Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation

Abstract

Infection during pregnancy can lead to activation of the maternal immune system and has been associated with an increased risk of having an offspring later diagnosed with a neurodevelopmental disorders (NDD) such as autism spectrum disorder (ASD) or schizophrenia (SZ). Most maternal immune activation (MIA) studies to date have been in rodents and usually involve the use of lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (poly I:C). However, since NDD are based on behavioral changes, a model of MIA in non-human primates could potentially provide data that helps illuminate complex behavioral and immune outputs in human NDD. In this study twenty-one pregnant rhesus macaques were either given three injections over 72 hours of poly I:C-LC, a double stranded RNA analog (viral mimic), or saline as a control. Injections were given near the end of the first trimester or near the end of the second trimester to determine if there were differences in immune output due to the timing of MIA.An additional three non-treated animals were used as controls. The offspring were followed until 4 years of age, with blood collected at the end of their first (year 1) and fourth (year 4) years to assess dynamic cellular immune function. Induced responses from peripheral immune cells were measured using multiplex assays.At one year of age, MIA exposed offspring displayed elevated production of innate inflammatory cytokines including: interleukin (IL)-1β, IL-6, IL-12p40, and tumor necrosis factor (TNF)α at baseline and following stimulation. At four years of age, the MIA exposed offspring continued to display elevated IL-1β, and there was also a pattern of an increased production of T-cell helper type (T_H)-2 cytokines, IL-4 and IL-13. Throughout this time period, the offspring of MIA treated dams exhibited altered behavioral phenotypes including increased stereotyped behaviors. During the first two years, stereotyped behaviors were associated with innate cytokine production. Self-directed behaviors were associated with T_H2 cytokine production at year 4. Data from this study suggests long-term behavioral and immune activation was present in offspring following MIA. This novel non-human primate model of MIA may provide a relevant clinically translational model to help further elucidate the role between immune dysfunction and complex behavioral outputs following MIA.

Keywords: Autism; Behavior; Cytokines; Fetal priming; Maternal immune activation; Non-human primate; schizophrenia.