Regulatory T Cells in Allergic Disease

  • Catherine Hawrylowicz


Allergic diseases, including asthma, are associated with the development of allergen-specific Th2 and IgE responses, which regulate the early and late phase allergic reactions. Naturally occurring T regulatory cells (Treg), which are present in all healthy individuals together with antigen-induced Treg that secrete inhibitory cytokines such as IL-10 and/or TGFβ, in the periphery. The balance between allergen-specific disease-promoting T helper 2 cells (Th2) and various Treg populations appears to be decisive in the development of a disease promoting allergic versus a non-disease promoting or tolerogenic immune response respectively. Treg specific for common environmental allergens represent the dominant subset in non-atopic individuals implying a state of natural or active tolerance to allergen in health. In contrast, there is a high frequency of allergen-specific Th2 cells in allergic individuals. The function of both naturally occurring and adaptive or inducible Treg appears to be impaired in active allergic disease. Therapies associated with amelioration of disease symptoms, including allergen immunotherapy and glucocorticoids, have been shown to modulate favourably Treg function. Strategies to improve current therapeutic regimens are increasingly focusing on manipulation of Treg for patient benefit.


Treg Cell Allergic Disease Airway Inflammation Pollen Season Allergen Exposure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The author gratefully acknowledges support from the European Union (EURO-Thymaide), the Medical Research Council of Great Britain, and Asthma UK.


  1. 1.
    Kay, A.B. 2001. Allergy and allergic diseases. First of two parts. N Engl J Med 344:30–37.PubMedCrossRefGoogle Scholar
  2. 2.
    Kay, A.B. 2001. Allergy and allergic diseases. Second of two parts. N Engl J Med 344: 109–113.PubMedCrossRefGoogle Scholar
  3. 3.
    Cookson, W.O.C.M., and M.F. Moffatt. 1997. Asthma: An epidemic in the absence of infection? Science 275:41–42.PubMedCrossRefGoogle Scholar
  4. 4.
    Jones, G. 2007. Susceptibility to asthma and eczema from mucosal and epidermal expression of distinctive genes. Curr Allergy Asthma Rep 7:11–17.PubMedCrossRefGoogle Scholar
  5. 5.
    Anderson, H.R., R. Gupta, D.P. Strachan, and E.S. Limb. 2007. 50 years of asthma: UK trends from 1955 to 2004. Thorax 62:85–90.PubMedCrossRefGoogle Scholar
  6. 6.
    Burney, P., E. Malmberg, S. Chinn, D. Jarvis, C. Luczynska, and E. Lai. 1997. The distribution of total and specific serum IgE in the European community respiratory health survey. J Allergy Clin Immunol 99:314–322.PubMedCrossRefGoogle Scholar
  7. 7.
    Yazdanbakhsh, M., P.G. Kremsner, and R. van Ree. 2002. Allergy, parasites, and the hygiene hypothesis. Science 296:490–494.PubMedCrossRefGoogle Scholar
  8. 8.
    Strachan, D.P. 1989. Hay fever, hygiene, and household size. BMJ Clin Res Ed 299: 1259–1260.CrossRefGoogle Scholar
  9. 9.
    Strachan, D. 1996. Socioeconomic factors and the development of allergy. Toxicol lett 86:199–203.PubMedCrossRefGoogle Scholar
  10. 10.
    Wills-Karp, M., J. Santeliz, and C.L. Karp. 2001. The germless theory of allergic disease: Revisiting the hygiene hypothesis. Nat Rev Immunol 1:69–75.PubMedCrossRefGoogle Scholar
  11. 11.
    Bach, J.F. 2002. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347:911–920.PubMedCrossRefGoogle Scholar
  12. 12.
    Barnes, P.J. 2006. Drugs for asthma. Br J Pharmacol 147 Suppl 1:S297–303.PubMedGoogle Scholar
  13. 13.
    Larche, M., C.A. Akdis, and R. Valenta. 2006. Immunological mechanisms of allergen-specific immunotherapy. Nat Rev Immunol 6:761–771.PubMedCrossRefGoogle Scholar
  14. 14.
    Passalacqua, G., and S.R. Durham. 2007. Allergic rhinitis and its impact on asthma update: Allergen immunotherapy. J Allergy Clin Immunol 119:881–891.PubMedCrossRefGoogle Scholar
  15. 15.
    Macaubas, C., R.H. DeKruyff, and D.T. Umetsu. 2003. Respiratory tolerance in the protection against asthma. Curr Drug Targets Inflamm Allergy 2:175–186.PubMedCrossRefGoogle Scholar
  16. 16.
    Maloy, K.J., and F. Powrie. 2001. Regulatory T cells in the control of immune pathology. Nat Immunol 2:816–822.PubMedCrossRefGoogle Scholar
  17. 17.
    Bluestone, J.A., and A.K. Abbas. 2003. Natural versus adaptive regulatory T cells. Nat Rev Immunol 3:253–257.PubMedCrossRefGoogle Scholar
  18. 18.
    O'Garra, A., and P. Vieira. 2004. Regulatory T cells and mechanisms of immune system control. Nat Med 10:801–805.PubMedCrossRefGoogle Scholar
  19. 19.
    Shevach, E. 2004. CD4+CD25+ suppressor T cells: More questions than answers. Nat Rev Immunol 2:389–400.Google Scholar
  20. 20.
    Kronenberg, M., and A. Rudensky. 2005. Regulation of immunity by self-reactive T cells. Nature 435:598–604.PubMedCrossRefGoogle Scholar
  21. 21.
