Tregs and allergic disease.

Allergic diseases such as asthma, rhinitis, and eczema are increasing in prevalence and affect up to 15% of populations in Westernized countries. The description of Tregs as T cells that prevent development of autoimmune disease led to considerable interest in whether these Tregs were also normally involved in prevention of sensitization to allergens and whether it might be possible to manipulate Tregs for the therapy of allergic disease. Current data suggest that Th2 responses to allergens are normally suppressed by both CD4+CD25+ Tregs and IL-10 Tregs. Furthermore, suppression by these subsets is decreased in allergic individuals. In animal models, Tregs could be induced by high- or low-dose inhaled antigen, and prior induction of such Tregs prevented subsequent development of allergen sensitization and airway inflammation in inhaled challenge models. For many years, allergen-injection immunotherapy has been used for the therapy of allergic disease, and this treatment may induce IL-10 Tregs, leading to both suppression of Th2 responses and a switch from IgE to IgG4 antibody production. Improvements in allergen immunotherapy, such as peptide therapy, and greater understanding of the biology of Tregs hold great promise for the treatment and prevention of allergic disease.

[1]  M. Noris,et al.  Natural versus adaptive regulatory T cells. , 2005, Contributions to nephrology.

[2]  A. Kay,et al.  Cat allergen peptide immunotherapy reduces CD4+ T cell responses to cat allergen but does not alter suppression by CD4+ CD25+ T cells: a double‐blind placebo‐controlled study , 2004, Allergy.

[3]  Clare Baecher-Allan,et al.  Suppressor T Cells in Human Diseases , 2004, The Journal of experimental medicine.

[4]  D. Robinson,et al.  Fluticasone propionate increases CD4CD25 T regulatory cell suppression of allergen-stimulated CD4CD25 T cells by an IL-10-dependent mechanism. , 2004, The Journal of allergy and clinical immunology.

[5]  B. Ameredes,et al.  Tolerance induced by inhaled antigen involves CD4+ T cells expressing membrane-bound TGF-β and FOXP3 , 2004 .

[6]  D. Robinson The role of the mast cell in asthma: induction of airway hyperresponsiveness by interaction with smooth muscle? , 2004, The Journal of allergy and clinical immunology.

[7]  E. Schmitt,et al.  Differential Regulatory Capacity of CD25+ T Regulatory Cells and Preactivated CD25+ T Regulatory Cells on Development, Functional Activation, and Proliferation of Th2 Cells1 , 2004, The Journal of Immunology.

[8]  M. Karlsson,et al.  Allergen-responsive CD4+CD25+ Regulatory T Cells in Children who Have Outgrown Cow's Milk Allergy , 2004, The Journal of experimental medicine.

[9]  C. Akdis,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 , 2004, The Journal of experimental medicine.

[10]  B. Stockinger,et al.  IL-10-Secreting Regulatory T Cells Do Not Express Foxp3 but Have Comparable Regulatory Function to Naturally Occurring CD4+CD25+ Regulatory T Cells 1 , 2004, The Journal of Immunology.

[11]  J. Garssen,et al.  Cow's milk-specific T-cell reactivity of children with and without persistent cow's milk allergy: key role for IL-10. , 2004, The Journal of allergy and clinical immunology.

[12]  L. Cosmi,et al.  Th2 cells are less susceptible than Th1 cells to the suppressive activity of CD25+ regulatory thymocytes because of their responsiveness to different cytokines. , 2004, Blood.

[13]  C. Berry,et al.  Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheumatoid arthritis , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Z. Jaffar,et al.  CD4+CD25+ T Cells Regulate Airway Eosinophilic Inflammation by Modulating the Th2 Cell Phenotype1 , 2004, The Journal of Immunology.

[15]  D. Nowak,et al.  Toll-like receptor 2 as a major gene for asthma in children of European farmers. , 2004, The Journal of allergy and clinical immunology.

[16]  S. Durham,et al.  Grass Pollen Immunotherapy Induces Mucosal and Peripheral IL-10 Responses and Blocking IgG Activity1 , 2004, The Journal of Immunology.

[17]  M. Dallman,et al.  Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease , 2004, The Lancet.

