Breast milk immune complexes are potent inducers of oral tolerance in neonates and prevent asthma development

Abstract

Allergic asthma is a chronic lung disease resulting from an inappropriate T helper (Th)-2 response to environmental antigens. Early tolerance induction is an attractive approach for primary prevention of asthma. Here, we found that breastfeeding by antigen-sensitized mothers exposed to antigen aerosols during lactation induced a robust and long-lasting antigen-specific protection from asthma. Protection was more profound and persistent than the one induced by antigen-exposed non-sensitized mothers. Milk from antigen-exposed sensitized mothers contained antigen-immunoglobulin (Ig) G immune complexes that were transferred to the newborn through the neonatal Fc receptor resulting in the induction of antigen-specific FoxP3(+) CD25(+) regulatory T cells. The induction of oral tolerance by milk immune complexes did not require the presence of transforming growth factor-beta in milk in contrast to tolerance induced by milk-borne free antigen. Furthermore, neither the presence of IgA in milk nor the expression of the inhibitory FcgammaRIIb in the newborn was required for tolerance induction. This study provides new insights on the mechanisms of tolerance induction in neonates and highlights that IgG immune complexes found in breast milk are potent inducers of oral tolerance. These observations may pave the way for the identification of key factors for primary prevention of immune-mediated diseases such as asthma.

Antitumor immunization of mothers delays tumor development in cancer-prone offspring

“…4 Besides being the main source of passive immunity in very early life, breastfeeding is also an important route for active immunization thanks to the efficient transfer of antigen-IgG immune complexes, contained in the milk, to the breastfed pups via the FcRn and across the proximal intestine. 31 We thus hypothesized that vaccine-transfected muscle cells might be the source of the neu protein, otherwise not present in a wild-type mouse. As happens normally, EC may be shed from transfected muscle cell membranes, 32 form complexes with vaccine-induced anti-neu antibodies, and accumulate in the milk and be passed to the pups, triggering an active immune response.…”

“…It is known that live-activated leukocytes, including CD8 C T cells, are present in mother's milk, and that they can be transferred during breastfeeding and that they can enter pups' intestinal tract tissue and mesenteric LNs in some species. 31 It can be hypothesized, in the case of syngeneic strains, that these passively transferred cells may survive in the pups and be found in mesenteric LNs 5 weeks after birth, when the in vivo cytotoxicity assay was conducted. Nevertheless, this possibility was ruled out by the results of the Vb-Jb spectratype analysis.…”

Neonatal Immune Tolerance Induction to Allow Long-Term Studies With an Immunogenic Therapeutic Monoclonal Antibody in Mice

“…It is, however, unclear, whether pups were also exposed to adalimumab-ADA immune complexes, which could have contributed to tolerance induction in addition to the free adalimumab. Notably, IgG immune complexes containing ovalbumin as antigen and transferred to mouse pups via milk have been shown to be more efficient than milk-born free antigen in inducing oral tolerance and preventing asthma (23). Ovalbumin-IgG immune complexes formed under excess of IgG have been shown to be excreted in mice via milk and to reach systemic circulation in nursed neonates (24).…”

The Role of Microbes in Developmental Immunologic Programming

“…Human probiotic prevention studies would point to the last month of gestation and first few months of life as the critical periods of immune development (81). Differences in microflora and the risk for atopic disease between infants born vaginally and those born by caesarean section highlight the importance of the immediate postnatal period (60) as do studies implicating breast milk components in the induction of oral tolerance and prevention of asthma (106). There may indeed be multiple windows of opportunity, and more work is clearly needed to better define them to help guide future therapeutic interventions.…”