    Sakaguchi, S., M. Ono, R. Setoguchi, H. Yagi, S. Hori, Z. Fehervari, J. Shimizu, T. Takahashi, and T. Nomura. 2006. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 212:8–27.PubMedCrossRefGoogle Scholar
  22. 22.
    Stock, P., T. Kallinich, O. Akbari, D. Quarcoo, K. Gerhold, U. Wahn, D.T. Umetsu, and E. Hamelmann. 2004. CD8(+) T cells regulate immune responses in a murine model of allergen-induced sensitization and airway inflammation. Eur J Immunol 34:1817–1827.PubMedCrossRefGoogle Scholar
  23. 23.
    Noble, A., A. Giorgini, and J.A. Leggat. 2006. Cytokine-induced IL-10-secreting CD8 T cells represent a phenotypically distinct suppressor T-cell lineage. Blood 107:4475–4483.PubMedCrossRefGoogle Scholar
  24. 24.
    Strober, S., L. Cheng, D. Zeng, R. Palathumpat, S. Dejbakhsh-Jones, P. Huie, and R. Sibley. 1996. Double negative (CD4–CD8– alpha beta+) T cells which promote tolerance induction and regulate autoimmunity. Immunol Rev 149:217–230.PubMedCrossRefGoogle Scholar
  25. 25.
    Seo, N., Y. Tokura, M. Takigawa, and K. Egawa. 1999. Depletion of IL-10- and TGF-beta-producing regulatory gamma delta T cells by administering a daunomycin-conjugated specific monoclonal antibody in early tumor lesions augments the activity of CTLs and NK cells. J Immunol 163:242–249.PubMedGoogle Scholar
  26. 26.
    Hayday, A., and R. Tigelaar. 2003. Immunoregulation in the tissues by gammadelta T cells. Nat Rev Immunol 3:233–242.PubMedCrossRefGoogle Scholar
  27. 27.
    Jiang, S., R.I. Lechler, X.S. He, and J.F. Huang. 2006. Regulatory T cells and transplantation tolerance. Hum Immunol 67:765–776.PubMedCrossRefGoogle Scholar
  28. 28.
    Thomson, C.W., B.P. Lee, and L. Zhang. 2006. Double-negative regulatory T cells: non-conventional regulators. Immunol Res 35:163–178.PubMedCrossRefGoogle Scholar
  29. 29.
    Akbari, O., R.H. DeKruyff, and D.T. Umetsu. 2001. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat Immunol 2: 725–731.PubMedCrossRefGoogle Scholar
  30. 30.
    Steinbrink, K., M. Wolfl, H. Jonuleit, J. Knop, and A. Enk. 1997. Induction of tolerance by IL-10-treated dendritic cells. J Immunol 159:4772–4780.PubMedGoogle Scholar
  31. 31.
    Mauri, C., D. Gray, N. Mushtaq, and M. Londei. 2003. Prevention of arthritis by interleukin 10-producing B cells. J Exp Med 197:489–501.PubMedCrossRefGoogle Scholar
  32. 32.
    Moore, K.W., A. O'Garra, R. de Waal Malefyt, P. Vieira, and T.R. Mosmann. 1993. Interleukin-10. Annu Rev Immunol 11:165–190.PubMedCrossRefGoogle Scholar
  33. 33.
    Li, M.O., Y.Y. Wan, S. Sanjabi, A.K. Robertson, and R.A. Flavell. 2006. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 24:99–146.PubMedCrossRefGoogle Scholar
  34. 34.
    Rubtsov, Y.P., and A.Y. Rudensky. 2007. TGFbeta signalling in control of T-cell-mediated self-reactivity. Nat Rev Immunol 7:443–453.PubMedCrossRefGoogle Scholar
  35. 35.
    Jordan, M.S., A. Boesteanu, A.J. Reed, A.L. Petrone, A.E. Holenbeck, M.A. Lerman, A. Naji, and A.J. Caton. 2001. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat Immunol 2:301–306.PubMedCrossRefGoogle Scholar
  36. 36.
    Liston, A., and A.Y. Rudensky. 2007. Thymic development and peripheral homeostasis of regulatory T cells. Curr Opin Immunol 19:176–185.PubMedCrossRefGoogle Scholar
  37. 37.
    Apostolou, I., and H. von Boehmer. 2004. In vivo instruction of suppressor commitment in naive T cells. J Exp Med 199:1401–1408.PubMedCrossRefGoogle Scholar
  38. 38.
    Kretschmer, K., I. Apostolou, D. Hawiger, K. Khazaie, M.C. Nussenzweig, and H. von Boehmer. 2005. Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol 6:1219–1227.PubMedCrossRefGoogle Scholar
  39. 39.
    von Boehmer, H. 2005. Peptide-based instruction of suppressor commitment in naive T cells and dynamics of immunosuppression in vivo. Scand J Immunol 62(Suppl 1):49–54.CrossRefGoogle Scholar
  40. 40.
    Chen, W., W. Jin, N. Hardegen, K.J. Lei, L. Li, N. Marinos, G. McGrady, and S.M. Wahl. 2003. Conversion of peripheral CD4+CD25– naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198:1875–1886.PubMedCrossRefGoogle Scholar
  41. 41.