[18]  A. Kay,et al.  Allergen-based peptide immunotherapy is associated with functional modifications in allergen-specific T-cell subpopulations , 2004 .

[19]  D. Robinson,et al.  Fluticasone propionate increases suppression of allergen-driven T cell proliferation by CD4+CD25+ T cells☆ , 2004 .

[20]  S. Akira,et al.  Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. , 2004, Gastroenterology.

[21]  A. Kay,et al.  Late asthmatic reactions induced by inhalation of allergen-derived T cell peptides. , 2004, American journal of respiratory and critical care medicine.

[22]  S. Durham,et al.  Immunological responses to allergen immunotherapy. , 2004, Clinical allergy and immunology.

[23]  Li Li,et al.  Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3 , 2003, The Journal of experimental medicine.

[24]  R. Medzhitov,et al.  Toll-like receptors: balancing host resistance with immune tolerance. , 2003, Current opinion in immunology.

[25]  S. Durham,et al.  Inhibition of allergen-IgE binding to B cells by IgG antibodies after grass pollen immunotherapy. , 2003, The Journal of allergy and clinical immunology.

[26]  D. Umetsu,et al.  Regulatory T cells control the development of allergic disease and asthma. , 2003, The Journal of allergy and clinical immunology.

[27]  R. Locksley,et al.  Lung CD25 CD4 Regulatory T Cells Suppress Type 2 Immune Responses But Not Bronchial Hyperreactivity1 , 2003, The Journal of Immunology.

[28]  S. Durham,et al.  Induction of IL-10+CD4+CD25+ T cells by grass pollen immunotherapy. , 2003, The Journal of allergy and clinical immunology.

[29]  Marek Jutel,et al.  IL‐10 and TGF‐β cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy , 2003, European journal of immunology.

[30]  I. Bellinghausen,et al.  Human CD4+CD25+ T cells derived from the majority of atopic donors are able to suppress TH1 and TH2 cytokine production. , 2003, The Journal of allergy and clinical immunology.

[31]  F. Ramsdell,et al.  An essential role for Scurfin in CD4+CD25+ T regulatory cells , 2003, Nature Immunology.

[32]  A. O’Garra,et al.  Twenty-first century Foxp3 , 2003, Nature Immunology.

[33]  A. Rudensky,et al.  Foxp3 programs the development and function of CD4+CD25+ regulatory T cells , 2003, Nature Immunology.

[34]  D. Wraith,et al.  Role for IL-10 in Suppression Mediated by Peptide-Induced Regulatory T Cells In Vivo 1 , 2003, The Journal of Immunology.

[35]  Ruslan Medzhitov,et al.  Toll Pathway-Dependent Blockade of CD4+CD25+ T Cell-Mediated Suppression by Dendritic Cells , 2003, Science.

[36]  T. Nomura,et al.  Control of Regulatory T Cell Development by the Transcription Factor Foxp3 , 2002 .

[37]  Kim Bottomly,et al.  Lipopolysaccharide-enhanced, Toll-like Receptor 4–dependent T Helper Cell Type 2 Responses to Inhaled Antigen , 2002, The Journal of experimental medicine.

[38]  A. Knulst,et al.  CD4 CD25 regulatory T cells are not functionally impaired in adult patients with IgE-mediated cow's milk allergy. , 2002, The Journal of allergy and clinical immunology.

[39]  G. Berry,et al.  Antigen-specific regulatory T cells develop via the ICOS–ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity , 2002, Nature Medicine.

[40]  D. Umetsu,et al.  Asthma: an epidemic of dysregulated immunity , 2002, Nature Immunology.

[41]  Ethan M. Shevach,et al.  CD4+CD25+ Regulatory T Cells Can Mediate Suppressor Function in the Absence of Transforming Growth Factor β1 Production and Responsiveness , 2002, The Journal of experimental medicine.

[42]  G. Schuler,et al.  Human CD4+CD25+ Regulatory, Contact-dependent T Cells Induce Interleukin 10–producing, Contact-independent Type 1-like Regulatory T Cells , 2002, The Journal of experimental medicine.

[43]  A. Kay,et al.  Effect of T-cell peptides derived from Fel d 1 on allergic reactions and cytokine production in patients sensitive to cats: a randomised controlled trial , 2002, The Lancet.

