T regulatory cells in allergy: novel concepts in the pathogenesis, prevention, and treatment of allergic diseases.

The identification of T regulatory (T(Reg)) 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(+) T(Reg) cells and inducible populations of allergen-specific IL-10-secreting T(R)1 cells inhibit allergen-specific effector cells in experimental models. Allergen-specific T(Reg) cell responses contribute to the control of allergic inflammation in several ways. Skewing of allergen-specific effector T cells to a T(Reg) 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-beta produced by T(Reg) cells can potently suppress IgE production while simultaneously increasing the production of the noninflammatory antibody isotypes IgG4 and IgA, respectively. T(Reg) 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.

[1]  C. Akdis,et al.  T cells and eosinophils cooperate in the induction of bronchial epithelial cell apoptosis in asthma. , 2002, The Journal of allergy and clinical immunology.

[2]  Hervé Groux,et al.  A CD4+T-cell subset inhibits antigen-specific T-cell responses and prevents colitis , 1997, Nature.

[3]  J. Del Valle,et al.  Novel insights into histamine H2receptor biology. , 1997, American journal of physiology. Gastrointestinal and liver physiology.

[4]  C. Heusser,et al.  Bee venom phospholipase A2‐specific T cell clones from human allergic and non‐allergic individuals: cytokine patterns change in response to the antigen concentration , 1992, European journal of immunology.

[5]  M. Luqman,et al.  Antigen-specific T cell tolerance down-regulates mast cell responses in vivo. , 2000, Cellular immunology.

[6]  E. Hamelmann,et al.  Anti-CD86 (B7.2) treatment abolishes allergic airway hyperresponsiveness in mice. , 1999, American journal of respiratory and critical care medicine.

[7]  C. Akdis,et al.  IL‐10‐induced anergy in peripheral T cell and reactivation by microenvironmental cytokines: two key steps in specific immunotherapy , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  J. Bousquet,et al.  Allergic rhinitis: a disease remodeling the upper airways? , 2004, The Journal of allergy and clinical immunology.

[9]  C. Akdis,et al.  Role of interleukin 10 in specific immunotherapy. , 1998, The Journal of clinical investigation.

[10]  H. Young,et al.  Histamine regulates cytokine production in maturing dendritic cells, resulting in altered T cell polarization. , 2001, The Journal of clinical investigation.

[11]  A. Kagey‐Sobotka,et al.  Effects of peptide therapy on ex vivo T-cell responses. , 1998, The Journal of allergy and clinical immunology.

[12]  C. Akdis,et al.  T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis. , 2000, The Journal of clinical investigation.

[13]  T. Haahtela,et al.  Airway mucosal inflammation even in patients with newly diagnosed asthma. , 1993, The American review of respiratory disease.

[14]  C. Akdis,et al.  A major allergen gene-fusion protein for potential usage in allergen-specific immunotherapy. , 2005, The Journal of allergy and clinical immunology.

[15]  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.

[16]  C. Hawrylowicz,et al.  Interleukin-10-secreting "regulatory" T cells induced by glucocorticoids and beta2-agonists. , 2005, American journal of respiratory cell and molecular biology.

[17]  H. Fujita,et al.  Induction of tolerance in influenza virus-immune T lymphocyte clones with synthetic peptides of influenza hemagglutinin , 1983, The Journal of experimental medicine.

[18]  M. Goldman,et al.  B7/CD28-dependent IL-5 production by human resting T cells is inhibited by IL-10. , 1994, Journal of immunology.

[19]  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.

[20]  N. Frossard,et al.  Transforming growth factor-β and its role in asthma , 2003 .

[21]  R. Pauwels,et al.  Induction of Rapid T Cell Activation, Division, and Recirculation by Intratracheal Injection of Dendritic Cells in a TCR Transgenic Model1 , 2000, The Journal of Immunology.

[22]  M. Jenmalm,et al.  Total and allergen‐specific immunoglobulin A levels in saliva in relation to the development of allergy in infants up to 2 years of age , 2002, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[23]  C. Akdis,et al.  Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma. , 2004, The Journal of allergy and clinical immunology.

[24]  S. Durham,et al.  Tregs and allergic disease. , 2004, The Journal of clinical investigation.

[25]  H. Nelson.  Advances in upper airway diseases and allergen immunotherapy. , 2003, The Journal of allergy and clinical immunology.

[26]  Y. Nakamura,et al.  Expression of growth factors and remodelling of the airway wall in bronchial asthma. , 1998, Thorax.

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

[28]  N. Yamaguchi,et al.  Transforming growth factor beta induces IgA production and acts additively with interleukin 5 for IgA production , 1989, The Journal of experimental medicine.

[29]  C. Akdis,et al.  Genes of tolerance , 2004, Allergy.

[30]  C. Pirquet.  Das Verhalten der kutanen Tuberkulinreaktion während der Masern , 1908 .

[31]  R. Pauwels,et al.  Specific Migratory Dendritic Cells Rapidly Transport Antigen from the Airways to the Thoracic Lymph Nodes , 2001, The Journal of experimental medicine.

[32]  C. Heldin,et al.  Activation of the TGF-beta/activin-Smad2 pathway during allergic airway inflammation. , 2001, American journal of respiratory cell and molecular biology.

[33]  Sergio Romagnani,et al.  Immunologic influences on allergy and the TH1/TH2 balance. , 2004, The Journal of allergy and clinical immunology.