    Cosmi, L., F. Liotta, R. Angeli, B. Mazzinghi, V. Santarlasci, R. Manetti, L. Lasagni, V. Vanini, P. Romagnani, E. Maggi, F. Annunziato, and S. Romagnani. 2004. Th2 cells are less susceptible than Th1 cells to the suppressive activity of CD25+ regulatory thymocytes because of their responsiveness to different cytokines. Blood 103:3117–3121.PubMedCrossRefGoogle Scholar
  42. 42.
    Stassen, M., H. Jonuleit, C. Muller, M. Klein, C. Richter, T. Bopp, S. Schmitt, and E. Schmitt. 2004. Differential regulatory capacity of CD25+ T regulatory cells and preactivated CD25+ T regulatory cells on development, functional activation, and proliferation of Th2 cells. J Immunol 173:267–274.PubMedGoogle Scholar
  43. 43.
    Bennett, C.L., J. Christie, F. Ramsdell, M.E. Brunkow, P.J. Ferguson, L. Whitesell, T.E. Kelly, F.T. Saulsbury, P.F. Chance, and H.D. Ochs. 2001. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27:20–21.PubMedCrossRefGoogle Scholar
  44. 44.
    Chatila, T.A., F. Blaeser, N. Ho, H.M. Lederman, C. Voulgaropoulos, C. Helms, and A.M. Bowcock. 2000. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest 106:R75–81.PubMedCrossRefGoogle Scholar
  45. 45.
    Wildin, R.S., F. Ramsdell, J. Peake, F. Faravelli, J.L. Casanova, N. Buist, E. Levy-Lahad, M. Mazzella, O. Goulet, L. Perroni, F.D. Bricarelli, G. Byrne, M. McEuen, S. Proll, M. Appleby, and M.E. Brunkow. 2001. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 27: 18–20.PubMedCrossRefGoogle Scholar
  46. 46.
    Lin, W., N. Truong, W.J. Grossman, D. Haribhai, C.B. Williams, J. Wang, M.G. Martin, and T.A. Chatila. 2005. Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice. J Allergy Clin Immunol 116:1106–1115.PubMedCrossRefGoogle Scholar
  47. 47.
    Ling, E.M., T. Smith, X.D. Nguyen, C. Pridgeon, M. Dallman, J. Arbery, V.A. Carr, and D.S. Robinson. 2004. Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet 363: 608–615.PubMedCrossRefGoogle Scholar
  48. 48.
    Cavani, A., F. Nasorri, C. Ottaviani, S. Sebastiani, O. De Pita, and G. Girolomoni. 2003. Human CD25+ regulatory T cells maintain immune tolerance to nickel in healthy, nonallergic individuals. J Immunol 171:5760–5768.PubMedGoogle Scholar
  49. 49.
    Karlsson, M.R., J. Rugtveit, and P. Brandtzaeg. 2004. Allergen-responsive CD4+CD25+ regulatory T cells in children who have outgrown cow's milk allergy. J Exp Med 199: 1679–1688.PubMedCrossRefGoogle Scholar
  50. 50.
    Hawrylowicz, C.M., and A. O'Garra. 2005. Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma. Nat Rev Immunol 5:271–283.PubMedCrossRefGoogle Scholar
  51. 51.
    Hawrylowicz, C.M. 2005. Regulatory T cells and IL-10 in allergic inflammation. J Exp Med 202:1459–1463.PubMedCrossRefGoogle Scholar
  52. 52.
    Kearley, J., J.E. Barker, D.S. Robinson, and C.M. Lloyd. 2005. Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent. J Exp Med 202:1539–1547.PubMedCrossRefGoogle Scholar
  53. 53.
    Joetham, A., K. Takada, C. Taube, N. Miyahara, S. Matsubara, T. Koya, Y.H. Rha, A. Dakhama, and E.W. Gelfand. 2007. Naturally occurring lung CD4+CD25+ T cell regulation of airway allergic responses depends on IL-10 induction of TGF-beta. J Immunol 178: 1433–1442.PubMedGoogle Scholar
  54. 54.
    Lewkowich, I.P., N.S. Herman, K.W. Schleifer, M.P. Dance, B.L. Chen, K.M. Dienger, A.A. Sproles, J.S. Shah, J. Kohl, Y. Belkaid, and M. Wills-Karp. 2005. CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J Exp Med 202:1549–1561.PubMedCrossRefGoogle Scholar
  55. 55.
    Strickland, D.H., P.A. Stumbles, G.R. Zosky, L.S. Subrata, J.A. Thomas, D.J. Turner, P.D. Sly, and P.G. Holt. 2006. Reversal of airway hyperresponsiveness by induction of airway mucosal CD4+CD25+ regulatory T cells. J Exp Med 203:2649–2660.PubMedCrossRefGoogle Scholar
  56. 56.
    Pasare, C., and R. Medzhitov. 2003. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299:1030–1031.CrossRefGoogle Scholar
  57. 57.
    Doganci, A., T. Eigenbrod, N. Krug, G.T. De Sanctis, M. Hausding, V.J. Erpenbeck, B. Haddad el, H.A. Lehr, E. Schmitt, T. Bopp, K.J. Kallen, U. Herz, S. Schmitt, C. Luft, O. Hecht, J.M. Hohlfeld, H. Ito, N. Nishimoto, K. Yoshizaki, T. Kishimoto, S. Rose-John, H. Renz, M.F. Neurath, P.R. Galle, and S. Finotto. 2005. The IL-6R alpha chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo. J Clin Invest 115:313–325.Google Scholar
  58. 58.
    van Amelsfort, J.M., J.A. van Roon, M. Noordegraaf, K.M. Jacobs, J.W. Bijlsma, F.P. Lafeber, and L.S. Taams. 2007. Proinflammatory mediator-induced reversal of CD4+,CD25+ regulatory T cell-mediated suppression in rheumatoid arthritis. Arthritis Rheum 56:732–742.PubMedCrossRefGoogle Scholar
  59. 59.
