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Downloaded for Personal Non-Commercial Research Or Study, Without Prior Permission Or Charge University of Southampton Research Repository Copyright © and Moral Rights for this thesis and, where applicable, any accompanying data are retained by the author and/or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis and the accompanying data cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder/s. The content of the thesis and accompanying research data (where applicable) must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holder/s. When referring to this thesis and any accompanying data, full bibliographic details must be given, e.g. Thesis: Dr Louise Jane Michaelis (2018) "The immunological mechanisms underlying the development of immune tolerance in childhood", University of Southampton, Faculty of Medicine, PhD Thesis, pagination. University of Southampton Faculty of Medicine The immunological mechanisms underlying the development of immune tolerance in childhood Thesis for the Degree of Doctor of Philosophy by Dr Louise Jane Michaelis BSc(Hons), MBChB, MRCPCH, MSc 2018 Clinical Supervisors: Prof. Graham Roberts, Prof. Hasan Arshad Collaborators: Prof. Catherine Thornton Laboratory Supervisors: Prof. Anthony Williams, Dr Paul Noakes, Dr Yfang Gao 1 UNIVERSITY OF SOUTHAMPTON ABSTRACT DEPARTMENT OF ORIGINS OF HEALTH AND DISEASE: Doctor of Philosophy THE IMMUNOLOGICAL MECHANISMS UNDERLYING THE DEVELOPMENT OF IMMUNE TOLERANCE IN EARLY CHILDHOOD By Louise Jane Michaelis 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. 2 3 Abstract ............................................................................................................ 2 Contents ............................................................................................................ 4 Figures ............................................................................................................. 10 Tables ............................................................................................................... 14 Declaration ...................................................................................................... 17 Acknowledgments ........................................................................................... 18 Publications ..................................................................................................... 19 Presentations .................................................................................................. 20 Abbreviations .................................................................................................. 25 Chapter 1: Literature review 1.0 Introduction 1.1 Current concepts of allergic disease 1.1.1 The public health burden of allergy……………………………………………... 37 1.1.2 Early life origins of allergy and atopic disease……………………………………37 1.2 Current concepts of the mechanisms and development of immune tolerance 1.2.1 The immune and adaptive immune system…………….………………………….....38 1.2.2 The definitions and development of immune tolerance…………...…………………40 1.2.3 Central (natural) tolerance………………………………………………....…...…….41 1.2.4 Peripheral (acquired) tolerance…………………………....…………………...…….42 1.3 The physiology of tolerance 1.3.1 Foetal development……………………………………………………………..……43 1.3.2 The microbiome and tolerance……………………………...…………………..……44 1.3.3 Hypersensitivity and oral tolerance…………………………………………………..44 1.3.4 The normal mechanisms of immune tolerance…………………………….……..…..45 1.4 Mechanistic pathways of immune tolerance and immunoregulation 1.4.1 T regulatory and iNKT cells…………………………………………………….……47 4 1.4.2 NODs and their essential role in immune tolerance………………………...…..…… 49 1.4.3 Inflammasomes and their essential role in immune tolerance………....…..……….…53 1.5 The public health burden of vitamin D deficiency 1.5.1 Current concepts of immune tolerance and the role of vitamin D….…………...…….58 1.6 Hypotheses and Aims for the Thesis 1.6.1 Hypotheses and Aims for The Vitamin D Immune Study (VIS)………………….….59 1.6.2 Hypotheses and Aims for The Immune Tolerance in Early Childhood Study (ITEC).60 Chapter 2: Design and set up 2.0 Introduction 2.1 Immune tolerance in early life 2.0.1 Early life origins of allergic disease……………….…………………………………65 2.0.2 Immune tolerance associate with allergic disease in childhood - mechanisms of immune tolerance - food allergy and asthma…………………………..……………...……66 2.0.3 Immune mechanisms comparing high and low risk populations…………..…………68 2.1 Vitamin D and the immune system 2.1.1 The public health burden of vitamin D deficiency…………………………...….……69 2.1.2 Current concepts of immune tolerance and the role of vitamin D……...………..……70 2.1.3 Vitamin D metabolism…………………………………………………………...……71 2.1.4 Vitamin D insufficiency and deficiency……………………………….……...….……71 2.1.5 Vitamin D and the development of allergic disease……………………….……….….72 2.1.6 Vitamin D as a modulator of the immune system…………………………………..…76 2.1.7 The immune response in allergic disease………………………………………..….…77 2.2 Immune Tolerance in Early Childhood (ITEC) 2.2.1 Study design……………………………………………………………………………84 2.2.2 Study population and demographics……………………………………………...……86 2.3 Vitamin D Immune Study (VIS) 2.3.1 Study design…………………………………………..………………………….……90 2.3.2 Study population and demographics……………………………………………..……91 2.3.3 Maternal history and planned study intervention for MAVIDOS……………….……92 2.3.4 Infants born into MAVIDOS………………………………….………………………93 5 Chapter 3: Methods The development and assessment of innate and adaptive immune responses 3.0 Introduction and Rationale 3.1 General methods 3.1.1 Processing of umbilical cord blood………………………...………………………..…95 3.1.2 Thawing of cryopreserved mononuclear cells…………………………………….……96 3.2 Specialised methods for the vitamin D study (VIS) 3.2.1 Total cord blood plasma Immunoglobulin E concentration……………..………….….99 3.2.2 Cord blood vitamin D3 Hormone assay……………………………………...…....……99 3.2.3 Phenotypic characterisation of cord blood mononuclear cells - flow cytometry.…….100 3.2.4 Cell culture…………………………...…………………………………...………..…103 3.2.5 Cytokine detection and analysis………………………………...………………….....104 3.2.6 Statistical analysis………………………………………...……………………….….107 3.3 Specialised methods for the Immune Tolerance study (ITEC) 3.3.1 Study design and demographics………………………………………...…….....…...107 3.3.2 ITEC validation laboratory work………………………………………...…...………108 3.3.3 ITEC main analysis of HR versus LR cord CBMCs samples…………………..….…110 3.3.4 Statistical analysis…………………………………...…………………………….….111 3.3.5 Methodology appendices contents and reference……………………….…..…….….111 Chapter 4 4.0 Results and specific discussion 4.1 Vitamin D Immune Study 4.1.1 Introduction and rational……………………………………………………......…….115 4.1.2 Study population and demographics……………………………………...……...…...115 4.1.3 Total cord blood plasma Immunoglobulin E concentration…………....……….....….116 4.1.4 Cord blood vitamin D3 hormone assay…………………………………………..........117 4.1.5 Phenotypic
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