title: Prophylactic Interleukin-2 Treatment Prevents Fetal Gut Inflammation and Injury in an Ovine Model of Chorioamnionitis.
abstract: BACKGROUND
  Chorioamnionitis results from an infection of the fetal membranes and is associated with fetal adverse outcomes notably in the intestine. Using a translational ovine model, we showed that intra-amniotic 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 thus aimed to augment the Treg/Teff cell ratio in the fetal gut by prophylactic IL-2 treatment and evaluate whether it is sufficient to prevent chorioamnionitis-induced intestinal inflammation and mucosal injury.
  
  
  METHODS
  Fetal sheep (122 d of gestation) were intra-amniotically exposed to lipopolysaccharide for 2 or 7 days with or without prophylactic IL-2 treatment (4 d). We evaluated the infiltration of inflammatory cells in the ileum and mesenteric lymph nodes. Cytokine gene expression was analyzed in fetal ileum and the inflammatory changes were correlated with gut wall integrity.
  
  
  RESULTS
  IL-2 administration preferentially increased intestinal Treg cells and thus the Treg/Teff cell ratio. Prophylactic IL-2 treatment reduced the lipopolysaccharide-induced influx of neutrophils and CD3(+) T cells and decreased the messenger RNA levels of proinflammatory 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.
  
  
  CONCLUSIONS
  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 the protective effects of IL-2.
authors.affiliation: *Department of Pediatrics, Maastricht University Medical Center (MUMC), Maastricht, the Netherlands; †School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands; ‡School of Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, the Netherlands; §Department of Transplantation Immunology, Tissue Typing Laboratory, Maastricht University Medical Center (MUMC), Maastricht, the Netherlands; ||Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio; and ¶Department of Internal Medicine, Division of Haematology, Maastricht University Medical Center (MUMC), Maastricht, the Netherlands.
authors.forename: Maria
authors.initials: M
authors.lastname: Nikiforou
authors.forename: Joris
authors.initials: J
authors.lastname: Vanderlocht
authors.forename: Claire A
authors.initials: CA
authors.lastname: Chougnet
authors.forename: Reint K
authors.initials: RK
authors.lastname: Jellema
authors.forename: Daan R M G
authors.initials: DR
authors.lastname: Ophelders
authors.forename: Mandy
authors.initials: M
authors.lastname: Joosten
authors.forename: Nico
authors.initials: N
authors.lastname: Kloosterboer
authors.forename: Birgit L M G
authors.initials: BL
authors.lastname: Senden-Gijsbers
authors.forename: Wilfred T V
authors.initials: WT
authors.lastname: Germeraad
authors.forename: Boris W
authors.initials: BW
authors.lastname: Kramer
authors.forename: Tim G A M
authors.initials: TG
authors.lastname: Wolfs
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D017252:CD3 Complex / Q000187:drug effects; D002821:Chorioamnionitis / Q000097:blood / Q000473:pathology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004751:Enteritis / Q000517:prevention & control*; D005260:Female; D007082:Ileum / Q000276:immunology / Q000473:pathology; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000293:injuries / Q000473:pathology; D008070:Lipopolysaccharides; D008198:Lymph Nodes / Q000378:metabolism; D008643:Mesentery; D009504:Neutrophils / Q000187:drug effects; D011247:Pregnancy; D049188:Prenatal Injuries / Q000209:etiology / Q000517:prevention & control*; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects; D011897:Random Allocation; D012756:Sheep; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D017252:CD3 Complex; D016207:Cytokines; D007376:Interleukin-2; D008070:Lipopolysaccharides; D020011:Protective Agents; D012333:RNA, Messenger