    Nadkarni, S., C. Mauri, and M.R. Ehrenstein. 2007. Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta. J Exp Med 204:33–39.PubMedCrossRefGoogle Scholar
  60. 60.
    Valencia, X., G. Stephens, R. Goldbach-Mansky, M. Wilson, E.M. Shevach, and P.E. Lipsky. 2006. TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. Blood 108:253–261.PubMedCrossRefGoogle Scholar
  61. 61.
    Ruprecht, C.R., M. Gattorno, F. Ferlito, A. Gregorio, A. Martini, A. Lanzavecchia, and F. Sallusto. 2005. Coexpression of CD25 and CD27 identifies FoxP3+ regulatory T cells in inflamed synovia. J Exp Med 201:1793–1803.PubMedCrossRefGoogle Scholar
  62. 62.
    Patel, M., D. Xu, P. Kewin, B. Choo-Kang, C. McSharry, N.C. Thomson, and F.Y. Liew. 2005. TLR2 agonist ameliorates established allergic airway inflammation by promoting Th1 response and not via regulatory T cells. J Immunol 174:7558–7563.PubMedGoogle Scholar
  63. 63.
    Sutmuller, R.P., M.E. Morgan, M.G. Netea, O. Grauer, and G.J. Adema. 2006. Toll-like receptors on regulatory T cells: expanding immune regulation. Trends immunol 27:387–393.PubMedCrossRefGoogle Scholar
  64. 64.
    Crellin, N.K., R.V. Garcia, O. Hadisfar, S.E. Allan, T.S. Steiner, and M.K. Levings. 2005. Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells. J Immunol 175:8051–8059.PubMedGoogle Scholar
  65. 65.
    Peng, G., Z. Guo, Y. Kiniwa, K.S. Voo, W. Peng, T. Fu, D.Y. Wang, Y. Li, H.Y. Wang, and R.F. Wang. 2005. Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 309:1380–1384.PubMedCrossRefGoogle Scholar
  66. 66.
    Goldman, M. 2007. Translational mini-review series on Toll-like receptors: Toll-like receptor ligands as novel pharmaceuticals for allergic disorders. Clin Exp Immunol 147:208–216.PubMedCrossRefGoogle Scholar
  67. 67.
    Creticos, P.S., J.T. Schroeder, R.G. Hamilton, S.L. Balcer-Whaley, A.P. Khattignavong, R. Lindblad, H. Li, R. Coffman, V. Seyfert, J.J. Eiden, and D. Broide. 2006. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med 355:1445–1455.PubMedCrossRefGoogle Scholar
  68. 68.
    Simons, F.E., Y. Shikishima, G. Van Nest, J.J. Eiden, and K.T. HayGlass. 2004. Selective immune redirection in humans with ragweed allergy by injecting Amb a 1 linked to immunostimulatory DNA. J Allergy Clin Immunol 113:1144–1151.PubMedCrossRefGoogle Scholar
  69. 69.
    Bellinghausen, I., B. Klostermann, J. Knop, and J. Saloga. 2003. Human CD4+CD25+ T cells derived from the majority of atopic donors are able to suppress TH1 and TH2 cytokine production. J Allergy Clin Immunol 111:862–868.PubMedCrossRefGoogle Scholar
  70. 70.
    Grindebacke, H., K. Wing, A.C. Andersson, E. Suri-Payer, S. Rak, and A. Rudin. 2004. Defective suppression of Th2 cytokines by CD4CD25 regulatory T cells in birch allergics during birch pollen season. Clin Exp Allergy 34:1364–1372.PubMedCrossRefGoogle Scholar
  71. 71.
    Bellinghausen, I., B. Konig, I. Bottcher, J. Knop, and J. Saloga. 2005. Regulatory activity of human CD4 CD25 T cells depends on allergen concentration, type of allergen and atopy status of the donor. Immunology 116:103–111.PubMedCrossRefGoogle Scholar
  72. 72.
    Hartl, D., B. Koller, A.T. Mehlhorn, D. Reinhardt, T. Nicolai, D.J. Schendel, M. Griese, and S. Krauss-Etschmann. 2007. Quantitative and functional impairment of pulmonary CD4+CD25hi regulatory T cells in pediatric asthma. J Allergy Clin Immunol 119: 1258–1266.PubMedCrossRefGoogle Scholar
  73. 73.
    Verhagen, J., M. Akdis, C. Traidl-Hoffmann, P. Schmid-Grendelmeier, D. Hijnen, E.F. Knol, H. Behrendt, K. Blaser, and C.A. Akdis. 2006. Absence of T-regulatory cell expression and function in atopic dermatitis skin. J Allergy Clin Immunol 117:176–183.PubMedCrossRefGoogle Scholar
  74. 74.
    Karagiannidis, C., M. Akdis, P. Holopainen, N.J. Woolley, G. Hense, B. Ruckert, P.Y. Mantel, G. Menz, C.A. Akdis, K. Blaser, and C.B. Schmidt-Weber. 2004. Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma. J Allergy Clin Immunol 114:1425–1433.PubMedCrossRefGoogle Scholar
  75. 75.
    Chen, X., J.J. Oppenheim, R.T. Winkler-Pickett, J.R. Ortaldo, and O.M. Howard. 2006. Glucocorticoid amplifies IL-2-dependent expansion of functional FoxP3(+)CD4(+)CD25(+) T regulatory cells in vivo and enhances their capacity to suppress EAE. Eur J Immunol 36:2139–2149.PubMedCrossRefGoogle Scholar
  76. 76.
    Dao Nguyen, X., and D.S. Robinson. 2004. Fluticasone propionate increases CD4CD25 T regulatory cell suppression of allergen-stimulated CD4CD25 T cells by an IL-10-dependent mechanism. J Allergy Clin Immunol 114:296–301.PubMedCrossRefGoogle Scholar
  77. 77.
    Battaglia, M., A. Stabilini, B. Migliavacca, J. Horejs-Hoeck, T. Kaupper, and M.G. Roncarolo. 2006. Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol 177: 8338–8347.PubMedGoogle Scholar
  78. 78.
    Levings, M.K., R. Sangregorio, and M.G. Roncarolo. 2001. Human CD25(+)CD4(+) t regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J. Exp. Med. 193:1295–1302.PubMedCrossRefGoogle Scholar
  79. 79.
    Bluestone, J.A. 2005. Regulatory T-cell therapy: is it ready for the clinic? Nat Rev Immunol 5:343–349.PubMedCrossRefGoogle Scholar
  80. 80.
    Kuball, J., M.L. Dossett, M. Wolfl, W.Y. Ho, R.H. Voss, C. Fowler, and P.D. Greenberg. 2007. Facilitating matched pairing and expression of TCR-chains introduced into human T-cells. Blood Mar 15; 109:2331–2338.Google Scholar
  81. 81.
    Faria, A.M., and H.L. Weiner. 2006. Oral tolerance and TGF-beta-producing cells. Inflamm Allergy Drug Targets 5:179–190.PubMedCrossRefGoogle Scholar
  82. 82.
    Kunzmann, S., P.-Y. Mantel, J.G. Wohlfahrt, M. Akdis, K. Blaser, and C.B. Schmidt-Weber. 2003. Histamine enhances TGF-beta1-mediated suppression of Th2 responses. Faseb J. 17:1089–1095.PubMedCrossRefGoogle Scholar
  83. 83.
    Hansen, G., J.J. McIntire, V.P. Yeung, G. Berry, G.J. Thorbecke, L. Chen, R.H. DeKruyff, and D.T. Umetsu. 2000. CD4(+) T helper cells engineered to produce latent TGF-beta1 reverse allergen-induced airway hyperreactivity and inflammation. J. Clin. Invest. 105: 61–70.PubMedCrossRefGoogle Scholar
  84. 84.
    Scherf, W., S. Burdach, and G. Hansen. 2005. Reduced expression of transforming growth factor beta 1 exacerbates pathology in an experimental asthma model. Eur J Immunol 35:198–206.PubMedCrossRefGoogle Scholar
  85. 85.
    Nakao, A., S. Miike, M. Hatano, K. Okumura, T. Tokuhisa, C. Ra, and I. Iwamoto. 2000. Blockade of transforming growth factor beta/Smad signaling in T cells by overexpression of Smad7 enhances antigen-induced airway inflammation and airway reactivity. J Exp Med 192:151–158.PubMedCrossRefGoogle Scholar
  86. 86.
    Ostroukhova, M., C. Seguin-Devaux, T.B. Oriss, B. Dixon-McCarthy, L. Yang, B.T. Ameredes, T.E. Corcoran, and A. Ray. 2004. Tolerance induced by inhaled antigen involves CD4(+) T cells expressing membrane-bound TGF-beta and FOXP3. J Clin Invest 114:28–38.PubMedGoogle Scholar
  87. 87.
    Gauldie, J., M. Kolb, K. Ask, G. Martin, P. Bonniaud, and D. Warburton. 2006. Smad3 signaling involved in pulmonary fibrosis and emphysema. Proc Am Thorac Soc 3:696–702.PubMedCrossRefGoogle Scholar
  88. 88.
    McMillan, S.J., G. Xanthou, and C.M. Lloyd. 2005. Manipulation of Allergen-Induced Airway Remodeling by Treatment with Anti-TGF-{beta} Antibody: Effect on the Smad Signaling Pathway. J Immunol 174:5774–5780.PubMedGoogle Scholar
  89. 89.
    Redington, A.E., J. Madden, A.J. Frew, R. Djukanovic, W.R. Roche, S.T. Holgate, and P.H. Howarth. 1997. Transforming growth factor-beta 1 in asthma. Measurement in bronchoalveolar lavage fluid. Am J Respir Crit Care Med 156:642–647.PubMedGoogle Scholar
  90. 90.
    Branton, M.H., and J.B. Kopp. 1999. TGF-beta and fibrosis. Microbes Infect 1:1349–1365.PubMedCrossRefGoogle Scholar
  91. 91.
    Asadullah, K., W. Sterry, and H.D. Volk. 2003. Interleukin-10 therapy--review of a new approach. Pharmacol Rev 55:241–269.PubMedCrossRefGoogle Scholar
  92. 92.
    Urry, Z., E. Xystrakis, and C.M. Hawrylowicz. 2006. Interleukin-10-secreting regulatory T cells in allergy and asthma. Curr Allergy Asthma Rep 6:363–371.PubMedCrossRefGoogle Scholar
  93. 93.
    Borish, L., A. Aarons, J. Rumbyrt, P. Cvietusa, J. Negri, and S. Wenzel. 1996. Interleukin-10 regulation in normal subjects and patients with asthma. J .Allergy Clin. Immunol. 97: 1288–1296.PubMedCrossRefGoogle Scholar
  94. 94.
