Project Details
Projekt
Mechanisms of prenatal glucocorticoid-induced changes on the offspring's immune system
Applicant
Professorin Dr. Eva Tolosa
Subject Area
Gynaecology and Obstetrics
Immunology
Immunology
Term
from 2015 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 255154572
Prenatal glucocorticoids (GCs) are routinely administered to pregnant women at risk of preterm delivery in order to improve survival of the newborn. Importantly, after treatment in half of the cases birth occurs outside the effective period for the pharmacological effects of GCs on lung development. Since GCs are potent immune modulators and cause apoptotic death of immature lymphocytes, we hypothesize that prenatal glucocorticoid treatment might affect the development of the offspring’s immune system and immunity later in life. To address this topic, we have developed a mouse model mimicking prenatal glucocorticoid treatment. Using this model, we have shown that betamethasone, at doses eliciting lung maturation, induces profound thymocyte apoptosis in the offspring, which lasts sufficiently to leave a mark in the peripheral T cell receptor (TCR) repertoire that persists into adulthood. These changes in the T-cell repertoire have unforeseeable consequences on development of autoimmune disease. Furthermore, analysis of the thymus size in foetuses from pregnancies of the PRINCE cohort revealed a reduced growth rate in the foetuses of betamethasone-treated mothers compared to untreated pregnancies at the same gestational week. Our preliminary data on immune phenotype analysis on cord blood samples of the PRINCE and PRINCE Preemies cohorts show a reduced frequency of hematopoietic stem cells (HSCs) in neonates that received prenatal steroids less than two weeks before birth. Our data suggest that despite the benefits of prenatal GCs for infants born prematurely, this treatment may be associated with long-term effects on immunity, and further studies are needed to assess the potential risks. In the next period, we aim to extend our human studies to a more comprehensive analysis of the immune system at birth and of the development of other immune cell subsets. In the mouse model, we will address the mechanistic basis for the bias in TCR repertoire, and will analyse the effects of steroids on hematopoietic development, peripheral seeding, and the consequences of prenatal steroids for neonatal infection.
DFG Programme
Clinical Research Units
