The development of the human immune system in early life, including in utero, impacts the risks of several diseases later in life, particularly immune-mediated diseases such as allergies, asthma, and autoimmunity. Yet, the mechanisms of early-life immune imprinting are poorly understood in humans due to difficulties in obtaining samples and the challenges of deriving critical data from small sample volumes. These studies are further complicated by the many simultaneous exposures with potential impacts on developing immune cells, colonising microbes, and immune-microbe mutualism.
INITIALISE addresses these challenges through a combined approach using intersecting multiple cohorts and existing biobanks, applying state-of-the-art technologies for exposure analyses and immune system investigation to understand the environmental factors shaping human immune systems early in life, their mechanisms of action, and impact on life-course health.
INITIALISE partners were brought together with the overall aim to improve life-course health by focusing on the shaping of the immune system in the earliest, most vulnerable period of life, including the prenatal period. Our shared view is that effective early-life interventions targeting the immune system will have large and beneficial impact on life-course health. To elucidate and exploit the complex crosstalk of environmental and genetic factors affecting the immune system in early life, INITIALISE mobilises clinicians and scientists with diverse and complementary expertise in the domains of immunology, paediatrics, microbiology, metabolism, metabolomics/lipidomics, proteomics, genetics, exposome, psychiatry, systems medicine, bioinformatics, and ICT.
INITIALISE includes eight prospective and longitudinal birth cohort studies, with diverse health outcomes including immune-mediated diseases, obesity, and neurocognitive disorders, as well as a study of human fetuses. Together, the INITIALISE participants have collated an unprecedented, diverse, and multi-modal volume of prospective birth cohorts, which currently comprise approximately 38,000 infants from 20 countries, with recruitment and follow-up being continued for most of them within INITIALISE.
The specific objectives of INITIALISE are:
Objective 1 is to elucidate how exposures and genome impact gut microbiome, host immune system and metabolism, and how the interplay between these factors impacts life-course health. Comprehensive multi-omics studies, including deep immunophenotyping, will be performed in prospective study settings, associating early-life multi-omics profiles with adverse health outcomes later in life.
Objective 2 is to define the role of immune system maturation as a mediator between exposures and life-course health. Functional studies will explore specific mechanisms by which environmental factors, differing among children with different health outcomes, imprint on developing immune cells.
Objective 3 is to perform a pilot clinical study, targeting the immune system, for personalised disease prevention. Based on project findings, a clinical demonstrator will be conducted as a Randomised Controlled Trial (RCT). This study will target the gut microbiome in at-risk children, aiming to improve immune status and reduce disease risk.
Objective 4 is to set up a collaborative data science platform for the investigation of early-life factors linked with life-course health. INITIALISE incorporates multiple clinical cohort studies, partly with already acquired data. IT infrastructure will be set up to facilitate collaboration, including data harmonisation and sharing.
INITIALISE will deliver a comprehensive overview of the immune system development, spanning the prenatal and postnatal early-life periods. The project will elucidate how various environmental and host (genotype, phenotype) factors shape the immune system, and how they may initiate the pro-inflammatory phenotype during this vulnerable period of life — for example via altering Th17/Treg balance — and in turn how such immune system imprinting leads to specific adverse health outcomes. We will achieve this by a combination of discovery-driven multi-omics and mechanistic/functional studies.
Our discovery-driven multi-omics studies will be conducted in longitudinal settings in participating prospective birth cohorts, linking early-life exposures (including chemical exposures), (epi)genome, metabolome, proteome, immunome (deep immune phenotyping using mass cytometry), transcriptome, and gut microbiome with specific adverse outcomes later in life, across three domains — immune (immune-mediated diseases), metabolic (obesity), and neurocognitive. The proteomics platform will cover 384 proteins involved in inflammation, immune response, and immune-mediated diseases.
Based on research findings and preliminary data, INITIALISE will establish a clinical Randomised Controlled Trial (RCT) demonstrator, which will provide evidence of the feasibility of disease prediction and prevention in healthcare settings.