T regulatory cells in allergy: Novel concepts in the pathogenesis, prevention, and treatment of allergic diseases
2005; Elsevier BV; Volume: 116; Issue: 5 Linguagem: Inglês
10.1016/j.jaci.2005.09.004
ISSN1097-6825
AutoresMübeccel Akdiş, Kurt Blaser, Cezmi A. Akdiş,
Tópico(s)T-cell and B-cell Immunology
ResumoThe identification of T regulatory (TReg) cells 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 TR1 cells inhibit allergen-specific effector cells in experimental models. Allergen-specific TReg cell responses contribute to the control of allergic inflammation in several ways. Skewing of allergen-specific effector T cells to a TReg phenotype appears to be a crucial event in the development of a healthy immune response to allergens and successful outcome in allergen-specific immunotherapy. The increased levels of IL-10 and TGF-β produced by TReg cells can potently suppress IgE production while simultaneously increasing the production of the noninflammatory antibody isotypes IgG4 and IgA, respectively. TReg cells directly or indirectly suppress effector cells of allergic inflammation, such as mast cells, basophils, and eosinophils, and contribute to remodeling in asthma and atopic dermatitis. In addition, mediators of allergic inflammation that trigger cyclic AMP–associated G protein–coupled receptors, such as histamine receptor 2, might play a role in peripheral tolerance mechanisms against allergens. Current strategies for drug development and allergen-specific immunotherapy exploit these observations with the potential to provide cure for allergic diseases. The identification of T regulatory (TReg) cells 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 TR1 cells inhibit allergen-specific effector cells in experimental models. Allergen-specific TReg cell responses contribute to the control of allergic inflammation in several ways. Skewing of allergen-specific effector T cells to a TReg phenotype appears to be a crucial event in the development of a healthy immune response to allergens and successful outcome in allergen-specific immunotherapy. The increased levels of IL-10 and TGF-β produced by TReg cells can potently suppress IgE production while simultaneously increasing the production of the noninflammatory antibody isotypes IgG4 and IgA, respectively. TReg cells directly or indirectly suppress effector cells of allergic inflammation, such as mast cells, basophils, and eosinophils, and contribute to remodeling in asthma and atopic dermatitis. In addition, mediators of allergic inflammation that trigger cyclic AMP–associated G protein–coupled receptors, such as histamine receptor 2, might play a role in peripheral tolerance mechanisms against allergens. Current strategies for drug development and allergen-specific immunotherapy exploit these observations with the potential to provide cure for allergic diseases. The initial event responsible for the development of allergic diseases is the generation of allergen-specific CD4+ TH cells.1Romagnani S. Immunologic influences on allergy and the TH1/TH2 balance.J Allergy Clin Immunol. 2004; 113: 395-400Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar Once generated, effector TH2 cells produce IL-4, IL-5, IL-9, and IL-13 and mediate several regulatory and effector functions. These cytokines induce the production of allergen-specific IgE by B cells, development and recruitment of eosinophils, production of mucus, and contraction of smooth muscles.1Romagnani S. Immunologic influences on allergy and the TH1/TH2 balance.J Allergy Clin Immunol. 2004; 113: 395-400Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar TH1 cells might also efficiently contribute to the effector phase in allergic diseases2Trautmann A. Akdis M. Kleemann D. Altznauer F. Simon H.U. Graeve T. et al.T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis.J Clin Invest. 2000; 106: 25-35Crossref PubMed Scopus (362) Google Scholar, 3Trautmann A. Schmid-Grendelmeier P. Krüger K. Crameri R. Akdis M. Akkaya A. et al.T cells and eosinophils cooperate in the induction of bronchial epithelial apoptosis in asthma.J Allergy Clin Immunol. 