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Your Environment. Your Health.

PRENATAL INFLAMMATORY EXPOSURES AND NEONATAL IMMUNE DEVELOPMENT

Export to Word (http://www.niehs.nih.gov//portfolio/index.cfm/portfolio/grantdetail/grant_number/U01ES029234/format/word)
Principal Investigator: Chougnet, Claire A
Institute Receiving Award Cincinnati Childrens Hosp Med Ctr
Location Cincinnati, OH
Grant Number U01ES029234
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Sep 2017 to 31 Aug 2022
DESCRIPTION (provided by applicant): ABSTRACT  The  “Developmental  Origin  of  Health  and  Disease”  hypothesis  posits  that  susceptibility  to  a  number  of  non-­ communicable  diseases  can  be  influenced  by  in  utero  exposures  (nutritional,  environmental,  inflammatory).  While this hypothesis is increasingly accepted, particularly for diseases with an immune etiology (i.e. allergic,  autoimmune), the mechanisms involved remain unresolved. A major knowledge gap that limits progress in this  area is the remaining paucity of information regarding the “normal” immune processes that occur during critical  pre-­ and perinatal periods, and how this development may be influenced by fetal exposures. One fetal exposure  with a repeated and robust impact on long-­term health is inflammation of the placenta – termed chorioamnionitis  (chorio), which, in severe cases, leads to inflammation of fetal membranes and increased levels of inflammatory  mediators in both the amniotic fluid and the neonates’ cord bloods. Our preliminary data show in human infants  that exposure to severe chorio (1) is associated with respiratory morbidity during early infancy, and (2) leads to  increased levels of the Th17-­associated transcription factor RORC in the circulation in the first month of life. To  get deeper insights into the underlying mechanisms, we have developed an experimental model of chorio in the  Rhesus  macaque,  which  presents  with  very  high  level  of  similarities  with  human  chorio.  Intra-­amniotic  (IA)  injection of LPS into pregnant animals leads to massive neutrophilic infiltration and up-­regulation of inflammatory  cytokines in the chorio-­decidua, and significant changes in the fetal immune system, including (1) severe lung  inflammation;; (2) alteration of the regulatory T cell (Treg)/Th17 balance in the spleen, with the increased accrual  of  “inflammatory  Tregs”;;  and  (3)  increased  proportion  of  activated  type  3  innate  lymphoid  cells  (ILC3)  in  the  mucosal areas. LPS-­induced fetal inflammation was largely driven by IL-­1-­dependent mechanisms.   These data lead us to hypothesize that exposure to chorio induces alterations of the fetal systemic and mucosal  immune system, notably through alterations of Tregs and ILCs, that predispose to post-­natal diseases, including  respiratory problems.  We will (1) analyze in depth the accrual of fetal inflammatory Tregs in the context of chorio,  using single cell RNAseq, methylation profiling and unique functional assays;; (2) analyze how fetal inflammation  directs  the  ontogeny  and  functional  development  of  ILC3  through  detailed  phenotyping  of  ILC  and  their  progenitors for homing/adhesion molecules, analysis of the transcriptome of fetal NHP ILC by scRNAseq, and  the  use  of  unique  ILC3  functional  assays  we  have  developed;;  and  3)  determine  how  fetal  inflammation  longitudinally impacts accumulation of inflammatory Tregs or ILC3 precursor development, and neonatal immune  function, by monitoring control and chorio-­exposed neonates from birth to 4 months of age, characterizing 1) the  normal course of recruitment of inflammatory Tregs and ILC3 in various compartments, and 2) immune responses  to common neonatal vaccines and environmental allergens.    
Science Code(s)/Area of Science(s) Primary: 52 - Immunology/Immunotoxicology
Publications See publications associated with this Grant.
Program Officer Michael Humble
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