PhD, University of Cincinnati, 2020, Medicine: Immunology

A complication that can occur during pregnancy is placenta inflammation, referred to as chorioamnionitis (chorio). Exposure to this inflammatory condition has been associated with several post-natal morbidities. Chorio, particularly severe chorio leads to the increased production of various inflammatory mediators in the amniotic fluid. This inflamed amniotic fluid encounters the fetus, resulting in systemic and mucosal immune responses. However, a full understanding of the fetal responses to the inflammatory milieu created by chorio and the contribution of inflammatory cytokines like IL-1 and TNFa to these responses remains limited. The work presented here examined and characterized the fetal systemic and mucosal immune response to chorio exposure in humans and in a non-human primate (NHP) animal model. Our NHP model in which using intra-amniotic (IA) LPS in the Rhesus macaque, phenocopies severe chorio and allowed us to evaluate the impact of chorio exposure on the fetus. Systemically we found that IA LPS leads to a decreased frequency of CD4+FoxP3+ regulatory T cells (Tregs). However, while CD4+FoxP3+ Tregs are reduced in the context of chorio, they markedly upregulate production of IL-17, becoming the most significant source of this cytokine in inflammatory conditions. A similar, but milder phenotype was found in the cord blood as well. We later found that the Th17-like response was partially controlled by IL-1 or TNFa signaling, but the frequency of CD4+FoxP3+ did not recover after blockade IL-1 or TNF. The presence of a chorio induced Th17-like signature was also found in human cord blood of severe chorio exposed fetuses with sustained elevation of RORC and RORC/FOXP3 mRNA ratio. These findings point to a regulatory/inflammatory disbalance in the fetal systemic response to chorio exposure that particularly impacts regulatory T cells. In our NHP Rhesus macaque model, we also conducted an in-depth analysis of the chorio-induced fetal mucosal immune response in (open full item for complete abstract)

Committee: Claire Chougnet Ph.D. (Committee Chair); David Hildeman Ph.D. (Committee Member); Edith Janssen Ph.D. (Committee Member); Alan Jobe M.D. (Committee Member); Ian Lewkowich Ph.D. (Committee Member) Subjects: Immunology