5 yr of age. METHODS In this double-blinded, randomized, placebo-controlled pilot study, 31 mono-/oligosensitized children to house-dust mite or grass pollen were included. SLIT with the respective source (n = 15) or placebo (n = 16) was applied. After dose-up-phase therapy was continued for 2 yr. Parents recorded clinical events, vaccinations, and drug intake in a diary. Skin prick testing and specific IgE and IgG measurements were recorded at baseline, 12 and 24 months. At the same time, allergen-specific proliferation and IL10- and TGFβ-dependent Treg function were measured. RESULTS Preventive application of SLIT in young children was safe (no relevant side effects in 21,170 single applications). After 12 and 24 months of treatment, the rate of allergen-specific sensitization (specific IgE and SPT reactivity) was comparable in the treatment and the placebo group. However, verum-treated patients displayed a significant up-regulation of allergen-specific IgG (p < 0.05). Furthermore, IL10-dependent inhibition (p < 0.05) was observed in vitro in the treatment group but not in the placebo group. CONCLUSION Preventive SLIT is safe in children 2-5 yr of age and induces regulatory mechanisms involving allergen-specific IgG and IL10. Based on this pilot study, large-scale trials will need to investigate the modulation of sensitization and clinically relevant allergy.
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Affiliation(s)
- Zsolt Szépfalusi
- Department of Paediatrics, Medical University of Vienna, Vienna, Austria
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Cingi C, Muluk NB, Hanci D, Ulusoy S, Sahin F. Updating the role played by immunotherapy for allergic rhinitis: meta-analysis. Int Forum Allergy Rhinol 2014; 5:132-42. [DOI: 10.1002/alr.21447] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Revised: 10/08/2014] [Accepted: 10/10/2014] [Indexed: 12/15/2022]
Affiliation(s)
- Cemal Cingi
- Department of Otorhinolaryngology; Medical Faculty, Eskisehir Osmangazi University; Eskisehir Turkey
| | - Nuray Bayar Muluk
- Department of Otorhinolaryngology; Medical Faculty, Kirikkale University; Kirikkale Turkey
| | - Deniz Hanci
- Ear Nose and Throat (ENT) Department; Liv Hospital; Istanbul Turkey
| | - Seckin Ulusoy
- ENT Clinics; Gaziosmanpaşa Taksim Education and Research Hospital; Istanbul Turkey
| | - Fezan Sahin
- Department of Biostatistics, Medical Faculty; Eskisehir Osmangazi University; Eskisehir Turkey
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Abstract
Sublingual immunotherapy (SLIT) is a well-established allergen-specific immunotherapy and a safe and effective strategy to reorient inappropriate immune responses in allergic patients. SLIT takes advantage of the tolerogenic environment of the oral mucosa to promote tolerance to the allergen. Several clinical studies have investigated the complex interplay of innate and adaptive immune responses that SLIT exploits. The oral immune system is composed of tolerogenic dendritic cells that, following uptake of allergen during SLIT, support the differentiation of T helper cell type 1 (Th1) and the induction of IL-10-producing regulatory T cells. Following SLIT, allergic disease-promoting T helper cell type 2 (Th2) responses shift to a Th1 inflammatory response, and IL-10 and transforming growth factor (TGF)-β production by regulatory T cells and tolerogenic dendritic cells suppress allergen-specific T cell responses. These immune changes occur both in the sublingual mucosa and in the periphery of a patient following SLIT. SLIT also promotes the synthesis of allergen-specific IgG and IgA antibodies that block allergen-IgE complex formation and binding to inflammatory cells, thus encouraging an anti-inflammatory environment. Several of these revealing findings have also paved the way for the identification of biomarkers of the clinical efficacy of SLIT. This review presents the emerging elucidation of the immune mechanisms mediated by SLIT.