2002; 109: 329-337Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar or dampen allergic inflammation, depending on specific disease model and stage of the inflammation.4Finotto S. Neurath M.F. Glickman J.N. Qin S. Lehr H.A. Green F.H. et al.Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet.Science. 2002; 295: 336-338Crossref PubMed Scopus (532) Google Scholar In addition to TH1 and TH2 cells, a further subtype of T cells with immunosuppressive function and cytokine profiles distinct from either TH1 or TH2 cells is termed regulatory-suppressor T cells (TReg cells, Fig 1).5Chen Y. Kuchroo V.K. Inobe J. Hafler D.A. Weiner H.L. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis.Science. 1994; 265: 1237-1240Crossref PubMed Scopus (1736) Google Scholar, 6Powrie F. Correa-Oliveira R. Mauze S. Coffman R.L. Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity.J Exp Med. 1994; 179: 589-600Crossref PubMed Scopus (552) Google Scholar, 7Groux H. O'Garra A. Bigler M. Rouleau M. Antonenko S. de Vries J.E. et al.A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis.Nature. 1997; 389: 737-742Crossref PubMed Scopus (3123) Google Scholar, 8Akdis C.A. Blesken T. Akdis M. Wuthrich B. Blaser K. Role of interleukin 10 in specific immunotherapy.J Clin Invest. 1998; 102: 98-106Crossref PubMed Scopus (880) Google Scholar TReg cells are able to inhibit the development of allergic TH2 responses and play a major role in allergen SIT.8Akdis C.A. Blesken T. Akdis M. Wuthrich B. Blaser K. Role of interleukin 10 in specific immunotherapy.J Clin Invest. 1998; 102: 98-106Crossref PubMed Scopus (880) Google Scholar, 9Jutel M. Akdis M. Budak F. Aebischer-Casaulta C. Wrzyszcz M. Blaser K. et al.IL-10 and TGF-β cooperate in regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy.Eur J Immunol. 2003; 33: 1205-1214Crossref PubMed Scopus (794) Google Scholar Subsets of TReg cells with distinct phenotypes and mechanisms of action include the naturally occurring, thymus-selected CD4+CD25+FoxP3+ TReg cells and the inducible type 1 TReg cells (TR1 cells).10Robinson D.S. Larche M. Durham S.R. Tregs and allergic disease.J Clin Invest. 2004; 114: 1389-1397PubMed Google Scholar, 11Akdis C.A. Blaser K. Akdis M. Genes of tolerance.Allergy. 2004; 59: 897-913Crossref PubMed Scopus (61) Google Scholar In addition, subsets of CD8+ T cells, γδ T cells, dendritic cells (DCs), IL-10–producing B cells, natural killer cells, and resident tissue cells, which might promote the generation of TReg cells, could contribute to suppressive and regulatory events.11Akdis C.A. Blaser K. Akdis M. Genes of tolerance.Allergy. 2004; 59: 897-913Crossref PubMed Scopus (61) Google Scholar During the last few years, the concept of TReg cells has received general attention by the scientific community, and excitement about the possibility of these cells in therapeutic applications for the treatment of diseases that are associated with a dysfunction in T-cell regulation has been augmented. As discussed in this review, understanding the immune mechanisms that prevent disease occurrence in nonallergic individuals and evidence for healing of altered regulatory mechanisms in allergic diseases offers promise for new immune interventions (Table I).Table IDefinitions of anergy, tolerance, suppression, and ignoranceAnergy: Clinically, anergy describes the lack of T cell–dependent, cutaneous, delayed-type hypersensitivity reactions to common antigens. Lymphocyte anergy is the failure of T- or B-cell clones to react to antigenic stimulation as a state of unresponsiveness.Immunologic ignorance: Lack of immune response development because of insufficient doses, stability, or inaccessibility of antigen to the immune system.Immune suppression: Suppression of the immune response by a defined molecular mechanism.Mucosal tolerance: A state of antigen-specific unresponsiveness after mucosal exposure to antigens.Suppressor T cell: T cells that block the activation and function of other effector T lymphocytes, a function that can now be attributed to TReg cells.Inducible TReg cells: TR1 cells and other TReg subsets, which are generated in the peripheral immune system.Natural TReg cells: Thymus-derived, CD4+CD25+ TReg cells.Tolerance: An induced state of antigen-specific immunologic