Increased Proinflammatory Cytokines Associated with Increased Abnormal Behaviors in a Non-Human Primate Model of Maternal Immune Activation

Background: Infection during pregnancy has been associated with an increased risk of having an offspring later diagnosed with an autism spectrum disorder (ASD). Infection during pregnancy can lead to activation of the maternal immune system and this activation of the immune system is thought to result in behavioral changes in the offspring. 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 IC).  Studies have shown that MIA results in behavioral changes in the offspring including reduced and altered ultrasonic vocalizations, reduced socialability and increased repetitive behaviors.  Furthermore, alterations in offspring immune systems have also been identified in these models such as decreases in regulatory T cell populations, increased production of  Il-6 and IL-17 from T cellsand increased production of IL-12p40 from macrophages. However, since neurodevelopmental disorders are based on behavioral changes, a non-human primate model could shed more light due to their closer relationship to humans.  

Objectives: To further investigate behavioral and immune abnormalities in a non human primate model of maternal immune activation.

Methods: Twenty-one pregnant rhesus macaques were placed into four treatment groups: first trimester poly IC, first trimester Saline, second trimester poly IC and second trimester saline.  Animals were given three injections over the course of 72 hours with either poly IC, a double stranded RNA analog, used to induce an immune response in the absence of an infection or saline as a control. Injections were given either near the end of the first trimester or near the end of the second trimester depending on the treatment group of the animal.  Over the next four years offspring from the treatment animals underwent several behavioral analysis and had blood collected at the end of their second and forth years. Plasma cytokine levels and supernatants from stimulated peripheral blood mononuclear cells (PBMC) were measured using a multiplex assay. 

Results: Animals injected with poly IC had offspring who demonstrated increased stereotyped behaviors. In addition to these differences in behaviors offspring also showed persistent elevated production of inflammatory cytokines under multiple conditions including: G-CSF, IL-1β, IL-2, IL-4, IL-8, IL-12p40 and MCP-1. Many of these cytokines positively correlated with increased self directed behavior including G-CSF, IL-1β, IL-4 and IL-12p40 while IL-1β and IL-8 negatively correlated with whole body stereotyped behaviors.

Conclusions: MIA increases the risk for offspring to exhibit an altered behavior phenotype. In addition, MIA affects the immune profile of the offspring. Neuro-immune interactions are increasingly associated with neurodevelopmental disorders. By further studying these interactions we can better our understanding of how these two systems work together in typical development and in neurodevelopmental disorders.