    Lim, S., E. Crawley, P. Woo, and P.J. Barnes. 1998. Haplotype associated with low interleukin-10 production in patients with severe asthma. Lancet 352:113.PubMedCrossRefGoogle Scholar
  95. 95.
    Heaton, T., J. Rowe, S. Turner, R.C. Aalberse, N. de Klerk, D. Suriyaarachchi, M. Serralha, B.J. Holt, E. Hollams, S. Yerkovich, K. Holt, P.D. Sly, J. Goldblatt, P. Le Souef, and P.G. Holt. 2005. An immunoepidemiological approach to asthma: identification of in-vitro T-cell response patterns associated with different wheezing phenotypes in children. Lancet 365:142–149.PubMedCrossRefGoogle Scholar
  96. 96.
    Akdis, M., J. Verhagen, A. Taylor, F. Karamloo, C. Karagiannidis, R. Crameri, S. Thunberg, G. Deniz, R. Valenta, H. Fiebig, C. Kegel, R. Disch, C.B. Schmidt-Weber, K. Blaser, and C.A. Akdis. 2004. 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 199:1567–1575.PubMedCrossRefGoogle Scholar
  97. 97.
    Akdis, C.A., T. Blesken, M. Akdis, B. Wüthrich, and K. Blaser. 1998. Role of IL-10 in specific immunotherapy. J. Clin. Invest. 102:98–106.PubMedCrossRefGoogle Scholar
  98. 98.
    Tiemessen, M.M., A.G. Van Ieperen-Van Dijk, C.A. Bruijnzeel-Koomen, J. Garssen, E.F. Knol, and E. Van Hoffen. 2004. Cow's milk-specific T-cell reactivity of children with and without persistent cow's milk allergy: key role for IL-10. J Allergy Clin Immunol 113: 932–939.Google Scholar
  99. 99.
    Stampfli, M.R., M. Cwiartka, B.U. Gajewska, D. Alvarez, S.A. Ritz, M.D. Inman, Z. Xing, and M. Jordana. 1999. Interleukin-10 gene transfer to the airway regulates allergic mucosal sensitization in mice. Am J Respir Cell Mol Biol 21:586–596.PubMedGoogle Scholar
  100. 100.
    Nakagome, K., M. Dohi, K. Okunishi, Y. Komagata, K. Nagatani, R. Tanaka, J. Miyazaki, and K. Yamamoto. 2005. In vivo IL-10 gene delivery suppresses airway eosinophilia and hyperreactivity by down-regulating APC functions and migration without impairing the antigen-specific systemic immune response in a mouse model of allergic airway inflammation. J Immunol 174:6955–6966.PubMedGoogle Scholar
  101. 101.
    Oh, J.W., C.M. Seroogy, E.H. Meyer, O. Akbari, G. Berry, C.G. Fathman, R.H. Dekruyff, and D.T. Umetsu. 2002. CD4 T-helper cells engineered to produce IL-10 prevent allergen-induced airway hyperreactivity and inflammation. Allergy Clin Immunol 110:460–468.CrossRefGoogle Scholar
  102. 102.
    Cottrez, F., S.D. Hurst, R.L. Coffman, and H. Groux. 2000. T regulatory cells 1 inhibit a Th2-specific response in vivo. J Immunol 165:4848–4853.PubMedGoogle Scholar
  103. 103.
    Akbari, O., G.J. Freeman, E.H. Meyer, E.A. Greenfield, T.T. Chang, A.H. Sharpe, G. Berry, R.H. DeKruyff, and D.T. Umetsu. 2002. Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med 8:1024–1032.PubMedCrossRefGoogle Scholar
  104. 104.
    Stock, P., O. Akbari, G. Berry, G.J. Freeman, R.H. Dekruyff, and D.T. Umetsu. 2004. Induction of T helper type 1-like regulatory cells that express Foxp3 and protect against airway hyper-reactivity. Nat Immunol 5:1149–1156.PubMedCrossRefGoogle Scholar
  105. 105.
    Zuany-Amorim, C., E. Sawicka, C. Manlius, A. Le Moine, L.R. Brunet, D.M. Kemeny, G. Bowen, G. Rook, and C. Walker. 2002. Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat. Med. 8: 625–629.PubMedCrossRefGoogle Scholar
  106. 106.
    Richards, D.F., M. Fernandez, J. Caulfield, and C.M. Hawrylowicz. 2000. Glucocorticoids drive human CD8(+) T cell differentiation towards a phenotype with high IL-10 and reduced IL-4, IL-5 and IL-13 production. Eur J Immunol 30:2344–2354.PubMedCrossRefGoogle Scholar
  107. 107.
    Barrat, F.J., D.J. Cua, A. Boonstra, D.F. Richards, C. Crain, H.F. Savelkoul, R. de Waal-Malefyt, R.L. Coffman, C.M. Hawrylowicz, and A. O'Garra. 2002. 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. J Exp Med 195: 603–616.PubMedCrossRefGoogle Scholar
  108. 108.
    Vieira, P.L., J.R. Christensen, S. Minaee, E.J. O'Neill, F.J. Barrat, A. Boonstra, T. Barthlott, B. Stockinger, D.C. Wraith, and A. O'Garra. 2004. IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J Immunol 172:5986–5993.PubMedGoogle Scholar
  109. 109.
