Project Details
Early Career
Status: Funded - Open
Longitudinal Immune Profiling of Preterm Infants
Benjamin Fensterheim, MD, PhD
Summary
BACKGROUND: Prematurity is the leading cause of infant mortality worldwide. Complications of prematurity that impact the immune system, including severe bloodstream infection and bronchopulmonary dysplasia (BPD), can entail significant morbidity for years after birth. GAP: The effects of different comorbidities of prematurity on immune development remain poorly defined. This gap limits progress in designing targeted immunotherapies for infants with severe infection or bronchopulmonary dysplasia (BPD) and hampers efforts to identify those at greatest risk for longterm immune complications. HYPOTHESIS: This study hypothesized that the peripheral blood preterm immune profile changes over gestation, and that it deviates from this development due to events in post-natal life. Additionally, we hypothesized that preterm infants who develop severe bloodstream infection or BPD have distinct immune development trajectories. METHODS: We scavenged soon-to-be-discarded whole blood from clinical labs sent every two weeks from preterm infants in the neonatal intensive care unit (NICU) at the Hospital of University of Pennsylvania and created a comprehensive cellular and protein immune profile from each sample, allowing us to track changes in the immune system over time and as infants develop different complications of prematurity. RESULTS: We identified core immune cells and proteins that changed across gestational time and elucidated the cells and proteins which most deviated from expected gestational development due to life after preterm birth. Infants deviated from their gestationally programmed trajectory in ways that related to their clinical comorbidities, including severe bloodstream infection and BPD. Preterm infants with severe infection demonstrated massive persistent oligoclonal activation of the T cell pool, including changes in CD8+, CD4+, and gdT cell populations. In contrast, preterm infants with severe BPD, when compared to age matched infants with moderate BPD, were defined by increased neutrophils, effector memory CD4+ T-cells, CD161+ CD4+ T cells, Th17 CD4+ T-cell polarization, and plasma Th17 cytokines, all of which demonstrate a divergence in Th17 biology. IMPACT: These results demonstrate that early life clinical comorbidities, such as bloodstream infection and BPD, can cause persistent divergent effects on the developing neonatal immune system. Specifically, they first raise the hypothesis that early-life bloodstream infection persistently changes the T cell pool in a way that changes future responses to stimuli. Second, they raise the hypothesis that hyperactivity of the Th17 pathway, which is targetable with available therapeutics, is a causal driver of inflammation in severe BPD. Future studies will aim to validate these findings and explore these novel hypotheses. This work also demonstrate how longitudinal immune profiling offers a powerful tool to uncover divergent immune trajectories in infants and identify potential targets for intervention.
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