[44]  G. Rook,et al.  Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells , 2002, Nature Medicine.

[45]  Ethan M. Shevach,et al.  CD4+CD25+ suppressor T cells: more questions than answers , 2002, Nature Reviews Immunology.

[46]  David F. Richards,et al.  In Vitro Generation of Interleukin 10–producing Regulatory CD4+ T Cells Is Induced by Immunosuppressive Drugs and Inhibited by T Helper Type 1 (Th1)– and Th2-inducing Cytokines , 2002, The Journal of experimental medicine.

[47]  Erkka Valovirta,et al.  Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). , 2002, The Journal of allergy and clinical immunology.

[48]  M. Byrne,et al.  CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. , 2002, Immunity.

[49]  J. Shimizu,et al.  Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance , 2002, Nature Immunology.

[50]  S. Szabo,et al.  Distinct Effects of T-bet in TH1 Lineage Commitment and IFN-γ Production in CD4 and CD8 T Cells , 2002, Science.

[51]  S. Szabo,et al.  Development of Spontaneous Airway Changes Consistent with Human Asthma in Mice Lacking T-bet , 2002, Science.

[52]  S. Durham,et al.  Grass pollen immunotherapy for hayfever is associated with increases in local nasal but not peripheral Th1 : Th2 cytokine ratios , 2002, Immunology.

[53]  Min Zhang,et al.  A novel human immunoglobulin Fc gamma Fc epsilon bifunctional fusion protein inhibits Fc epsilon RI-mediated degranulation. , 2002, Nature medicine.

[54]  S. Szabo,et al.  Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. , 2002, Science.

[55]  Y. Lei,et al.  Hyper Immunoglobulin E Response in Mice with Monoclonal Populations of B and T Lymphocytes 〉 , 2001, The Journal of experimental medicine.

[56]  S. Durham,et al.  Grass pollen immunotherapy inhibits seasonal increases in basophils and eosinophils in the nasal epithelium , 2001, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[57]  R. Lechler,et al.  Human CD4(+)CD25(+) cells: a naturally occurring population of regulatory T cells. , 2001, Blood.

[58]  W. Strober,et al.  Cell Contact–Dependent Immunosuppression by Cd4+Cd25+Regulatory T Cells Is Mediated by Cell Surface–Bound Transforming Growth Factor β , 2001, The Journal of experimental medicine.

[59]  F. Powrie,et al.  Regulatory T cells in the control of immune pathology , 2001, Nature Immunology.

[60]  N. York,et al.  Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy. A six‐year follow‐up study. , 2001, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[61]  Kotaro Suzuki,et al.  Role of CD4(+) CD25(+) regulatory T cells in T helper 2 cell-mediated allergic inflammation in the airways. , 2001, American journal of respiratory and critical care medicine.

[62]  A. Kay,et al.  Allergen-Derived T Cell Peptide-Induced Late Asthmatic Reactions Precede the Induction of Antigen-Specific Hyporesponsiveness in Atopic Allergic Asthmatic Subjects1 , 2001, The Journal of Immunology.

[63]  J. Lamb,et al.  Notch signalling in the regulation of peripheral immunity , 2001, Immunological reviews.

[64]  D. Umetsu,et al.  Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen , 2001, Nature Immunology.

[65]  G. Freeman,et al.  CD4+CD25high Regulatory Cells in Human Peripheral Blood1 , 2001, The Journal of Immunology.

[66]  G. Schuler,et al.  Ex Vivo Isolation and Characterization of Cd4+Cd25+ T Cells with Regulatory Properties from Human Blood , 2001, The Journal of experimental medicine.

[67]  M. Roncarolo,et al.  Human Cd25+Cd4+ T Regulatory Cells Suppress Naive and Memory T Cell Proliferation and Can Be Expanded in Vitro without Loss of Function , 2001, The Journal of experimental medicine.

[68]  A. Enk,et al.  Identification and Functional Characterization of Human Cd4+Cd25+ T Cells with Regulatory Properties Isolated from Peripheral Blood , 2001, The Journal of experimental medicine.

[69]  R. Coffman,et al.  Modulation of Inhaled Antigen-Induced IgE Tolerance by Ongoing Th2 Responses in the Lung1 , 2001, The Journal of Immunology.

