Skip to main content
SpringerLink
Log in

Understanding primary oral tolerance induction: the end of the beginning

  • Die Ontogenese der Immun-Kompetenz und Allergie-Entstehung
  • Published:
Monatsschrift Kinderheilkunde Aims and scope Submit manuscript

Zusammenfassung

Eine fehlende klinische Reaktion der Mukosa auf Nahrungsantigene überwiegt in der Mehrheit der Bevölkerung. Zusätzlich bestehen klinische und experimentelle Beweise für eine orale Toleranz beim Menschen. Der Zeitpunkt der Antigen- bzw. Nahrungszufuhr ist ein wichtiger Faktor in der Entwicklung einer Nahrungsmittelallergie. Die Induktion einer Toleranz wird oft als Th2-vermittelte Reaktion angesehen, die auf der einen Seite vor schädlichen mukosalen Immunreaktionen schützt, auf der anderen Seite jedoch zu überschießenden Abwehrreaktionen bei anfälligen Individuen beiträgt. Die primären Mechanismen der Toleranz schließen T-Zell-Zerstörung, Anergie, Suppression, "Ignoranz" und Apoptose ein. Th1-zellvermittelte verzögerte Hypersensitivitätsreaktionen, die an der Pathogenese von autoimmunen und gastrointestinalen Entzündungen beteiligt sind, sind besonders stark unterdrückt.

Die Ereignisse während der Induktion von oraler Toleranz (oder Sensibilisierung) sind zur Zeit auf molekularer Ebene noch unklar. Die Balance zwischen Toleranz (Suppression) and Sensibilisierung (Priming) ist abhängig von verschiedensten Faktoren: genetischer Hintergrund, Art und Dosis des Antigens, Häufigkeit der Aufnahme, Alter bei erster Antigenexposition, immunologischer Status (z. B. Virusinfektion), Exposition der Mutter, Antigentransmission über Muttermilch, bakterielle Besiedlung und andere Faktoren.

Abstract

Clinical non-responsiveness to food antigens is the mucosal default mechanism in the majority of the population. Good clinical and experimental evidence suggests that oral tolerance exists in humans. The timing of antigen (food) administration is an important factor in the development of food allergic sensitisation and disease. Induction of tolerance is often seen as a Th2 skewed response, which on the one hand may prevent harmful mucosal immune reactions but on the other may contribute to adverse responses in the susceptible individual. The primary mechanisms by which tolerance may be mediated include T-cell deletion, anergy, suppression, "ignorance" and apoptosis. Cell-mediated delayed hypersensitivity reactions (Th1), which are implicated as a pathogenetic principle in the development of autoimmune and gastrointestinal inflammation, are particularly well suppressed.

Regulatory events during the induction of tolerance (or sensitisation) are not well understood at the molecular level. The balance between tolerance (suppression) and sensitisation (priming) is dependent on several factors such as genetic background, nature and dose of antigen, frequency of administration, age at first antigen exposure, immunological status of the host (e.g. virus infection), dietary exposure of the mother, antigen transmission via breast milk, bacterial colonization and other factors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Garside P, Mowat AM (1997) Mechanisms of oral tolerance. Crit Rev Immunol 17: 119–137

    Article  CAS  PubMed  Google Scholar 

  2. Weiner HR (1996) Oral tolerance: Immunologic mechanisms and treatment of autoimmune diseases. In: Kagnoff MF, Kiyono H (eds) Essentials of mucosal immunology. Academic Press, San Diego, pp 555–561

  3. Strobel S, Mowat AM (1998) Immunity to dietary antigens: oral tolerance. Immunol Today 19: 173–181

    Article  CAS  PubMed  Google Scholar 

  4. Billingham RE, Brent L (1953) Actively acquired tolerance of foreign cells. Nature 172: 603–606

    Article  CAS  PubMed  Google Scholar 

  5. Powrie F, Leach MW (1995) Genetic and spontaneous models of inflammatory bowel disease in rodents: evidence for abnormalities in mucosal immune regulation. Ther Immunol 2: 115–123

