The immunological mechanisms underlying the development of immune tolerance in childhood

Abstract

The increasing prevalence of allergic disease is linked to changes in the development of immune tolerance in early childhood. Better understanding of immune tolerance mechanisms that underpin these changes and the identification of strategies to prevent the development of allergy are required. Here the potential of maternal vitamin D supplementation in pregnancy to modify immune function at birth was investigated. The effects of familial risk of atopy on immune function at birth was also considered. Vitamin D might be an important factor in the development of the immune system in early life and in the development of allergy. Interventional studies focusing on vitamin D supplementation during pregnancy suggest supplementation will prevent the development of allergy. Here, the opportunity was taken as part of a larger vitamin D supplementation in pregnancy study (MAVIDOS) to investigate the effects of the infant’s vitamin D level at birth on various features of immune function at this same time. Parameters measured included total T, B and NK cells, T memory cells, T regulatory cells, iNKT cells and dendritic cells in cord blood mononuclear cells (CBMC) as well as the cytokine response to lipopolysaccharide (LPS) or phytohaemagglutinin (PHA). The key findings were a positive association between neonatal 25(OH)D3 and total naive CD4+ T cells and CD4+ and non-CD4+ CCR9+ putative gut homing T cells; PHA-stimulated TNFα and TNFβ levels were both inversely related to neonatal 25(OH)D3. In a parallel study, the effects of familial risk - high risk (HR) with two first degree relatives with allergic disease versus low risk (LR) with no first-degree relatives with allergic disease – on the innate immune response at birth was considered. This was part of a larger ongoing birth cohort to study the development of immune tolerance in early life. A comparison of the response of CBMC from HR versus LR newborns to various activators of pattern recognition receptors (Toll like receptors, NOD-like receptors and inflammasome) formed a critical first step to the longer-term analysis plans for this cohort. Statistically significant cytokine responses were found for IL10 for NOD1, NLRP3 and NLRP3/LPS; IL-13 responses for TLR4, TLR2/6, TLR7/8 and NOD1 and IL-6 for TLR7/8. In each occasion, the responses were higher in the LR than the HR group. The novel findings presented in this thesis will inform the proposed longer term follow up of the children born onto these two studies with the goal of alleviating the burden of allergic diseases.

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Identifiers

ORCID for Graham Roberts: orcid.org/0000-0003-2252-1248

ORCID for Paul S Noakes: orcid.org/0000-0002-2678-1971

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