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Affiliation(s)
- David C Jay
- Institute of Immunity, Transplantation and Infectious Diseases, Stanford University, 269 Campus Drive, CCSR Building, Room 3215, Stanford, CA, USA
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Mari A, Antonietta Ciardiello M, Passalacqua G, Vliagoftis H, Wardlaw AJ, Wickman M. Developments in the field of allergy in 2012 through the eyes of Clinical & Experimental Allergy. Clin Exp Allergy 2014; 43:1309-32. [PMID: 24118214 DOI: 10.1111/cea.12212] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In 2012, we received 683 submissions and published 20 editorials, 38 reviews, 11 letters and 128 original articles. This represents an acceptance rate for original papers in the range of 20%. About 30% of original papers were triaged not to go out to review, either because the editors did not feel they had sufficient priority for publication or because the topic did not feel right for the readers of the journal. We place great emphasis on obtaining sufficient high-quality reviews to make our decisions on publication fair and consistent. Inevitably, however, there is a degree of luck about what gets published and which papers miss out, and we are always happy to receive an appeal on our decisions either at the triage stage or after review. This gives us the opportunity to revisit the decision and revise it or explain in more detail to the authors the basis for the decision. Once again in 2012, we were delighted by the quality of the papers submitted and the breadth and depth of research into allergic disease that it revealed. The pattern of papers submitted was similar in previous years with considerable emphasis on all aspects of asthma and rhinitis. We were particularly pleased with our special issue on severe asthma. Elucidating mechanisms using either animal models or patients has always been a major theme of the journal, and the excellent work in these areas has been summarized by Harissios Vliagoftis with a particularly interesting section on early-life events guiding the development of allergic disease, which understandably continue to be a major theme of research. Magnus Wickman summarized the papers looking at the epidemiology of allergic disease including work from birth cohorts, which are an increasingly rich source of data on risk factors for allergic disease, and two papers on the epidemiology of anaphylaxis. Giovanni Passalacqua discussed the papers in the clinical allergy section of the journal, and Adriano Mari who runs the excellent Allergome website discussed the papers looking at allergens including characterization and the relative usefulness of allergen arrays versus single extracts in diagnosis and management.
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Affiliation(s)
- A Mari
- Allergome, Allergy Data Laboratories s.c., Latina, Italy
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33
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Canonica GW, Cox L, Pawankar R, Baena-Cagnani CE, Blaiss M, Bonini S, Bousquet J, Calderón M, Compalati E, Durham SR, van Wijk RG, Larenas-Linnemann D, Nelson H, Passalacqua G, Pfaar O, Rosário N, Ryan D, Rosenwasser L, Schmid-Grendelmeier P, Senna G, Valovirta E, Van Bever H, Vichyanond P, Wahn U, Yusuf O. Sublingual immunotherapy: World Allergy Organization position paper 2013 update. World Allergy Organ J 2014; 7:6. [PMID: 24679069 PMCID: PMC3983904 DOI: 10.1186/1939-4551-7-6] [Citation(s) in RCA: 328] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Accepted: 02/07/2014] [Indexed: 02/07/2023] Open
Abstract
We have prepared this document, "Sublingual Immunotherapy: World Allergy Organization Position Paper 2013 Update", according to the evidence-based criteria, revising and updating chapters of the originally published paper, "Sublingual Immunotherapy: World Allergy Organization Position Paper 2009", available at http://www.waojournal.org. Namely, these comprise: "Mechanisms of sublingual immunotherapy;" "Clinical efficacy of sublingual immunotherapy" - reporting all the data of all controlled trials published after 2009; "Safety of sublingual immunotherapy" - with the recently published Grading System for adverse reactions; "Impact of sublingual immunotherapy on the natural history of respiratory allergy" - with the relevant evidences published since 2009; "Efficacy of SLIT in children" - with detailed analysis of all the studies; "Definition of SLIT patient selection" - reporting the criteria for eligibility to sublingual immunotherapy; "The future of immunotherapy in the community care setting"; "Methodology of clinical trials according to the current scientific and regulatory standards"; and "Guideline development: from evidence-based medicine to patients' views" - including the evolution of the methods to make clinical recommendations.Additionally, we have added new chapters to cover a few emerging crucial topics: "Practical aspects of schedules and dosages and counseling for adherence" - which is crucial in clinical practice for all treatments; "Perspectives and new approaches" - including recombinant allergens, adjuvants, modified allergens, and the concept of validity of the single products. Furthermore, "Raising public awareness about sublingual immunotherapy", as a need for our patients, and strategies to increase awareness of allergen immunotherapy (AIT) among patients, the medical community, all healthcare stakeholders, and public opinion, are also reported in detail.
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Affiliation(s)
- Giorgio Walter Canonica
- Respiratory and Allergy Clinic, DIMI—Department of Internal Medicine, University of Genoa, IRCCS Aou San Martino, Largo Rosanna Benzi 10, Genoa 1-16132, Italy
| | - Linda Cox
- Department of Medicine, Nova Southeastern University, College of Osteopathic Medicine, Davie Florida, USA
| | - Ruby Pawankar
- Division of Allergy, Department of Pediatrics, Nippon Medical School, Tokyo, Japan
| | - Carlos E Baena-Cagnani
- Research Center for Respiratory Medicine (CIMER), Catholic University, Fundación LIBRA, Córdoba, Argentina
| | - Michael Blaiss
- Department of Pediatrics and Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Sergio Bonini
- Department of Medicine, Second University of Naples, Institute of Translational Pharmacology, Italian National Research Council, Rome, Italy
| | - Jean Bousquet
- Centre Hospitalier Regional Universitaire de Montpellier, Université de Montpellier, Montpellier, France
| | - Moises Calderón
- Section of Allergy and Clinical Immunology, Imperial College of London, National Heart and Lung Institute, Royal Brompton Hospital, London, UK
| | - Enrico Compalati
- Allergy and Respiratory Diseases Clinic, Department of Internal Medicine, University of Genoa, Genova, Italy
| | - Stephen R Durham
- Allergy and Clinical Immunology, National Heart and Lung Institute, Imperial College of London, London, UK
| | - Roy Gerth van Wijk
- Department of Allergology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | | | - Harold Nelson
- National Jewish Health, University of Colorado – Denver School of Medicine, Denver, Colorado, USA
| | - Giovanni Passalacqua
- Allergy and Respiratory Diseases, IRCCS San Martino IST, University of Genoa, Genova, Italy
| | - Oliver Pfaar
- Center for Rhinology and Allergology Wiesbaden, Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Mannheim, Mannheim, Germany
| | - Nelson Rosário
- Pediatric Allergy and Immunology Division, Hospital de Clínicas, Federal University of Parana, Curitiba, Brazil
| | - Dermot Ryan
- Academic Centre of Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK
| | - Lanny Rosenwasser
- Children’s Mercy Hospital, University of Missouri – Kansas City School of Medicine, Kansas City, Missouri
| | | | | | - Erkka Valovirta
- Department of Clinical Allergology and Pulmonary Diseases, University of Turku, Finland, and Allergy Clinic, Terveystalo, Turku, Finland
| | - Hugo Van Bever
- Department of Paediatrics, University Children’s Medical Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Pakit Vichyanond
- Department of Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Ulrich Wahn
- Department of Pediatric Pneumology and Immunology, Charité, Humboldt University, Berlin, Germany
| | - Osman Yusuf
- The Allergy and Asthma Institute, Islamabad, Pakistan
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Popescu FD. Molecular biomarkers for grass pollen immunotherapy. World J Methodol 2014; 4:26-45. [PMID: 25237628 PMCID: PMC4145574 DOI: 10.5662/wjm.v4.i1.26] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2013] [Revised: 01/05/2014] [Accepted: 02/18/2014] [Indexed: 02/06/2023] Open
Abstract
Grass pollen allergy represents a significant cause of allergic morbidity worldwide. Component-resolved diagnosis biomarkers are increasingly used in allergy practice in order to evaluate the sensitization to grass pollen allergens, allowing the clinician to confirm genuine sensitization to the corresponding allergen plant sources and supporting an accurate prescription of allergy immunotherapy (AIT), an important approach in many regions of the world with great plant biodiversity and/or where pollen seasons may overlap. The search for candidate predictive biomarkers for grass pollen immunotherapy (tolerogenic dendritic cells and regulatory T cells biomarkers, serum blocking antibodies biomarkers, especially functional ones, immune activation and immune tolerance soluble biomarkers and apoptosis biomarkers) opens new opportunities for the early detection of clinical responders for AIT, for the follow-up of these patients and for the development of new allergy vaccines.
