Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Breast milk–mediated transfer of an antigen induces tolerance and protection from allergic asthma

This article has been updated

Abstract

Allergic asthma is a chronic disease characterized by airway obstruction in response to allergen exposure. It results from an inappropriate T helper type 2 response to environmental airborne antigens and affects 300 million individuals1. Its prevalence has increased markedly in recent decades, most probably as a result of changes in environmental factors2. Exposure to environmental antigens during infancy is crucial to the development of asthma3. Epidemiological studies on the relationship between breastfeeding and allergic diseases have reached conflicting results4,5,6,7,8. Here, we have investigated whether the exposure of lactating mice to an airborne allergen affects asthma development in progeny. We found that airborne antigens were efficiently transferred from the mother to the neonate through milk and that tolerance induction did not require the transfer of immunoglobulins. Breastfeeding-induced tolerance relied on the presence of transforming growth factor (TGF)-β during lactation, was mediated by regulatory CD4+ T lymphocytes and depended on TGF-β signaling in T cells. In conclusion, breast milk–mediated transfer of an antigen to the neonate resulted in oral tolerance induction leading to antigen-specific protection from allergic airway disease. This study may pave the way for the design of new strategies to prevent the development of allergic diseases.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: AHR and airway inflammation in mice breastfed by OVA-exposed mothers.
Figure 2: Immunoglobulin and T cell responses in mice breastfed by OVA-exposed mothers.
Figure 3: Breast milk factors involved in breastfeeding-induced tolerance.
Figure 4: Treg cells in mice breastfed by OVA-exposed mothers.

Change history

  • 29 January 2008

    In the version of this article initially published online, the affiliation numbers were incorrectly assigned. Each institution now has its own affilation number. The errors have been corrected for all versions of the article.

References

  1. Masoli, M., Fabian, D., Holt, S. & Beasley, R. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 59, 469–478 (2004).

    Article  Google Scholar 

  2. Eder, W., Ege, M.J. & von Mutius, E. The asthma epidemic. N. Engl. J. Med. 355, 2226–2235 (2006).

    Article  CAS  Google Scholar 

  3. Holt, P.G. & Thomas, W.R. Sensitization to airborne environmental allergens: unresolved issues. Nat. Immunol. 6, 957–960 (2005).

    Article  CAS  Google Scholar 

  4. Gdalevich, M., Mimouni, D. & Mimouni, M. Breast-feeding and the risk of bronchial asthma in childhood: a systematic review with meta-analysis of prospective studies. J. Pediatr. 139, 261–266 (2001).

    Article  CAS  Google Scholar 

  5. Friedman, N.J. & Zeiger, R.S. The role of breast-feeding in the development of allergies and asthma. J. Allergy Clin. Immunol. 115, 1238–1248 (2005).

    Article  Google Scholar 

  6. van Odijk, J. et al. Breastfeeding and allergic disease: a multidisciplinary review of the literature (1966–2001) on the mode of early feeding in infancy and its impact on later atopic manifestations. Allergy 58, 833–843 (2003).

    Article  CAS  Google Scholar 

  7. Kramer, M.S. et al. Effect of prolonged and exclusive breast feeding on risk of allergy and asthma: cluster randomised trial. Br. Med. J. 335, 815 (2007).

    Article  Google Scholar 

  8. Guilbert, T.W., Stern, D.A., Morgan, W.J., Martinez, F.D. & Wright, A.L. Effect of breastfeeding on lung function in childhood and modulation by maternal asthma and atopy. Am. J. Respir. Crit. Care Med. 176, 843–848 (2007).

    Article  Google Scholar 

  9. Frentsch, M. et al. Direct access to CD4+ T cells specific for defined antigens according to CD154 expression. Nat. Med. 11, 1118–1124 (2005).

    Article  CAS  Google Scholar 

  10. Julia, V. et al. A restricted subset of dendritic cells captures airborne antigens and remains able to activate specific T cells long after antigen exposure. Immunity 16, 271–283 (2002).

    Article  CAS  Google Scholar 

  11. Labbok, M.H., Clark, D. & Goldman, A.S. Breastfeeding: maintaining an irreplaceable immunological resource. Nat. Rev. Immunol. 4, 565–572 (2004).

    Article  CAS  Google Scholar 

  12. Palmer, D.J. & Makrides, M. Diet of lactating women and allergic reactions in their infants. Curr. Opin. Clin. Nutr. Metab. Care 9, 284–288 (2006).

    Article  CAS  Google Scholar 

  13. Willoughby, J.B. & Willoughby, W.F. In vivo responses to inhaled proteins. I. Quantitative analysis of antigen uptake, fate, and immunogenicity in a rabbit model system. J. Immunol. 119, 2137–2146 (1977).