unresponsiveness by exposure to antigens in an immunocompetent individual. Open table in a new tab DCs not only control immunity but also maintain peripheral tolerance, 2 complementary functions that would ensure the integrity of the organism in an environment full of pathogens and allergens. The tolerogenic function of DCs depends on certain maturation stages and subsets of different ontogenies and can be influenced by immunomodulatory agents. The differentiation of thymus-derived TReg cells does not depend on the interaction with specialized DCs,12Jordan M.S. Riley M.P. von Boehmer H. Caton A.J. Anergy and suppression regulate CD4(+) T cell responses to a self peptide.Eur J Immunol. 2000; 30: 136-144Crossref PubMed Scopus (105) Google Scholar whereas a role for DCs in the induction of TR1 cells has been supported by several studies. Immature DCs control peripheral tolerance by inducing the differentiation of TR1-like cells.13Jonuleit H. Schmitt E. Schuler G. Knop J. Enk A.H. Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells.J Exp Med. 2000; 192: 1213-1222Crossref PubMed Scopus (1338) Google Scholar Related to the prevention and development of asthma, airway DCs control the pulmonary immune response and determine tolerance and immunity to newly encountered antigens. Immature DCs are distributed throughout the lungs and capture allergens and migrate to the T-cell area of mediastinal lymph nodes within 12 hours.14Vermaelen K.Y. Carro-Muino I. Lambrecht B.N. Pauwels R.A. Specific migratory dendritic cells rapidly transport antigen from the airways to the thoracic lymph nodes.J Exp Med. 2001; 193: 51-60Crossref PubMed Scopus (458) Google Scholar They express a partially mature phenotype with an intermediate array of costimulatory molecules and induce T-cell tolerance.15Lambrecht B.N. Pauwels R.A. Fazekas De St Groth B. Induction of rapid T cell activation, division, and recirculation by intratracheal injection of dendritic cells in a TCR transgenic model.J Immunol. 2000; 164: 2937-2946PubMed Google Scholar Antigen presentation by partially mature airway DCs that express IL-10 induce the formation of TR1-like cells, which inhibit subsequent inflammatory responses.16Akbari O. DeKruyff R.H. Umetsu D.T. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen.Nat Immunol. 2001; 2: 725-731Crossref PubMed Scopus (1084) Google Scholar Moreover, depletion and adoptive transfer of pulmonary plasmacytoid DCs has demonstrated an important role for these cells in protection from allergen sensitization and asthma development in mice.17de Heer H.J. Hammad H. Soullie T. Hijdra D. Vos N. Willart M.A. et al.Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen.J Exp Med. 2004; 200: 89-98Crossref PubMed Scopus (657) Google Scholar Although molecular mechanisms of TReg cell generation remain to be elucidated, some existing therapies for allergic diseases, such as treatment with glucocorticoids and β2-agonists, might function to promote the numbers and function of IL-10–secreting TR1-like cells.18Peek E.J. Richards D.F. Faith A. Lavender P. Lee T.H. Corrigan C.J. et al.Interleukin-10-secreting “regulatory” T cells induced by glucocorticoids and beta2-agonists.Am J Respir Cell Mol Biol. 2005; 33: 105-111Crossref PubMed Scopus (88) Google Scholar, 19Karagiannidis C. Akdis M. Holopainen P. Woolley N.J. Hense G. 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Taylor A. Karamloo F. Karagiannidis C. Crameri R. et al.Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells.J Exp Med. 2004; 199: 1567-1575Crossref PubMed Scopus (887) Google Scholar Accordingly, active regulation emerges as a very essential mechanism for both inducing and maintaining peripheral tolerance to allergens. The analysis of T-cell subsets specific to various food or inhaled antigens enables a suitable human model to investigate how harmless environmental proteins are recognized and tolerated by the immune system. Single allergen-specific T cells constitute less than 0.1% of the whole CD4+ T-cell repertoire and can be isolated from the peripheral blood of human subjects according to their cytokine profile.22Akdis M. Verhagen J. Taylor A. Karamloo F. Karagiannidis C. Crameri R. et al.Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells.J Exp Med. 2004; 199: 1567-1575Crossref PubMed Scopus (887) Google Scholar Freshly purified IFN-γ–, IL-4–, and IL-10–producing allergen-specific CD4+ T cells display characteristics of TH1, TH2, and IL-10–secreting TReg cells (TR1–like cells), respectively.22Akdis M. Verhagen J. Taylor A. Karamloo F. Karagiannidis C. Crameri R. et al.Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells.J Exp Med. 2004; 199: 1567-1575Crossref PubMed Scopus (887) Google Scholar Specific TR1 cells consistently represent the dominant subset against common environmental allergens in healthy individuals, in contrast to the high frequency of allergen-specific IL-4–secreting T cells in allergic individuals. TR1 cells can act by secreting cytokines, such as IL-10 and TGF-β, but contact-dependent signals, such as programmed death-1, glucocorticoid-induced TNF receptor, membrane TGF-β, and cytotoxic T lymphocyte–associated antigen 4 (CTLA4), appear to be important in some situations.10Robinson D.S. Larche M. Durham S.R. Tregs and allergic disease.J Clin Invest. 2004; 114: 1389-1397PubMed Google Scholar, 22Akdis M. Verhagen J. Taylor A. Karamloo F. Karagiannidis C. Crameri R. et al.Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells.J Exp Med. 2004; 199: 1567-1575Crossref PubMed Scopus (887) Google Scholar Healthy and allergic individuals exhibit all 3 allergen-specific subsets in different proportions, indicating that a change in dominant subset might lead to allergy development or recovery. The ratio between specific TR1 and TH2 cells determines the development of a healthy or an allergic immune response. Although in low frequency, the existence of potential suppressive allergen-specific TR1 cells in allergic individuals suggests a possible method of treatment. Allergen SIT is most efficiently used in allergy to insect venoms and allergic rhinitis.23Till S.J. Francis J.N. Nouri-Aria K. Durham S.R. Mechanisms of immunotherapy.J Allergy Clin Immunol. 2004; 113: 1025-1035Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar, 24Nelson H.S. Advances in upper airway diseases and allergen immunotherapy.J Allergy Clin Immunol. 2005; 115: 676-684Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Despite its use in clinical practice for nearly a century, the underlying immunologic mechanisms are slowly being elucidated.11Akdis C.A. Blaser K. Akdis M. Genes of tolerance.Allergy. 2004; 59: 897-913Crossref PubMed Scopus (61) Google Scholar, 23Till S.J. Francis J.N. Nouri-Aria K. Durham S.R. Mechanisms of immunotherapy.J Allergy Clin Immunol. 2004; 113: 1025-1035Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar Increased IgG4 isotype antibodies supposedly block IgE-facilitated allergen presentation.25Nouri-Aria K.T. Wachholz P.A. Francis J.N. Jacobson M.R. Walker S.M. Wilcock L.K. et al.Grass pollen immunotherapy induces mucosal and peripheral IL-10 responses and blocking IgG activity.J Immunol. 2004; 172: 3252-3259PubMed Google Scholar A reduction in the numbers of mast cells and eosinophils, including the release of mediators,26Creticos P.S. Adkinson Jr., N.F. Kagey-Sobotka A. Proud D. Meier H.L. Naclerio R.M. et al.Nasal challenge with ragweed pollen in hay fever patients. Effect of immunotherapy.J Clin Invest. 1985; 76: 2247-2253Crossref PubMed Scopus (181) Google Scholar, 27Rak S. Lowhagen O. Venge P. The effect of immunotherapy on bronchial hyperresponsiveness and eosinophil cationic protein in pollen-allergic patients.J Allergy Clin Immunol. 1988; 82: 470-480Abstract Full Text PDF PubMed Scopus (249) Google Scholar is associated with successful allergen SIT. It appears, however, that the induction of a tolerant state in peripheral T cells represents an essential step in allergen SIT (Fig 1).8Akdis C.A. Blesken T. Akdis M. Wuthrich B. Blaser K. Role of interleukin 10 in specific immunotherapy.J Clin Invest. 1998; 102: 98-106Crossref PubMed Scopus (880) Google Scholar, 9Jutel M. Akdis M. Budak F. Aebischer-Casaulta C. Wrzyszcz M. Blaser K. et al.IL-10 and TGF-β cooperate in regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy.Eur J Immunol. 