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
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
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
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).
Eder, W., Ege, M.J. & von Mutius, E. The asthma epidemic. N. Engl. J. Med. 355, 2226–2235 (2006).
Holt, P.G. & Thomas, W.R. Sensitization to airborne environmental allergens: unresolved issues. Nat. Immunol. 6, 957–960 (2005).
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).
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).
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).
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).
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).
Frentsch, M. et al. Direct access to CD4+ T cells specific for defined antigens according to CD154 expression. Nat. Med. 11, 1118–1124 (2005).
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).
Labbok, M.H., Clark, D. & Goldman, A.S. Breastfeeding: maintaining an irreplaceable immunological resource. Nat. Rev. Immunol. 4, 565–572 (2004).
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).
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).
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).
Bensch, K.G., Dominguez, E. & Liebow, A.A. Absorption of intact protein molecules across the pulmonary air-tissue barrier. Science 157, 1204–1206 (1967).
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).
Letterio, J.J. et al. Maternal rescue of transforming growth factor-β1 null mice. Science 264, 1936–1938 (1994).
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).
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).
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).
Robinson, D.S., Larche, M. & Durham, S.R. Tregs and allergic disease. J. Clin. Invest. 114, 1389–1397 (2004).
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).
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).
Faria, A.M. & Weiner, H.L. Oral tolerance. Immunol. Rev. 206, 232–259 (2005).
Adkins, B., Leclerc, C. & Marshall-Clarke, S. Neonatal adaptive immunity comes of age. Nat. Rev. Immunol. 4, 553–564 (2004).
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).
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).
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).
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).
Apostolou, I. & von Boehmer, H. In vivo instruction of suppressor commitment in naive T cells. J. Exp. Med. 199, 1401–1408 (2004).
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
Corresponding authors
Supplementary information
Supplementary Text and Figures
Supplementary Figs. 1–6, Supplementary Table 1 and Supplementary Methods (PDF 213 kb)
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm1718
This article is cited by
-
Association of cesarean section with asthma in children/adolescents: a systematic review and meta-analysis based on cohort studies
BMC Pediatrics (2023)
-
The therapeutic age of the neonatal Fc receptor
Nature Reviews Immunology (2023)
-
Immunomodulatory and anti-inflammatory effects of N-acetylcysteine in ovalbumin-sensitized rats
Beni-Suef University Journal of Basic and Applied Sciences (2022)
-
Breastmilk, Stool, and Meconium: Bacterial Communities in South Africa
Microbial Ecology (2022)
-
Analysing the protection from respiratory tract infections and allergic diseases early in life by human milk components: the PRIMA birth cohort
BMC Infectious Diseases (2022)