Mechanisms and treatment of allergic disease in the big picture of regulatory T cells
2009; Elsevier BV; Volume: 123; Issue: 4 Linguagem: Inglês
10.1016/j.jaci.2009.02.030
ISSN1097-6825
AutoresCezmi A. Akdiş, Mübeccel Akdiş,
Tópico(s)Allergic Rhinitis and Sensitization
ResumoVarious populations of regulatory T (Treg) cells have been shown to play a central role in the maintenance of peripheral homeostasis and the establishment of controlled immune responses. Their identification as key regulators of immunologic processes in peripheral tolerance to allergens has opened an important era in the prevention and treatment of allergic diseases. Both naturally occurring CD4+CD25+ Treg cells and inducible populations of allergen-specific, IL-10–secreting Treg type 1 (TR1) cells inhibit allergen-specific effector cells in experimental models. Skewing of allergen-specific effector T cells to a regulatory phenotype appears to be a key event in the development of healthy immune response to allergens and successful outcome in allergen-specific immunotherapy. Forkhead box protein 3–positive CD4+CD25+ Treg cells and TR1 cells contribute to the control of allergen-specific immune responses in several major ways, which can be summarized as suppression of dendritic cells that support the generation of effector T cells; suppression of effector TH1, TH2, and TH17 cells; suppression of allergen-specific IgE and induction of IgG4; suppression of mast cells, basophils, and eosinophils; interaction with resident tissue cells and remodeling; and suppression of effector T-cell migration to tissues. Current strategies for drug development and allergen-specific immunotherapy exploit these observations, with the potential for preventive therapies and cure for allergic diseases. Various populations of regulatory T (Treg) cells have been shown to play a central role in the maintenance of peripheral homeostasis and the establishment of controlled immune responses. Their identification as key regulators of immunologic processes in peripheral tolerance to allergens has opened an important era in the prevention and treatment of allergic diseases. Both naturally occurring CD4+CD25+ Treg cells and inducible populations of allergen-specific, IL-10–secreting Treg type 1 (TR1) cells inhibit allergen-specific effector cells in experimental models. Skewing of allergen-specific effector T cells to a regulatory phenotype appears to be a key event in the development of healthy immune response to allergens and successful outcome in allergen-specific immunotherapy. Forkhead box protein 3–positive CD4+CD25+ Treg cells and TR1 cells contribute to the control of allergen-specific immune responses in several major ways, which can be summarized as suppression of dendritic cells that support the generation of effector T cells; suppression of effector TH1, TH2, and TH17 cells; suppression of allergen-specific IgE and induction of IgG4; suppression of mast cells, basophils, and eosinophils; interaction with resident tissue cells and remodeling; and suppression of effector T-cell migration to tissues. Current strategies for drug development and allergen-specific immunotherapy exploit these observations, with the potential for preventive therapies and cure for allergic diseases. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: April 2009. Credit may be obtained for these courses until March 31, 2011.Copyright Statement: Copyright © 2009-2011. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members:Authors: Cezmi A. Akdis, MD, and Mübeccel Akdis, MD, PhDActivity Objectives1. To review the role of different regulatory T (Treg) cells in controlling immune responses.2. To understand how effector T cells regulate the healthy immune response.3. To understand how Treg cells affect the outcome of allergen-specific immunotherapy.4. To review the strategies for drug development to prevent and cure allergic diseases.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: C. A. Akdis has received research support from the Swiss National Foundation, AllergoPharma Joachim-Ganzer KG, Stallargenes, Imvision, and SARM and is the Vice President of the European Academy of Allergology and Clinical Immunology, was a member and is the representative of Switzerland and an Assembly member of the Global Allergy and Asthma European Network, and is a fellow of the American Academy of Allergy, Asthma & Immunology. M. Akdis has received research support from the Swiss National Foundation, AllergoPharma Joachim-Ganzer KG, Stallargenes, Imvision, and SARM and is a Board member of the European Academy of Allergology and Clinical Immunology and a council member of Collegium Internationals Allergologicum.The immune system is a highly interactive network, which makes its decisions on the basis of all body tissues, infections, normal flora bacteria, and almost any environmental agents. Extensive progress has been made in the understanding of mechanisms of allergic disease with the complex interaction of effector T cells, natural killer (NK) T cells, other effector cells, resident tissue cells, and regulatory T (Treg) cells. In recent years, Treg cells have become a prime target for strategies aimed at inducing tolerance. Immune tolerance in the context of allergy can be defined as persistence of efficacy after discontinuation of treatment, implying an altered allergen-specific memory T- and B-cell response.1Akdis M. Akdis C.A. Mechanisms of allergen-specific immunotherapy.J Allergy Clin Immunol. 2007; 119: 780-791Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar, 2Akdis M. Healthy immune response to allergens: T regulatory cells and more.Curr Opin Immunol. 2006; 18: 738-744Crossref PubMed Scopus (78) Google Scholar, 3Larche M. Akdis C.A. Valenta R. Immunological mechanisms of allergen-specific immunotherapy.Nat Rev Immunol. 2006; 6: 761-771Crossref PubMed Scopus (361) Google Scholar, 4Durham S.R. Walker S.M. Varga E.-V. Jacobson M.R. O'Brien F. Noble W. et al.Long-term clinical efficacy of grass-pollen immunotherapy.N Engl J Med. 1999; 341: 468-475Crossref PubMed Scopus (879) Google Scholar In addition, prevention of new antigen sensitizations5Pajno G.B. Barberio G. De Luca F. Morabito L. Parmiani S. Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy. A six-year follow-up study.Clin Exp Allergy. 2001; 31: 1392-1397Crossref PubMed Scopus (388) Google Scholar and prevention of progression to more severe disease, such as the development of asthma after allergic rhinitis,6Moller C. Dreborg S. Ferdousi H.A. Halken S. Host A. Jacobsen L. et al.Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study).J Allergy Clin Immunol. 2002; 109: 251-256Abstract Full Text Full Text PDF PubMed Scopus (738) Google Scholar are essential clinical implications of immune tolerance. The pivotal role of Treg cells in inducing and maintaining immune tolerance has been demonstrated in that their adoptive transfer was shown to prevent or cure several T cell–mediated diseases, including allergy, asthmatic lung inflammation, autoimmune diseases, and allograft rejection, by restoring immune tolerance to allergens, self-antigens, or alloantigens in animal models. In the clinical setting allergen-specific immunotherapy (SIT) has been the only treatment that induces specific Treg cells in human subjects. The role of Treg cells in allergen-specific tolerance, their interaction with other cells in the inflamed tissues, and their role in antibody regulation have been demonstrated in several studies. This review article discusses the role of Treg cells in the treatment of allergy, as well as the healthy immune response to allergens, in the big picture of immune regulation. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: April 2009. Credit may be obtained for these courses until March 31, 2011. Copyright Statement: Copyright © 2009-2011. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. List of Design Committee Members:Authors: Cezmi A. Akdis, MD, and Mübeccel Akdis, MD, PhD Activity Objectives 1. To review the role of different regulatory T (Treg) cells in controlling immune responses. 2. To understand how effector T cells regulate the healthy immune response. 3. To understand how Treg cells affect the outcome of allergen-specific immunotherapy. 4. To review the strategies for drug development to prevent and cure allergic diseases. Recognition of Commercial Support: This CME activity has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: C. A. Akdis has received research support from the Swiss National Foundation, AllergoPharma Joachim-Ganzer KG, Stallargenes, Imvision, and SARM and is the Vice President of the European Academy of Allergology and Clinical Immunology, was a member and is the representative of Switzerland and an Assembly member of the Global Allergy and Asthma European Network, and is a fellow of the American Academy of Allergy, Asthma & Immunology. M. Akdis has received research support from the Swiss National Foundation, AllergoPharma Joachim-Ganzer KG, Stallargenes, Imvision, and SARM and is a Board member of the European Academy of Allergology and Clinical Immunology and a council member of Collegium Internationals Allergologicum. Depending on the adjuvanticity of the substances coexposed with the antigen and the status of the cells and cytokines in the microenvironment, CD4+ naive T cells can differentiate into TH1, TH2, TH9, or TH17 effector cells. Based on their respective cytokine profiles, responses to chemokines, and interactions with other cells, these T-cell subsets can promote different types of inflammatory responses (Fig 1). During the development of allergic disease, effector TH2 cells produce IL-4, IL-5, IL-9, and IL-13,1Akdis M. Akdis C.A. Mechanisms of allergen-specific immunotherapy.J Allergy Clin Immunol. 2007; 119: 780-791Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar, 2Akdis M. 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