BackgroundMaternal viral infection during pregnancy is associated with an increase in the incidence of psychiatric disorders with presumed neurodevelopmental origin, including autism spectrum disorders and schizophrenia. The enhanced risk for developing mental illness appears to be caused by deleterious effects of innate immune response-associated factors on the development of the central nervous system, which predispose the offspring to pathological behaviors in adolescence and adulthood. To identify the immune response-associated soluble factors that may affect central nervous system development, we examined the effect of innate immune response activation by polyriboinosinic-polyribocytidylic acid (poly(I:C)), a synthetic analogue of viral double-stranded RNA, on the expression levels of pro- and anti-inflammatory cytokines, chemokines and colony stimulating factors in fetal and postnatal mouse brain 6 h and 24 h after treatment.MethodsC57BL/6J pregnant mice (gestational day 16) or newborn mice (postnatal day 4) received a single intraperitoneal injection of the synthetic analogue of viral double-stranded RNA poly(I:C) (20 mg/kg). Thirty-two immune response-associated soluble factors, including pro- and anti-inflammatory cytokines, chemokines and colony stimulating factors, were assayed 6 h and 24 h after poly(I:C) injection using multiplexed bead-based immunoassay (Milliplex Map) and processed in a Luminex 100 IS instrument.ResultsMaternal exposure to poly(I:C) at gestational day 16 induced a significant increase in cytokines interleukin (IL)-1β, IL-7 and IL-13; chemokines monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein (MIP)-1α, interferon gamma-induced protein (IP)-10 and monokine induced by IFN-gamma (MIG); and in the colony stimulating factor vascular endothelial growth factor (VEGF) in the fetal brain. IL-1β showed the highest concentration levels in fetal brains and was the only cytokine significantly up-regulated 24 h after maternal poly(I:C) injection, suggesting that IL-1β may have a deleterious impact on central nervous system development. In contrast, poly(I:C) treatment of postnatal day 4 pups induced a pronounced rise in chemokines and colony stimulating factors in their brains instead of the pro-inflammatory cytokine IL-1β.ConclusionsThis study identified a significant increase in the concentration levels of the cytokines IL-1β and IL-13, the chemokine MCP-1 and the colony stimulating factor VEGF in the developing central nervous system during activation of an innate immune response, suggesting that these factors are mediators of the noxious effects of maternal immune activation on central nervous system development, with potential long-lasting effects on animal behavior.

Infusion of a simianized anti-αβ mAb (Rh-αβ) just before and following SIV infection protected rhesus macaques from developing AIDS and partially from vaginal SIV acquisition. Recently, short-term treatment with Rh-αβ in combination with cART was found to lead to prolonged viral suppression after withdrawal of all therapeutic interventions. The humanized form of Rh-αβ, vedolizumab, is a highly effective treatment for inflammatory bowel disease. To clarify the mechanism of action of Rh-αβ, naive macaques were infused with Rh-αβ and sampled in blood and tissues before and after treatment to monitor several immune cell subsets. In blood, Rh-αβ increased the CD4 and CD8 T cell counts, but not B cell counts, and preferentially increased CCR6 subsets while decreasing CD103 and CD69 lymphocytes. In mucosal tissues, surprisingly, Rh-αβ did not impact integrin α cells, but decreased the frequencies of CCR6 and CD69 CD4 T cells and, in the gut, Rh-αβ transiently decreased the frequency of memory and IgA B cells. In summary, even in the absence of inflammation, Rh-αβ impacted selected immune cell subsets in different tissues. These data provide new insights into the mechanisms by which Rh-αβ may mediate its effect in SIV-infected macaques with implications for understanding the effect of treatment with vedolizumab in patients with inflammatory bowel disease.

No abstract