    Xystrakis, E., S. Kusumakar, S. Boswell, E. Peek, Z. Urry, D.F. Richards, T. Adikibi, C. Pridgeon, M. Dallman, T.K. Loke, D.S. Robinson, F.J. Barrat, A. O'Garra, P. Lavender, T.H. Lee, C. Corrigan, and C.M. Hawrylowicz. 2006. Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest 116:146–155.PubMedCrossRefGoogle Scholar
  110. 110.
    Adorini, L. 2002. Immunomodulatory effects of vitamin D receptor ligands in autoimmune diseases. Int Immunopharmacol 2:1017–1028.PubMedCrossRefGoogle Scholar
  111. 111.
    Peek, E.J., D.F. Richards, A. Faith, P. Lavender, T.H. Lee, C.J. Corrigan, and C.M. Hawrylowicz. 2005. Interleukin-10-secreting “regulatory” T cells induced by glucocorticoids and beta2-agonists. Am J Respir Cell Mol Biol 33:105–111.PubMedCrossRefGoogle Scholar
  112. 112.
    Kussebi, F., F. Karamloo, M. Akdis, K. Blaser, and C.A. Akdis. 2003. Advances in immunological treatment of allergy. Curr Med Chem 2:297–308.Google Scholar
  113. 113.
    Bousquet, J., R. Lockey, H.J. Malling, E. Alvarez-Cuesta, G.W. Canonica, M.D. Chapman, P.J. Creticos, J.M. Dayer, S.R. Durham, P. Demoly, R.J. Goldstein, T. Ishikawa, K. Ito, D. Kraft, P.H. Lambert, H. Lowenstein, U. Muller, P.S. Norman, R.E. Reisman, R. Valenta, E. Valovirta, and H. Yssel. 1998. Allergen immunotherapy: therapeutic vaccines for allergic diseases. World Health Organization. American academy of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol 81:401–405.PubMedCrossRefGoogle Scholar
  114. 114.
    Durham, S.R., S.M. Walker, E.-V. Varga, M.R. Jacobson, F. O'Brien, W. Noble, S.J. Till, Q.A. Hamid, and K.T. Nouri-Aria. 1999. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 341:468–475.PubMedCrossRefGoogle Scholar
  115. 115.
    Bonifazi, F., M. Jutel, B.M. Bilo, J. Birnbaum, and U. Muller. 2005. Prevention and treatment of hymenoptera venom allergy: guidelines for clinical practice. Allergy 60: 1459–1470.PubMedCrossRefGoogle Scholar
  116. 116.
    Pajno, G.B., G. Barberio, F. De Luca, L. Morabito, and S. Parmiani. 2001. Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy. A six-year follow-up study. Clin Exp Allergy 31:1392–1397.PubMedCrossRefGoogle Scholar
  117. 117.
    Moller, C., S. Dreborg, H.A. Ferdousi, S. Halken, A. Host, L. Jacobsen, A. Koivikko, D.Y. Koller, B. Niggemann, L.A. Norberg, R. Urbanek, E. Valovirta, and U. Wahn. 2002. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 109:251–256.PubMedCrossRefGoogle Scholar
  118. 118.
    Eng, P.A., M. Reinhold, and H.P. Gnehm. 2002. Long-term efficacy of preseasonal grass pollen immunotherapy in children. Allergy 57:306–312.PubMedCrossRefGoogle Scholar
  119. 119.
    Walker, S.M., G.B. Pajno, M.T. Lima, D.R. Wilson, and S.R. Durham. 2001. Grass pollen immunotherapy for seasonal rhinitis and asthma: a randomized, controlled trial. J Allergy Clin Immunol 107:87–93.PubMedCrossRefGoogle Scholar
  120. 120.
    Akdis, C.A., M. Akdis, T. Blesken, D. Wymann, S.S. Alkan, U. Müller, and K. Blaser. 1996. 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 98:1676–1683.PubMedCrossRefGoogle Scholar
  121. 121.
    Akdis, C.A., and K. Blaser. 1999. IL-10 induced anergy in peripheral T cell and reactivation by microenvironmental cytokines: two key steps in specific immunotherapy. Faseb J 13: 603–609.PubMedGoogle Scholar
  122. 122.
    Müller, U.R., C.A. Akdis, M. Fricker, M. Akdis, F. Bettens, T. Blesken, and K. Blaser. 1998. 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 101: 747–754.PubMedCrossRefGoogle Scholar
  123. 123.
    Bellinghausen, I., G. Metz, A.H. Enk, S. Christmann, J. Knop, and J. Saloga. 1997. Insect venom immunotherapy induces interleukin-10 production and a Th2-to-Th1 shift, and changes surface marker expression in venom-allergic subjects. Eur J Immunol 27: 1131–1139.PubMedCrossRefGoogle Scholar
  124. 124.
    Marcotte, G.V., C.M. Braun, P.S. Norman, C.F. Nicodemus, A. Kagey-Sobotka, L.M. Lichtenstein, and D.M. Essayan. 1998. Effects of peptide therapy on ex vivo T-cell responses. J Allergy Clin Immunol 101:506–513.PubMedCrossRefGoogle Scholar
  125. 125.
    Jutel, M., M. Akdis, F. Budak, C. Aebischer-Casaulta, M. Wrzyszcz, K. Blaser, and A.C. Akdis. 2003. IL-10 and TGF-β cooperate in regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol 33: 1205–1214.PubMedCrossRefGoogle Scholar
  126. 126.
    Jutel, M., W.J. Pichler, D. Skrbic, A. Urwyler, C. Dahinden, and U.R. Müller. 1995. Bee venom immunotherapy results in decrease of IL-4 and IL-5 and increase of IFN-g secretion in specific allergen stimulated T cell cultures. J Immunol 154:4178–4194.Google Scholar
  127. 127.
    Durham, S.R., and S.J. Till. 1998. Immunologic changes associated with allergen immunotherapy. J Allergy Clin Immunol 102:157–164.PubMedCrossRefGoogle Scholar
  128. 128.
    Varney, V.A., Q.A. Hamid, M. Gaga, S. Ying, M. Jacobson, A.J. Frew, A.B. Kay, and S.R. Durham. 1993. Influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses. J Clin Invest 92:644–651.PubMedCrossRefGoogle Scholar
  129. 129.
    Varga, E.M., P. Wachholz, K.T. Nouri-Aria, A. Verhoef, C.J. Corrigan, S.J. Till, and S.R. Durham. 2000. T cells from human allergen-induced late asthmatic responses express IL-12 receptor beta 2 subunit mRNA and respond to IL-12 in vitro. J Immunol 165: 2877–2885.PubMedGoogle Scholar
  130. 130.
    Hamid, Q.A., E. Schotman, M.R. Jacobson, S.M. Walker, and S.R. Durham. 1997. Increases in IL-12 messenger RNA+ cells accompany inhibition of allergen-induced late skin responses after successful grass pollen immunotherapy. J Allergy Clin Immunol 99: 254–260.PubMedCrossRefGoogle Scholar
  131. 131.
    Durham, S.R., S. Ying, V.A. Varney, M.R. Jacobson, R.M. Sudderick, I.S. Mackay, A.B. Kay, and Q.A. Hamid. 1996. 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. J Allergy Clin Immunol 97:1356–1365.PubMedCrossRefGoogle Scholar
  132. 132.
    Wachholz, P.A., and S.R. Durham. 2004. Mechanisms of immunotherapy: IgG revisited. Curr Opin Allergy Clin Immunol 4:313–318.PubMedCrossRefGoogle Scholar
  133. 133.
    Akdis, C.A., K. Blaser, and M. Akdis. 2004. Apoptosis in tissue inflammation and allergic disease. Curr Opin Immunol 16:717–723.PubMedCrossRefGoogle Scholar
  134. 134.
    Smith, T.R., C. Alexander, A.B. Kay, M. Larche, and D.S. Robinson. 2004. 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. Allergy 59:1097–1101.PubMedCrossRefGoogle Scholar
  135. 135.
    Nelson, H.S. 2007. Allergen immunotherapy: where is it now? J Allergy Clin Immunol 119:769–779.PubMedCrossRefGoogle Scholar
  136. 136.
    Valenta, R., and V. Niederberger. 2007. Recombinant allergens for immunotherapy. J Allergy Clin Immunol 119:826–830.PubMedCrossRefGoogle Scholar
  137. 137.
    Larche, M. 2007. Update on the current status of peptide immunotherapy. J Allergy Clin Immunol 119:906–909.PubMedCrossRefGoogle Scholar
  138. 138.
    Casale, T.B., W.W. Busse, J.N. Kline, Z.K. Ballas, M.H. Moss, R.G. Townley, M. Mokhtarani, V. Seyfert-Margolis, A. Asare, K. Bateman, and Y. Deniz. 2006. Omalizumab pretreatment decreases acute reactions after rush immunotherapy for ragweed-induced seasonal allergic rhinitis. J Allergy Clin Immunol 117:134–140.PubMedCrossRefGoogle Scholar
  139. 139.
    Ulisse, S., P. Gionchetti, S. D'Alo, F.P. Russo, I. Pesce, G. Ricci, F. Rizzello, U. Helwig, M.G. Cifone, M. Campieri, and C. De Simone. 2001. Expression of cytokines, inducible nitric oxide synthase, and matrix metalloproteinases in pouchitis: effects of probiotic treatment. Am J gastroenterol 96:2691–2699.PubMedCrossRefGoogle Scholar
  140. 140.
    Guarner, F., R. Bourdet-Sicard, P. Brandtzaeg, H.S. Gill, P. McGuirk, W. van Eden, J. Versalovic, J.V. Weinstock, and G.A. Rook. 2006. Mechanisms of disease: the hygiene hypothesis revisited. Nat Clin Pract 3:275–284.CrossRefGoogle Scholar
  141. 141.
    Wan, S., J.L. LeClerc, and J.L. Vincent. 1997. Cytokine responses to cardiopulmonary bypass: lessons learned from cardiac transplantation. Ann Thorac Surg 63:269–276.PubMedCrossRefGoogle Scholar
  142. 142.
    John, M., Lim, S., Seybold, J., Jose, P., Robichaud, A., O'Connor, B., Barnes, P.J., and Chung, K.F. 1998. Inhaled corticosteroids increase interleukin-10 but reduce macrophage inflammatory protein-1a, granulocyte-macrophage stimulating factor and Interferon-g release from alveolar macrophages in asthma. Am J Respir Crit Care Med 157:256–262.PubMedGoogle Scholar
  143. 143.
    Hawrylowicz, C., D. Richards, T.K. Loke, C. Corrigan, and T. Lee. 2002. A defect in corticosteroid-induced IL-10 production in T lymphocytes from corticosteroid-resistant asthmatic patients. J Allergy Clin Immunol 109:369–370.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Department of AsthmaAllergy and Respiratory ScienceUK

Personalised recommendations