2003; 33: 1205-1214Crossref PubMed Scopus (794) Google Scholar, 28Akdis C.A. Akdis M. Blesken T. Wymann D. Alkan S.S. 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Muller U. et al.Epitope-specific T cell tolerance to phospholipase A2 in bee venom immunotherapy and recovery by IL-2 and IL-15 in vitro.J Clin Invest. 1996; 98: 1676-1683Crossref PubMed Scopus (284) Google Scholar The generation of allergen-specific TReg cells and increased production of their suppressive cytokines IL-10 and TGF-β are essential early events in allergen SIT.8Akdis C.A. Blesken T. Akdis M. Wuthrich B. Blaser K. Role of interleukin 10 in specific immunotherapy.J Clin Invest. 1998; 102: 98-106Crossref PubMed Scopus (880) Google Scholar, 9Jutel M. Akdis M. Budak F. Aebischer-Casaulta C. Wrzyszcz M. Blaser K. et al.IL-10 and TGF-β cooperate in regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy.Eur J Immunol. 2003; 33: 1205-1214Crossref PubMed Scopus (794) Google Scholar Targeting pathogenic T cells with vaccines consisting of synthetic T-cell epitope peptides (peptide immunotherapy) is another attractive approach for investigation of peripheral T-cell tolerance in human subjects. To date, clinical trials of peptide immunotherapy have been performed in 2 allergies.30Müller U.R. Akdis C.A. Fricker M. Akdis M. Bettens F. Blesken T. et al.Successful immunotherapy with T cell epitope peptides of bee venom phospholipase A2 induces specific T cell anergy in bee sting allergic patients.J Allergy Clin Immunol. 1998; 101: 747-754Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar, 31Marcotte G.V. Braun C.M. Norman P.S. Nicodemus C.F. Kagey-Sobotka A. 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Schmid-Grendelmeier P. Salagianni M. Mannhart C. et al.A major allergen gene-fusion protein for potential usage in allergen-specific immunotherapy.J Allergy Clin Immunol. 2005; 115: 323-329Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar As a promising model for other allergies, single-dose administration of a hybrid vaccine that combines 2 major allergens of bee venom, phospholipase A2 and hyaluronidase, prevents IgE development on exposure to native allergen in mice.33Kussebi F. Karamloo F. Rhyner C. Schmid-Grendelmeier P. Salagianni M. Mannhart C. et al.A major allergen gene-fusion protein for potential usage in allergen-specific immunotherapy.J Allergy Clin Immunol. 2005; 115: 323-329Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar How different subsets of TReg cells cross-talk to B cells, which leads to regulation of antibody production, is an essential question. CD4+CD25+CD69− TReg cells can migrate to germinal centers and negatively regulate T cell–dependent B-cell antibody production in mice.34Lim H.W. Hillsamer P. Kim C.H. Regulatory T cells can migrate to follicles upon T cell activation and suppress GC-Th cells and GC-Th cell-driven B cell responses.J Clin Invest. 2004; 114: 1640-1649Crossref PubMed Scopus (248) Google Scholar In humans the serum levels of specific IgE and IgG4 antibodies delineate allergic and normal immunity to allergen. Although peripheral tolerance was demonstrated in specific T cells, the capacity of B cells to produce specific IgE and IgG4 antibodies was not abolished during allergen SIT.28Akdis C.A. Akdis M. Blesken T. Wymann D. Alkan S.S. Muller U. et al.Epitope-specific T cell tolerance to phospholipase A2 in bee venom immunotherapy and recovery by IL-2 and IL-15 in vitro.J Clin Invest. 1996; 98: 1676-1683Crossref PubMed Scopus (284) Google Scholar In fact, specific serum levels of both isotypes increased during the early phase of treatment. The increase in antigen-specific IgG4 levels was more pronounced, and the ratio of specific IgE to IgG4 decreased by 10- to 100-fold. A similar change in specific isotype ratio was observed in SIT of various allergies. Moreover, IL-10, which is induced and increasingly secreted by SIT, counterregulates antigen-specific IgE and IgG4 antibody synthesis.8Akdis C.A. Blesken T. Akdis M. Wuthrich B. Blaser K. Role of interleukin 10 in specific immunotherapy.J Clin Invest. 1998; 102: 98-106Crossref PubMed Scopus (880) Google Scholar IL-10 is a potent suppressor of both total and allergen-specific IgE, whereas it simultaneously increases IgG4 production.8Akdis C.A. Blesken T. Akdis M. Wuthrich B. Blaser K. Role of interleukin 10 in specific immunotherapy.J Clin Invest. 