    CAS  PubMed  Google Scholar 

  6. Guarner F, Casellas F, Borruel N, et al (2002) Role of microecology in chronic inflammatory bowel diseases. Eur J Clin Nutr 56 [Suppl 4]: 34–38

  7. Strober W, Kelsall B, Marth T (1998) Oral tolerance. J Clin Immunol 18: 1–30

    Article  CAS  PubMed  Google Scholar 

  8. Weiner HL, Friedman A, Miller A, et al (1994) Oral tolerance: immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. Annual Review of Immunology 12: 809–837

    Article  CAS  PubMed  Google Scholar 

  9. Garside P, Mowat AM, Khoruts A (1999) Oral tolerance in disease. Gut 44: 137–142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Husband AJ, Bao S, McClure SJ, Emery DL, Ramsay AJ (1996) Antigen delivery strategies for mucosal vaccines. Int J Parasitol 26: 825–834

    Article  CAS  PubMed  Google Scholar 

  11. Garside P, Steel M, Worthey EA, et al (1995) T helper 2 cells are subject to high dose oral tolerance and are not essential for its induction. J Immunol 154: 5649–5655

    CAS  PubMed  Google Scholar 

  12. Strachan DP, Wong HJ, Spector TD (2001) Concordance and interrelationship of atopic diseases and markers of allergic sensitization among adult female twins. J Allergy Clin Immunol 108: 901–907

    Article  CAS  PubMed  Google Scholar 

  13. Heinzmann A, Deichmann KA (2001) Genes for atopy and asthma. Curr Opin Allergy Clin Immunol 1: 387–392

    Article  CAS  PubMed  Google Scholar 

  14. Laitinen T, Laitinen LA, Kere J (2000) Genetics of asthma and atopy--how to interpret results from the candidate gene studies? Duodecim 116: 1743–1749

    CAS  PubMed  Google Scholar 

  15. Walley AJ, Wiltshire S, Ellis CM, Cookson WO (2001) Linkage and allelic association of chromosome 5 cytokine cluster genetic markers with atopy and asthma associated traits. Genomics 72: 15–20

    Article  CAS  PubMed  Google Scholar 

  16. Chaouat G, Cayol V, Mairovitz V, Dubanchet S (1999) Localization of the Th2 cytokines IL-3, IL-4, IL-10 at the fetomaternal interface during human and murine pregnancy and lack of requirement for Fas/Fas ligand interaction for a successful allogeneic pregnancy. Am J Reprod Immunol 42: 1–13

    Article  CAS  PubMed  Google Scholar 

  17. Jenkins C, Roberts J, Wilson R, MacLean MA, Shilito J, Walker JJ (2000) Evidence of a T(H) 1 type response associated with recurrent miscarriage. Fertil Steril 73: 1206–1208

    Article  CAS  PubMed  Google Scholar 

  18. Prescott SL (2003) Early origins of allergic disease: a review of processes and influences during early immune development. Curr Opin Allergy Clin Immunol 3: 125–132

    Article  CAS  PubMed  Google Scholar 

  19. Høst A, Halken S (1990) A prospective study of cow milk allergy in Danish infants during the first 3 years of life. Clinical course in relation to clinical and immunological type of hypersensitivity reaction. Allergy 45: 587–596

    Article  PubMed  Google Scholar 

  20. Host A, Halken S (1998) Epidemiology and prevention of cow's milk allergy. Allergy 53: 111–113

    Article  CAS  PubMed  Google Scholar 

  21. Miller A, Lider O, Abramsky O, Weiner HL (1994) Orally administered myelin basic protein in neonates primes for immune responses and enhances experimental autoimmune encephalomyelitis in adult animals. Eur J Immunol 24: 1026–1032

    Article  CAS  PubMed  Google Scholar 

  22. Strobel S (1996) Neonatal oral tolerance. Ann NY Acad Sci 778: 88–102

    Article  CAS  PubMed  Google Scholar 

  23. Strachan DP (1989) Hay fever, hygiene, and household size. BMJ 299: 1259–1260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Braun-Fahrlander C (2000) Allergic diseases in farmers' children. Pediatr Allergy Immunol 11 [Suppl 13]: 19–22