    CAS  PubMed  Google Scholar 

  14. Holt, P.G., Batty, J.E. & Turner, K.J. Inhibition of specific IgE responses in mice by pre-exposure to inhaled antigen. Immunology 42, 409–417 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Bensch, K.G., Dominguez, E. & Liebow, A.A. Absorption of intact protein molecules across the pulmonary air-tissue barrier. Science 157, 1204–1206 (1967).

    Article  CAS  Google Scholar 

  16. Braley, J.F., Dawson, C.A., Moore, V.L. & Cozzini, B.O. Absorption of inhaled antigen into the circulation of isolated lungs from normal and immunized rabbits. J. Clin. Invest. 61, 1240–1246 (1978).

    Article  CAS  Google Scholar 

  17. Letterio, J.J. et al. Maternal rescue of transforming growth factor-β1 null mice. Science 264, 1936–1938 (1994).

    Article  CAS  Google Scholar 

  18. Penttila, I.A. et al. Transforming growth factor-β levels in maternal milk and expression in postnatal rat duodenum and ileum. Pediatr. Res. 44, 524–531 (1998).

    Article  CAS  Google Scholar 

  19. Saito, S., Yoshida, M., Ichijo, M., Ishizaka, S. & Tsujii, T. Transforming growth factor-β (TGF-β) in human milk. Clin. Exp. Immunol. 94, 220–224 (1993).

    Article  CAS  Google Scholar 

  20. Penttila, I. Effects of transforming growth factor-β and formula feeding on systemic immune responses to dietary β-lactoglobulin in allergy-prone rats. Pediatr. Res. 59, 650–655 (2006).

    Article  CAS  Google Scholar 

  21. Robinson, D.S., Larche, M. & Durham, S.R. Tregs and allergic disease. J. Clin. Invest. 114, 1389–1397 (2004).

    Article  CAS  Google Scholar 

  22. Lewkowich, I.P. et al. CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J. Exp. Med. 202, 1549–1561 (2005).

    Article  CAS  Google Scholar 

  23. Lucas, P.J., Kim, S.J., Melby, S.J. & Gress, R.E. Disruption of T cell homeostasis in mice expressing a T cell–specific dominant negative transforming growth factor-β II receptor. J. Exp. Med. 191, 1187–1196 (2000).

    Article  CAS  Google Scholar 

  24. Faria, A.M. & Weiner, H.L. Oral tolerance. Immunol. Rev. 206, 232–259 (2005).

    Article  CAS  Google Scholar 

  25. Adkins, B., Leclerc, C. & Marshall-Clarke, S. Neonatal adaptive immunity comes of age. Nat. Rev. Immunol. 4, 553–564 (2004).

    Article  CAS  Google Scholar 

  26. Miller, A., Lider, O., Abramsky, O. & Weiner, H.L. 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 (1994).

    Article  CAS  Google Scholar 

  27. Strobel, S. & Ferguson, A. Immune responses to fed protein antigens in mice. 3. Systemic tolerance or priming is related to age at which antigen is first encountered. Pediatr. Res. 18, 588–594 (1984).

    Article  CAS  Google Scholar 

  28. Hanson, D.G. Ontogeny of orally induced tolerance to soluble proteins in mice. I. Priming and tolerance in newborns. J. Immunol. 127, 1518–1524 (1981).

    CAS  PubMed  Google Scholar 

  29. Faria, A.M. et al. Oral tolerance induced by continuous feeding: enhanced up-regulation of transforming growth factor-β/interleukin-10 and suppression of experimental autoimmune encephalomyelitis. J. Autoimmun. 20, 135–145 (2003).

    Article  CAS  Google Scholar 

  30. Apostolou, I. & von Boehmer, H. In vivo instruction of suppressor commitment in naive T cells. J. Exp. Med. 199, 1401–1408 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank F. Powrie (University of Oxford) for D0.11.10 TCR transgenic mice and P.J. Lucas (US National Institutes of Health) for TGF-β DNRII mice. We thank F. Aguila for his help with figures and N. Guy and the animal facility staff for their excellent animal care. This work was supported by a grant from the Fondation Pour la Recherche Médicale (to V.J.) and by a grant from the European Union (DC-THERA) (to N.G.). V.V. was sponsored by fellowships from the Fondation Pour la Recherche Médicale, the US Juvenile Diabetes Research Foundation and the Belgian Fond National de la Recherche Scientifique.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Valérie Verhasselt or Valérie Julia.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–6, Supplementary Table 1 and Supplementary Methods (PDF 213 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Verhasselt, V., Milcent, V., Cazareth, J. et al. Breast milk–mediated transfer of an antigen induces tolerance and protection from allergic asthma. Nat Med 14, 170–175 (2008). https://doi.org/10.1038/nm1718

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1718

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing