Allergy prevention starts before conception: Maternofetal transfer of tolerance protects against the development of asthma

Background: Allergy prevention must start early because environmental exposures during pregnancy and young life determine disease risk. Objective: In this study we analyzed whether prevention can start even earlier before conception by transfer of immunologic tolerance from the mother to the offspring preventing the offspring from having asthma. Methods: BALB/c mice were orally tolerized with ovalbumin before conception by means of oral application of antigen. The offspring of tolerized and naive mothers were immunized with ovalbumin at 6 weeks and 4 months of age and analyzed in our murine asthma model. Results: Although the offspring of naive mothers had an asthma-like phenotype, the offspring of tolerized mice were completely protected, even when immunized as late as 8 months after birth. Critically involved in the tolerance transfer was allergen-specific IgG, levels of which were increased in the sera of the mother, fetus, and pup and breast milk. FcRn(-/-) mice, which cannot transport IgG through the placenta, transferred tolerance to the offspring only when the missing diaplacental IgG transfer was compensated by IgG transfer through breast milk from tolerant mothers but not when weaned by naive wet nurses. Inhibition of IFN-gamma, produced by memory T cells in the offspring, abrogated the protective effect of maternal tolerance, demonstrating a crucial role for IFN-gamma in the maintenance of allergen-specific tolerance. Conclusion: Our data show that maternal immunologic memory has a significant and persistent effect on the immune response of the offspring. (J Allergy Clin Immunol 2008;122:1022-30.)