  25. Moreau MC, Gaboriau Routhiau V (1996) The absence of gut flora, the doses of antigen ingested and aging affect the long-term peripheral tolerance induced by ovalbumin feeding in mice. Res Immunol 147: 49–59

    Article  CAS  PubMed  Google Scholar 

  26. He F, Morita H, Hashimoto H, et al (2002) Intestinal Bifidobacterium species induce varying cytokine production. J Allergy Clin Immunol 109: 1035–1036

    Article  PubMed  Google Scholar 

  27. Pessi T, Isolauri E, Sutas Y, Kankaanranta H, Moilanen E, Hurme M (2001) Suppression of T-cell activation by Lactobacillus rhamnosus GG-degraded bovine casein. Int Immunopharmacol 1: 211–218

    Article  CAS  PubMed  Google Scholar 

  28. Isolauri E (2000) The use of probiotics in paediatrics. Hosp Med 61: 6–7

    Article  CAS  PubMed  Google Scholar 

  29. Kirjavainen PV, Salminen SJ, Isolauri E (2003) Probiotic bacteria in the management of atopic disease: underscoring the importance of viability. J Pediatr Gastroenterol Nutr 36: 223–227

    Article  PubMed  Google Scholar 

  30. Grulee CG, Sanford HN (1936) The influence of breast feeding on infantile eczema. J Pediatr 9: 223–228

    Article  Google Scholar 

  31. Tang ML (2002) Is prevention of childhood asthma possible? Allergens, infections and animals. Med J Aust 177 [Suppl]: 75–77

  32. Schoetzau A, Gehring U, Franke K, et al (2002) Maternal compliance with nutritional recommendations in an allergy preventive programme. Arch Dis Child 86: 180–184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Murray E (2003) Breastfeeding, atopy, and asthma. Lancet 361: 174–176

    Article  PubMed  Google Scholar 

  34. Gdalevich M, Mimouni D, David M, Mimouni M (2001) Breast-feeding and the onset of atopic dermatitis in childhood: a systematic review and meta-analysis of prospective studies. J Am Acad Dermatol 45: 520–527

    Article  CAS  PubMed  Google Scholar 

  35. Duchén K, Björkstén B (1991) Sensitisation via breast milk. In: Mestecky J (ed) Immunology of milk and the neonate. Plenum, New York pp 427–436

  36. Wilson NW, Self TW, Hamburger RN (1990) Severe cow's milk induced colitis in an exclusively breast-fed neonate. Case report and clinical review of cow's milk allergy. Clin Pediatr (Phila) 29: 77–80

    Google Scholar 

  37. Peng HJ, Turner MW, Strobel S (1989) The kinetics of oral hyposensitisation to a protein antigen are determined by immune status and the timing, dose and frequency of antigen administration. Immunology 67: 425–431

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Husby S, Jensenius JC, Svehag SE (1985) Passage of undegraded dietary antigen into the blood of healthy adults. Quantification, estimation of size distribution and relation of uptake levels of specific antibodies. Scand J Immunol 22: 83–92

    Article  CAS  PubMed  Google Scholar 

  39. Smith KM, Brewer JM, Webb P, Coyle AJ, Gutierrez-Ramos C, Garside P (2003) Inducible costimulatory molecule-B7-related protein 1 interactions are important for the clonal expansion and B cell helper functions of naive, Th1, and Th2 T cells. J Immunol 170: 2310–2315

    Article  CAS  PubMed  Google Scholar 

  40. Astori M, von Garnier C, Kettner A, Dufour N, Corradin G, Spertini F (2000) Inducing tolerance by intranasal administration of long peptides in naive and primed CBA/J mice. J Immunol 165: 3497–3505

    Article  CAS  PubMed  Google Scholar 

  41. Sharpe AH, Freeman GJ (2002) The B7-CD28 superfamily. Nature Rev Immunol 2: 116–126

    Article  CAS  Google Scholar 

  42. Sundstedt A, O'Neill EJ, Nicolson KS, Wraith DC (2003) Role for IL-10 in suppression mediated by Peptide-induced regulatory T cells in vivo. J Immunol 170: 1240–1248