[70]  D. Mason,et al.  Human CD4+CD25+ thymocytes and peripheral T cells have immune suppressive activity in vitro , 2001, European journal of immunology.

[71]  M. Salmon,et al.  Human anergic/suppressive CD4+CD25+ T cells: a highly differentiated and apoptosis‐prone population , 2001, European journal of immunology.

[72]  T. Platts-Mills,et al.  Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study , 2001, The Lancet.

[73]  A B Kay,et al.  Allergy and allergic diseases. Second of two parts. , 2001, The New England journal of medicine.

[74]  A B Kay,et al.  Allergy and allergic diseases. First of two parts. , 2001, The New England journal of medicine.

[75]  J. Gutiérrez-Ramos,et al.  Mouse models of allergic airway disease. , 2001, Advances in immunology.

[76]  J. Casanova,et al.  X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy , 2001, Nature Genetics.

[77]  R. Coffman,et al.  T Regulatory Cells 1 Inhibit a Th2-Specific Response In Vivo1 , 2000, The Journal of Immunology.

[78]  Oster,et al.  Comparison of genetically engineered hypoallergenic rBet v 1 derivatives with rBet v 1 wild‐type by skin prick and intradermal testing: results obtained in a French population , 2000, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[79]  Fiona Powrie,et al.  Cytotoxic T Lymphocyte–Associated Antigen 4 Plays an Essential Role in the Function of Cd25+Cd4+ Regulatory Cells That Control Intestinal Inflammation , 2000, The Journal of experimental medicine.

[80]  T. Mak,et al.  Immunologic Self-Tolerance Maintained by Cd25+Cd4+Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte–Associated Antigen 4 , 2000, The Journal of experimental medicine.

[81]  E. Raz,et al.  Conjugation of immunostimulatory DNA to the short ragweed allergen amb a 1 enhances its immunogenicity and reduces its allergenicity. , 2000, The Journal of allergy and clinical immunology.

[82]  S. Sakaguchi Regulatory T cells , 2006, Springer Seminars in Immunopathology.

[83]  D. Mason,et al.  Subpopulations − and CD 25 + Are Found in Both CD 25 But Peripheral T Cells with This Function That Prevent Autoimmune Diabetes in Rats , Thymocytes + CD 25 Is a Marker for CD 4 , 2000 .

[84]  D. Robinson Th-2 cytokines in allergic disease. , 2000, British medical bulletin.

[85]  R. Homer,et al.  T Helper 1 Cells and Interferon γ Regulate Allergic Airway Inflammation and Mucus Production , 1999, The Journal of experimental medicine.

[86]  D. Wraith,et al.  Peptide-induced T cell regulation of experimental autoimmune encephalomyelitis: a role for IL-10. , 1999, International immunology.

[87]  R. V. van Neerven,et al.  Blocking antibodies induced by specific allergy vaccination prevent the activation of CD4+ T cells by inhibiting serum-IgE-facilitated allergen presentation. , 1999, Journal of immunology.

[88]  S. Durham,et al.  Allergen immunotherapy: does it work and, if so, how and for how long? , 2000, Thorax.

[89]  B. Haselden,et al.  Immunoglobulin E–independent Major Histocompatibility Complex–restricted T Cell Peptide Epitope–induced Late Asthmatic Reactions , 1999, The Journal of experimental medicine.

[90]  P. Holt,et al.  A Polymorphism* in the 5' flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. , 1999, American journal of respiratory cell and molecular biology.

[91]  Giorgio Walter Canonica,et al.  Allergen immunotherapy: therapeutic vaccines for allergic diseases , 1998 .

[92]  Ethan M. Shevach,et al.  CD4+CD25+ Immunoregulatory T Cells Suppress Polyclonal T Cell Activation In Vitro by Inhibiting Interleukin 2 Production , 1998, The Journal of experimental medicine.

[93]  C. Akdis,et al.  Successful immunotherapy with T-cell epitope peptides of bee venom phospholipase A2 induces specific T-cell anergy in patients allergic to bee venom. , 1998, The Journal of allergy and clinical immunology.