[34]  A. Enk,et al.  Induction of Interleukin 10–Producing, Nonproliferating Cd4+ T Cells with Regulatory Properties by Repetitive Stimulation with Allogeneic Immature Human Dendritic Cells , 2000, The Journal of experimental medicine.

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

[36]  H. Hammad,et al.  Essential Role of Lung Plasmacytoid Dendritic Cells in Preventing Asthmatic Reactions to Harmless Inhaled Antigen , 2004, The Journal of experimental medicine.

[37]  Sarah J. McMillan,et al.  Manipulation of Allergen-Induced Airway Remodeling by Treatment with Anti-TGF-β Antibody: Effect on the Smad Signaling Pathway1 , 2005, The Journal of Immunology.

[38]  K. Min,et al.  Allergen‐specific conventional immunotherapy decreases immunoglobulin E‐mediated basophil histamine releasability , 2003, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[39]  D. Leung,et al.  Differential control of TH1 versus TH2 cell responses by the combination of low-dose steroids with beta2-adrenergic agonists. , 2004, The Journal of allergy and clinical immunology.

[40]  P. Hillsamer,et al.  Regulatory T cells can migrate to follicles upon T cell activation and suppress GC-Th cells and GC-Th cell-driven B cell responses. , 2004, The Journal of clinical investigation.

[41]  P. Eigenmann,et al.  Antigen-specific secretory IgA antibodies in the gut are decreased in a mouse model of food allergy. , 2004, The Journal of allergy and clinical immunology.

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

[43]  P. Venge,et al.  The effect of immunotherapy on bronchial hyperresponsiveness and eosinophil cationic protein in pollen-allergic patients. , 1988, The Journal of allergy and clinical immunology.

[44]  G. Nossal,et al.  Clonal anergy: persistence in tolerant mice of antigen-binding B lymphocytes incapable of responding to antigen or mitogen. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[45]  S. Durham,et al.  Mechanisms of immunotherapy. , 2004, The Journal of allergy and clinical immunology.

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

[47]  R. Coffman,et al.  Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell- mediated immunity , 1994, The Journal of experimental medicine.

[48]  C. Akdis,et al.  A molecular basis for T cell suppression by IL‐10: CD28‐associated IL‐10 receptor inhibits CD28 tyrosine phosphorylation and phosphatidylinositol 3‐kinase binding , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[49]  J. Virchow,et al.  T cell subsets and their soluble products regulate eosinophilia in allergic and nonallergic asthma. , 1991, Journal of immunology.

[50]  C. Akdis,et al.  Histamine in the immune regulation of allergic inflammation. , 2003, The Journal of allergy and clinical immunology.

[51]  Philip Smith,et al.  Helminth Infection Protects Mice from Anaphylaxis via IL-10-Producing B Cells1 , 2004, The Journal of Immunology.

[52]  J. Bonnefoy,et al.  IgE versus IgG4 production can be differentially regulated by IL-10. , 1998, Journal of immunology.

[53]  R. Naclerio,et al.  Nasal challenge with ragweed pollen in hay fever patients. Effect of immunotherapy. , 1985, The Journal of clinical investigation.

[54]  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.

[55]  J. Allison,et al.  ICOS co-stimulatory receptor is essential for T-cell activation and function , 2001, Nature.

[56]  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.

[57]  D Bergsma,et al.  Orphan G-protein coupled receptors: novel drug targets for the pharmaceutical industry. , 2000, Drug design and discovery.

[58]  H. von Boehmer,et al.  Anergy and suppression regulate CD4+ T cell responses to a self peptide , 2000, European journal of immunology.

[59]  R. Leurs,et al.  Histamine inhibits the production of interleukin-12 through interaction with H2 receptors. , 1998, The Journal of clinical investigation.

[60]  C. Akdis,et al.  Impact of Sublingual Immunotherapy on Specific Antibody Levels in Asthmatic Children Allergic to House Dust Mites , 2005, International Archives of Allergy and Immunology.

[61]  T. Supali,et al.  Detection of filaria-specific IgG4 antibodies and filarial DNA, for the screening of blood spots for Brugia timori , 2005, Annals of tropical medicine and parasitology.

[62]  N. Osna,et al.  Regulation of interleukin-10 secretion by histamine in TH2 cells and splenocytes. , 2001, International immunopharmacology.

[63]  R. Kroczek,et al.  ICOS is critical for T helper cell–mediated lung mucosal inflammatory responses , 2001, Nature Immunology.

[64]  M. Jordana,et al.  Interleukin (IL)-10 inhibits long-term IL-6 production but not preformed mediator release from rat peritoneal mast cells. , 1996, The Journal of clinical investigation.

[65]  N. Najafian,et al.  Nonallergic individuals recognize the same T cell epitopes of Bet v 1, the major birch pollen allergen, as atopic patients. , 1995, Journal of immunology.

[66]  V. Boussiotis,et al.  IL-10-producing T cells suppress immune responses in anergic tuberculosis patients. , 2000, The Journal of clinical investigation.

[67]  Marek Jutel,et al.  Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors , 2001, Nature.

[68]  M. Akdiş,et al.  Histamine enhances TGF‐β1‐mediated suppression of Th2 responses , 2003 .

[69]  I. van Ark,et al.  Murine CTLA4-IgG treatment inhibits airway eosinophilia and hyperresponsiveness and attenuates IgE upregulation in a murine model of allergic asthma. , 1997, American journal of respiratory cell and molecular biology.

[70]  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.

[71]  T. Macdonald,et al.  Immunity, Inflammation, and Allergy in the Gut , 2005, Science.