    Article  CAS  PubMed  Google Scholar 

  43. Melamed D, Friedman A (1993) Direct evidence for anergy in T lymphocytes tolerized by oral administration of ovalbumin. Eur J Immunol 23: 935–942

    Article  CAS  PubMed  Google Scholar 

  44. Viney JL, Mowat AM, O'Malley JM, Williamson E, Fanger NA (1998) Expanding dendritic cells in vivo enhances the induction of oral tolerance. J Immunol 160: 5815–5825

    CAS  PubMed  Google Scholar 

  45. Chen Y, Inobe J, Weiner HL (1997) Inductive events in oral tolerance in the TCR transgenic adoptive transfer model. Cell Immunol 178: 62–68

    Article  CAS  PubMed  Google Scholar 

  46. Whitacre CC, Gienapp IE, Meyer A, Cox KL, Javed N (1996) Oral tolerance in experimental autoimmune encephalomyelitis. Ann N Y Acad Sci 778: 217–227

    Article  CAS  PubMed  Google Scholar 

  47. Garside P, Steel M, Worthey EA, et al (1996) Lymphocytes from orally tolerized mice display enhanced susceptibility to death by apoptosis when cultured in the absence of antigen in vitro. Am J Pathol 149: 1971–1979

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Weiner HL (1997) Oral tolerance for the treatment of autoimmune diseases. Annu Rev Med 48: 341–351

    Article  CAS  PubMed  Google Scholar 

  49. Garside P, Steel M, Liew FY, Mowat AM (1995) CD4+ but not CD8+ T cells are required for the induction of oral tolerance. Int Immunol 7: 501–504

    Article  CAS  PubMed  Google Scholar 

  50. McMenamin C, McKersey M, Kuhnlein P, Hunig T, Holt PG (1995) Gammadelta T cells down-regulate primary IgE responses in rats to inhaled soluble protein antigens. J of Immunology 154: 4390–4394

    CAS  Google Scholar 

  51. Singh B, Read S, Asseman C, et al (2001) Control of intestinal inflammation by regulatory T cells. Immunol Rev 182: 190–200

    Article  CAS  PubMed  Google Scholar 

  52. Asseman C, Powrie F (1998) Interleukin 10 is a growth factor for a population of regulatory T cells. Gut 42: 157–158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kweon MN, Kiyono H (2002) CD40L in autoimmunity and mucosally induced tolerance. J Clin Invest 109: 171–173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Becker AB, Chan-Yeung M (2002) Primary prevention of asthma. Curr Opin Pulm Med 8: 16–24

    Article  PubMed  Google Scholar 

  55. Johnson KP, Brooks BR, Cohen JA, et al (1998) Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group. Neurology 50:701–708

    Article  CAS  PubMed  Google Scholar 

  56. Lai WC, Bennett M (1998) DNA vaccines. Crit Rev Immunol 18: 449–484

    Article  CAS  PubMed  Google Scholar 

  57. Burks W, Bannon G, Lehrer SB (2001) Classic specific immunotherapy and new perspectives in specific immunotherapy for food allergy. Allergy 56: 121–124

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

I would like to acknowledge the Deutsche Forschungsgemeinschaft (DFG), the Medical Research Council (MRC) and Nestec SA, which in part supported the work cited in this article. I also would like to thank A. Mowat and. A. Afuwape for stimulating discussions.

Author information

Authors and Affiliations

  1. Immunobiology Unit, Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust, London, GB

    S. Strobel

  2. Immunobiology Unit, Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust, London WC 1 N 1EH, GB

    S. Strobel

Authors
  1. S. Strobel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. Strobel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Strobel, S. Understanding primary oral tolerance induction: the end of the beginning. Monatsschr Kinderheilkd 151 (Suppl 1), S10–S16 (2003). https://doi.org/10.1007/s00112-003-0801-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00112-003-0801-3

Schlüsselwörter

Keywords

Search

Navigation