Prophylactic Interleukin-2 Treatment Prevents Fetal Gut Inflammation and Injury in an Ovine Model of Chorioamnionitis

Chorioamnionitis, which results from an infection of the fetal membranes, is associated with adverse fetal intestinal outcomes. Using a translational ovine model, we showed that intra-amniotic (IA) exposure to inflammatory stimuli decreased the regulatory/effector T (Treg/Teff) cell balance in the gut, which was accompanied by intestinal inflammation and mucosal injury. We aimed to augment the Treg/Teff cell ratio in the fetal gut by systemic prophylactic IL-2 treatment, to prevent chorioamnionitis-induced intestinal inflammation and subsequent injury. Fetal sheep were intra-amniotically exposed to LPS for 2 or 7 days, with or without prophylactic IL-2 treatment. Infiltration of inflammatory cells and cytokine gene expression in the fetal ileum were analyzed and correlated with gut wall integrity. IL-2 administration increased intestinal Treg cells and thus the Treg/Teff cell ratio. Prophylactic IL-2 treatment reduced the LPS-induced influx of neutrophils and CD3+ cells and decreased the mRNA levels of pro-inflammatory cytokines including IL-6 and IL-17 in the fetal ileum. Importantly, prophylactic IL-2 treatment prevented mucosal damage without inducing fetal adverse treatment outcomes. Our data show that prophylactic IL-2 treatment prevents fetal intestinal inflammation and mucosal injury in the context of experimental chorioamnionitis. Modulation of the Treg/Teff cell balance may contribute to these IL-2-induced protective effects.