1998; 102: 98-106Crossref PubMed Scopus (880) Google Scholar IL-10 has 2 major effects on B cells, which could result in the shift in balance as observed. IL-10 decreases ε transcript expression and therefore production of IgE when added to PBMCs during the first 3 days of culture. However, IL-10 induces further upregulation of IgE production when added to already committed B cells.35Jeannin P. Lecoanet S. Delneste Y. Gauchat J.F. Bonnefoy J.Y. IgE versus IgG4 production can be differentially regulated by IL-10.J Immunol. 1998; 160: 3555-3561PubMed Google Scholar Furthermore, IL-10 enhances γ4 transcript expression and IgG4 production induced by IL-4.35Jeannin P. Lecoanet S. Delneste Y. Gauchat J.F. Bonnefoy J.Y. IgE versus IgG4 production can be differentially regulated by IL-10.J Immunol. 1998; 160: 3555-3561PubMed Google Scholar Thus IL-10 not only generates tolerance in T cells, it also regulates specific isotype formation and skews the specific response from an IgE- to an IgG4-dominated phenotype (Fig 1). In healthy individuals antibody response to Der p 1 is characterized by specific IgA and IgG4 levels, small amounts of IgG1, and almost undetectable IgE antibodies in serum.9Jutel M. Akdis M. Budak F. Aebischer-Casaulta C. Wrzyszcz M. Blaser K. et al.IL-10 and TGF-β cooperate in regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy.Eur J Immunol. 2003; 33: 1205-1214Crossref PubMed Scopus (794) Google Scholar House dust mite SIT did not significantly change specific IgE levels after 70 days of treatment; however, a significant increase in specific IgA, IgG1, and IgG4 levels was observed.9Jutel M. Akdis M. Budak F. Aebischer-Casaulta C. Wrzyszcz M. Blaser K. et al.IL-10 and TGF-β cooperate in regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy.Eur J Immunol. 2003; 33: 1205-1214Crossref PubMed Scopus (794) Google Scholar The increase of specific IgA and IgG4 levels in serum coincides with increased TGF-β and IL-10 levels, respectively. Although further studies are required, this might account for the role of IgA and TGF-β, as well as IgG4 and IL-10, in mucosal immune responses to allergens in healthy individuals.8Akdis C.A. Blesken T. Akdis M. Wuthrich B. Blaser K. Role of interleukin 10 in specific immunotherapy.J Clin Invest. 1998; 102: 98-106Crossref PubMed Scopus (880) Google Scholar, 36Sonoda E. Matsumoto R. Hitoshi Y. Ishii T. Sugimoto M. Araki S. et al.Transforming growth factor beta induces IgA production and acts additively with interleukin 5 for IgA production.J Exp Med. 1989; 170: 1415-1420Crossref PubMed Scopus (343) Google Scholar These findings suggest a regulatory function in addition to the well-known suppressor function of TReg cells. Despite the fact that a definite decrease in IgE antibody levels and IgE-mediated skin sensitivity normally requires several years of SIT, most patients are protected against bee stings already at an early stage of bee venom SIT. The reason for this is that effector cells of allergic inflammation, such as mast cells, basophils, and eosinophils, require T-cell cytokines for priming, survival, and activity,37Walker C. Virchow J.-C. Bruijnzeel P.L.B. Blaser K. T cell subsets and their soluble products regulate eosinophilia in allergic and nonallergic asthma.J Immunol. 1991; 146: 1829-1835PubMed Google Scholar which are not efficiently provided by suppressed TH2 cells (Fig 1). TReg cells generated by SIT might efficiently modulate the thresholds for mast cell and basophil activation and decrease IgE-mediated histamine release.38Treter S. Luqman M. Antigen-specific T cell tolerance down-regulates mast cell responses in vivo.Cell Immunol. 2000; 206: 116-124Crossref PubMed Scopus (27) Google Scholar, 39Shim Y.K. Kim B.S. Cho S.H. Min K.U. Hong S.J. Allergen-specific conventional immunotherapy decreases immunoglobulin E-mediated basophil histamine releasability.Clin Exp Allergy. 2003; 33: 52-57Crossref PubMed Scopus (64) Google Scholar Inaddition, IL-10 reduces proinflammatory cytoki
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