Developmental programming of allergic susceptibility

Abstract

Allergic susceptibility is associated with early life exposures, including intrauterine growth restriction and maternal allergy. Epidemiological and animal model studies suggest that restricted growth before birth is protective against later allergy development, whilst maternal allergy is generally associated with increased allergy risk in progeny. Causality and mechanisms mediating these associations are poorly understood, and I therefore investigated immune and allergic responses in ovine models following these prenatal exposures. The first aim of study one (chapter 2) was to determine the effects of intrauterine growth restriction, due to placental restriction (PR), on allergic susceptibility. The second aim (chapter 3) was to determine the effects of maternal dietary methyl donor and cofactor supplementation during late pregnancy on allergic susceptibility of PR progeny, since methyl donors can regulate gene methylation via the one-carbon pathway. Placental restriction was induced by pre-pregnancy surgical reduction of placental attachment sites and its effects on progeny immune function and underlying mechanisms were investigated. Allergen-induced antibody and cutaneous hypersensitivity responses were measured in progeny from control and PR pregnancies following sensitisation to house dust mite and ovalbumin allergens. Effects of PR on cutaneous hypersensitivity responses did not correspond with effects on allergen-specific IgE responses. Delayed-phase cutaneous responses to ovalbumin were reduced in PR compared to control singletons, consistent with reports of epidemiological studies where low birth weight or poor fetal growth are generally protective against allergy, and despite no loss of IgE antibody response. Delayed-phase cutaneous responses to house dust mite were normal in PR singletons, despite enhanced IgE responses. Maternal dietary methyl donor and cofactor supplementation decreased antibody responses to allergens in some subgroups, but not those in which PR reduced cutaneous responses. This discord between antibody and cutaneous hypersensitivity responses suggests that mast cell function or other factors contribute to prenatally programmed regulation of allergy. The aim of study two (chapter 4) was to investigate the effects of maternal allergic asthma on the fetal immune system in an ovine model. Maternal allergic asthma reduced relative fetal size and lung development in late gestation, but did not alter fetal immune tissue weights. In late gestation we detected an increase in thymocyte CD44 expression in fetuses from allergic compared to control ewes, suggestive of increased thymocyte activation. In conclusion, maternal dietary supplementation with methyl donors and cofactors partially reversed the protective effects of restricted fetal growth against allergy, consistent with an epigenetic mechanism contributing to prenatal programming of allergic phenotype. Further research should include direct measures of one-carbon metabolism and methylation of immune-regulatory genes after PR and methyl donor supplementation, and of mast cell function as a potential mechanism for altered skin inflammatory responses to allergens. Results in the ovine model of maternal allergic asthma suggest that altered immune development may contribute to associations between maternal asthma and increased risk of allergy in progeny observed in human cohorts. The findings in this thesis provide direct evidence that allergic susceptibility can be programmed before birth.