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Steinke JW, Lawrence MG. T-cell biology in immunotherapy. Ann Allergy Asthma Immunol 2014; 112:195-9. [PMID: 24565594 DOI: 10.1016/j.anai.2013.12.020] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 12/18/2013] [Accepted: 12/23/2013] [Indexed: 11/29/2022]
Abstract
OBJECTIVE This review discusses the current state of immunotherapy and how the CD4 T-cell response is pivotal in altering the allergic response. DATA SOURCES PubMed literature review. STUDY SELECTIONS Articles pertaining to subcutaneous, sublingual, and oral immunotherapies, with specific emphasis on those describing the T-cell response. RESULTS Although many drugs are available that help ameliorate allergic symptoms, the only intervention that has proved to provide long-term benefit and modulation of disease is immunotherapy. Many routes of immunotherapy are being pursued, including subcutaneous, sublingual, and oral immunotherapies; however, subcutaneous immunotherapy has the historical record of leading to immune changes that alter the immune response at subsequent allergen exposure. These changes are mediated by the induction of peripherally derived T-regulatory cells and appear to occur only after high-dose therapy for 3 to 5 years. Newer methods of sublingual and oral immunotherapies are currently being investigated, but their efficacy is not yet on par with subcutaneous immunotherapy. CONCLUSION The primary cells ultimately responsible for successful immunomodulation are CD4 T cells, specifically peripherally derived T-regulatory cells.
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Affiliation(s)
- John W Steinke
- Asthma and Allergic Disease Center, Carter Immunology Center, University of Virginia Health Systems, Charlottesville, Virginia.
| | - Monica G Lawrence
- Asthma and Allergic Disease Center, Carter Immunology Center, University of Virginia Health Systems, Charlottesville, Virginia
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Smith KA, Gray NJ, Saleh F, Cheek E, Frew AJ, Kern F, Tarzi MD. Characterisation of CD154+ T cells following ex vivo allergen stimulation illustrates distinct T cell responses to seasonal and perennial allergens in allergic and non-allergic individuals. BMC Immunol 2013; 14:49. [PMID: 24188324 PMCID: PMC4228241 DOI: 10.1186/1471-2172-14-49] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Accepted: 10/11/2013] [Indexed: 01/31/2023] Open
Abstract
Background Allergic sensitisation has been ascribed to a dysregulated relationship between allergen-specific Th1, Th2 and regulatory T cells. We sought to utilise our short-term CD154 detection method to further analyse the relationship between these T cell subsets and investigate differences between seasonal and perennial allergens. Using peripheral blood samples from grass-allergic, cat-allergic and healthy non-atopic subjects, we compared the frequencies and phenotype of CD154-positive T helper cells following stimulation with seasonal (grass) and perennial (cat dander) allergens. Results We identified a higher frequency of CD154+ T cells in grass-allergic individuals compared to healthy controls; this difference was not evident following stimulation with cat allergen. Activated Th1, Th2 and Tr1-like cells, that co-express IFNγ, IL4 and IL10, respectively, were identified in varying proportions in grass-allergic, cat-allergic and non-allergic individuals. We confirmed a close correlation between Th1, Th2 and Tr1-like cell frequency in non-allergic volunteers, such that the three parameters increased together to maintain a low Th2: Th1 ratio. This relationship was dysregulated in grass-allergic individuals with no correlation between the T cell subsets and a higher Th2: Th1 ratio. We confirmed previous reports of a late-differentiated T cell phenotype in response to seasonal allergens compared to early-differentiated T cell responses to perennial allergens. Conclusions The findings confirm our existing work illustrating an important balance between Th1, Th2 and Tr1-like responses to allergens in health, where Th2 responses are frequently observed, but balanced by Th1 and regulatory responses. We confirm previous tetramer-based reports of phenotypic differences in T cells responding to seasonal and perennial allergens.
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Affiliation(s)
| | | | | | | | | | | | - Michael D Tarzi
- Brighton and Sussex Medical School, division of clinical medicine, pathogen-host-interactions group, University of Sussex, Brighton BN1 9PS, UK.
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Niedoszytko M, Gruchała-Niedoszytko M, Jassem E. Gene expression analysis in allergology: the prediction of Hymenoptera venom allergy severity and treatment efficacy. Clin Transl Allergy 2013; 3:35. [PMID: 24160178 PMCID: PMC3815075 DOI: 10.1186/2045-7022-3-35] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Accepted: 10/25/2013] [Indexed: 01/25/2023] Open
Abstract
Insect venom allergy (IVA) may result in the most severe systemic reactions seen in allergology. The only potentially curative treatment option is venom immunotherapy (VIT) over 3 to 5 years. This treatment is effective in more than 90% of subjects but no reliable predictors of VIT effectiveness exist. Sting challenge with a living insect can be performed to assess the effectiveness of VIT: the predictive value of sting challenge can be highly sensitive in patients with honeybee venom allergy whereas in yellow jacket allergy, a negative result can be reliable if the challenge has been repeated at least 3 times. The analysis of gene expression may be a step towards personalized venom immunotherapy assessing the effectiveness of treatment, the minimal required time for VIT and the persistence of long term tolerance induced by the treatment. Recent studies have enabled construction of a predictive model that could potentially be used in clinical practice to assess the efficacy of insect venom immunotherapy. A set of 69 genes that may be responsible for long-term protection was identified. Further analysis of the previously identified 6 transcripts make up the 18 gene predictive peripheral blood showed differences in patients treated with IVA. Further studies are needed to investigate the usefulness of gene expression analysis and other markers in the prediction of VIT effectiveness.
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Affiliation(s)
- Marek Niedoszytko
- Department of Allergology, Medical University of Gdansk, Debinki 7, 80-210, Gdansk, Poland.
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Bacher P, Scheffold A. Flow-cytometric analysis of rare antigen-specific T cells. Cytometry A 2013; 83:692-701. [PMID: 23788442 DOI: 10.1002/cyto.a.22317] [Citation(s) in RCA: 123] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Revised: 05/09/2013] [Accepted: 05/14/2013] [Indexed: 12/20/2022]
Abstract
The cytometric enumeration and characterization of antigen-specific lymphocytes, as introduced about 15 years ago, has contributed significantly to our understanding of adaptive immune responses in health and disease. Despite the development of several technologies, allowing to directly or indirectly analyze many aspects of lymphocyte specificity and function, several unresolved issues remain, due to the low frequency of certain antigen-specific lymphocyte subsets and the complexity of T cell antigen recognition. This is especially true for CD4(+) conventional as well as regulatory T cells, which bring major contributions to immune protection and pathology. Here we review the current technologies for the analysis of antigen specific T cells within the physiologic T cell repertoire and with a special focus on recent technologies addressing the analysis of rare antigen-specific T cell populations including naive and regulatory T cells.
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Affiliation(s)
- Petra Bacher
- Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
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Moingeon P. Update on immune mechanisms associated with sublingual immunotherapy: practical implications for the clinician. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2013; 1:228-41. [PMID: 24565479 DOI: 10.1016/j.jaip.2013.03.013] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Revised: 03/11/2013] [Accepted: 03/19/2013] [Indexed: 10/26/2022]
Abstract
Sublingual immunotherapy (SLIT) is established as a safe and efficacious treatment for patients with type I respiratory allergies. The ability of SLIT to elicit antigen (allergen)-specific tolerance is linked to the peculiar biology of oral antigen-presenting cells. In the absence of danger signals, Langerhans cells, myeloid dendritic cells, and macrophages located in oral tissues, tonsils, and draining cervical lymph nodes are biased toward the induction of T(H)1 and IL-10-producing CD4(+) regulatory T cells, thus supporting tolerance as opposed to inflammation. Sublingual administration does not lead to any detectable systemic exposure of intact allergens nor to IgE neosensitization. Oral tissues contain limited numbers of mast cells located in submucosal areas, thereby explaining the well-established safety profile of SLIT, with mostly local but rare systemic reactions. The induction of CD4(+) regulatory T cells and blocking anti-inflammatory IgGs or IgAs are considered important for tolerance induction after SLIT. Specific molecular signatures associated with tolerogenic dendritic cells were recently reported during the onset of SLIT efficacy in the peripheral blood of patients exhibiting clinical benefit. Collectively, these observations confirm the induction of strong allergen-specific suppressive/tolerogenic immune responses during SLIT and pave the ground for the identification of biomarkers of efficacy. Practical implications of this emerging scientific knowledge are presented (1) to support the rational design of second-generation sublingual vaccines based on purified allergens, vector systems and/or adjuvants and (2) to help the clinician in decision making during his/her practice.
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Nomura T, Tsuge I, Inuo C, Nakajima Y, Tanaka K, Naruse N, Suzuki S, Ando H, Kondo Y, Saitoh S, Urisu A. Effect of Japanese cedar specific immunotherapy on allergen-specific T(H)2 cells in peripheral blood. Ann Allergy Asthma Immunol 2013; 110:380-385.e1. [PMID: 23622011 DOI: 10.1016/j.anai.2013.02.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2012] [Revised: 02/16/2013] [Accepted: 02/20/2013] [Indexed: 10/27/2022]
Abstract
BACKGROUND The involvement of a shift from TH2 to TH1 responses in peripheral blood in pollen subcutaneous immunotherapy (SCIT) has been contentious, partly because of difficulties analyzing antigen-specific TH cells. OBJECTIVES To use recent technical advances to establish a more direct and simple method to analyze antigen-specific TH cells and to clarify the involvement of a TH2/TH1 shift in peripheral blood in pollen specific immunotherapy. METHODS After short-term (6-hour) antigen stimulation, antigen-specific TH cells in peripheral blood of Japanese children and young adults with Japanese cedar pollinosis undergoing SCIT were analyzed by multicolor flow cytometry for the presence of the activation marker CD154 and intracellular cytokines. RESULTS Twenty-eight patients between 5 and 22 years of age were enrolled in the study; 22 had started SCIT after enrolling in the study (SCIT group), and the remaining 6 were planning to start SCIT in the next off-season (control group). The number of Japanese cedar-specific interleukin (IL) 5-, IL-4-, interferon γ-, IL-17A-, IL-10-, and tumor necrosis factor α-producing TH cells without antigen-driven cell proliferation was determined. The seasonal increase in the number of Japanese cedar-specific IL-5- and IL-4-producing TH cells seen in the control group was suppressed in the SCIT group (P < .005 and <.001, respectively). CONCLUSION We report a powerful method for the analysis of antigen-specific TH cells in peripheral blood. This method will contribute to our understanding of immune mechanisms of immunotherapy and help us develop more sophisticated allergen specific immunotherapy.
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Affiliation(s)
- Takayasu Nomura
- Department of Pediatrics, School of Medicine, Fujita Health University, Toyoake, Japan.
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Anderson RP, Jabri B. Vaccine against autoimmune disease: antigen-specific immunotherapy. Curr Opin Immunol 2013; 25:410-7. [PMID: 23478068 DOI: 10.1016/j.coi.2013.02.004] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2013] [Accepted: 02/08/2013] [Indexed: 02/08/2023]
Abstract
Recent interest in testing whether the success of antigen-specific immunotherapy (ASIT) for autoimmune diseases in mice can be translated to humans has highlighted the need for better tools to study and understand human autoimmunity. Clinical development of ASIT for allergy has been instructive, but limited understanding of CD4 T cell epitope/determinant hierarchies hampers the rational design and monitoring of ASIT. Definitive identification of pathogenic T cell epitopes as is now known in celiac disease and recent initiatives to optimize immune monitoring will facilitate rational design, monitoring and mechanistic understanding of ASIT for human autoimmune diseases.
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