[94]  Victor L. J. Tybulewicz,et al.  Fcε Receptor I-Associated lyn-Dependent Phosphorylation of Fcγ Receptor IIB During Negative Regulation of Mast Cell Activation , 1998, The Journal of Immunology.

[95]  J. Bousquet,et al.  Allergen immunotherapy: therapeutic vaccines for allergic diseases. World Health Organization. American academy of Allergy, Asthma and Immunology. , 1998, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[96]  W. Fridman,et al.  Fc epsilon receptor I-associated lyn-dependent phosphorylation of Fc gamma receptor IIB during negative regulation of mast cell activation. , 1998, Journal of immunology.

[97]  S. Durham,et al.  IL‐5 production by allergen‐stimulated T cells following grass pollen immunotherapy for seasonal allergic rhinitis , 1997, Clinical and experimental immunology.

[98]  M. Willheim,et al.  Immunological changes during specific immunotherapy of grass pollen allergy: reduced lymphoproliferative responses to allergen and shift from TH2 to TH1 in T‐cell clones specific for Phi p 1, a major grass pollen allergen , 1997, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[99]  A. Enk,et al.  Insect venom immunotherapy induces interleukin‐10 production and a Th2‐to‐Th1 shift, and changes surface marker expression in venom‐allergic subjects , 1997, European journal of immunology.

[100]  W. Kuis,et al.  Peptide-induced nasal tolerance for a mycobacterial heat shock protein 60 T cell epitope in rats suppresses both adjuvant arthritis and nonmicrobially induced experimental arthritis. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[101]  C. Akdis,et al.  Epitope-specific T cell tolerance to phospholipase A2 in bee venom immunotherapy and recovery by IL-2 and IL-15 in vitro. , 1996, The Journal of clinical investigation.

[102]  S. Durham,et al.  Grass pollen immunotherapy inhibits allergen-induced infiltration of CD4+ T lymphocytes and eosinophils in the nasal mucosa and increases the number of cells expressing messenger RNA for interferon-gamma. , 1996, The Journal of allergy and clinical immunology.

[103]  D. Wegmann,et al.  Protection of nonobese diabetic mice from diabetes by intranasal or subcutaneous administration of insulin peptide B-(9-23). , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[104]  W. Fridman,et al.  The same tyrosine-based inhibition motif, in the intracytoplasmic domain of Fc gamma RIIB, regulates negatively BCR-, TCR-, and FcR-dependent cell activation. , 1995, Immunity.

[105]  M. Toda,et al.  Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. , 1995, Journal of immunology.

[106]  M. Jutel,et al.  Bee venom immunotherapy results in decrease of IL-4 and IL-5 and increase of IFN-gamma secretion in specific allergen-stimulated T cell cultures. , 1995, Journal of immunology.

[107]  P. Holt,et al.  Regulation of IgE responses to inhaled antigen in mice by antigen-specific gamma delta T cells. , 1994, Science.

[108]  H. Weiner,et al.  Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. , 1994, Science.

[109]  R. O’Hehir,et al.  Inhibition of T cell and antibody responses to house dust mite allergen by inhalation of the dominant T cell epitope in naive and sensitized mice , 1993, The Journal of experimental medicine.

[110]  D. Wraith,et al.  Inhibition of experimental autoimmune encephalomyelitis by inhalation but not oral administration of the encephalitogenic peptide: influence of MHC binding affinity. , 1993, International immunology.

[111]  S. Durham,et al.  Influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses. , 1993, The Journal of clinical investigation.

[112]  A. Gaur,et al.  Amelioration of autoimmune encephalomyelitis by myelin basic protein synthetic peptide-induced anergy. , 1992, Science.

[113]  S. Durham,et al.  Usefulness of immunotherapy in patients with severe summer hay fever uncontrolled by antiallergic drugs. , 1991, BMJ.

[114]  L. Hood,et al.  Peptide-specific prevention of experimental allergic encephalomyelitis. Neonatal tolerance induced to the dominant T cell determinant of myelin basic protein , 1989, The Journal of experimental medicine.

[115]  L. Lichtenstein,et al.  Studies on allergoids from naturally occurring allergens. IV. Efficacy and safety of long-term allergoid treatment of ragweed hay fever. , 1981, The Journal of allergy and clinical immunology.