Cytokine levels during pregnancy influence immunological profiles and neurobehavioral patterns of the offspring

Abstract

The underlying causes of autism spectrum disorders (ASD) are unknown, but clinical and experimental studies indicate immune mechanisms, in general, and cytokine dysregulation, in particular, as contributing factors in their etiology. We developed a prenatal mouse model of autism to demonstrate that circulating levels of defined cytokines in pregnant dams could influence fetal development and behavioral characteristics in their offspring. We administered daily injections of murine IL-2 (0.4 mug in phosphate-buffered saline [PBS]) to pregnant mice during mid-gestation, and analyzed their offspring (IL-2 pups) in comparison to offspring of pregnant mice injected with vehicle only (PBS pups). Significant levels of IL-2 were present in amniotic fluid and tissues from embryos of dams given radiolabeled IL-2, indicating that the injected IL-2 crossed the placenta and entered the fetuses. Lymphocytes from IL-2 pups demonstrated accelerated T cell development, with a skewing toward TH1 cell differentiation. IL-2 pups also showed in vitro proliferative and cytotoxicity responses that were significantly higher than control PBS pups when stimulated with syngeneic B lymphoma cells or allogeneic spleen cells. In addition to their previously shown increases in open-field activity, grooming and rearing behavior, offspring of IL-2-injected (vs. PBS-injected) dams also displayed abnormal new motor learning as assessed through acquisition of the classically conditioned eyeblink response. These results suggest that increases in maternal levels of IL-2 during pregnancy induce in their offspring long-lasting increased vulnerability to neurobehavioral abnormalities associated with autism, and provide a valid animal model to determine the underlying immunological mechanisms.