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Mili Mandal
Molecular Pathology and Immunology Program
M.S. 2005, West Virginia University
M.S. 2001, Chattrapati Shahu Ji Maharaj University, Kanpur, India
B.S. 1999, Chattrapati Shahu Ji Maharaj University, Kanpur, India

Thesis Advisor: Nicholas M. Ponzio, Ph.D.
Department of Pathology and Laboratory Medicine

Wednesday, February 22, 2012
10:30 A.M., MSB Room C-600


Epidemiological and clinical studies show that infection during pregnancy increases the risk of neurodevelopmental disorders in children. In rodents, injection of pregnant dams with infectious pathogens or agents that mimic viral or bacterial infections (e.g., poly(I:C) and LPS) also leads to neurological, behavioral, and immunological abnormalities in their offspring.
The objective of the present study is to determine if in utero exposure (i.e., acting as a first hit) of the fetus to inflammatory mediators (e.g. cytokines) elicited by maternal immune stimulation, results in developmental programming of the immune system in offspring, such that upon subsequent postnatal exposure to an immune stimulus (i.e., second hit), these offspring exhibit altered immune responses.
Wild type (WT) female C57BL/6 (B6) and IL-6 KO (IL-6-/-) mice were mated with WT B6 males and injected with PBS or poly(I:C) on gestational day 12. Increased cytokine levels in pregnant dams correlated with appearance of sickness behavior after poly(I:C) injections. Sera and amniotic fluids from dams were also tested for multiple cytokines, and lymphocyte phenotype and functional analyses were performed on their offspring. In addition, offspring were given immune stimuli, either by zymosan injection to induce an antigen non-specific acute inflammatory response or MOG35-55 to induce antigen-specific experimental autoimmune encephalomyelitis (EAE). Offspring were assessed for qualitative and quantitative differences in their responses to these immune stimuli.
Poly(I:C)-injected pregnant dams showed significant sickness behavior and a transient increase in pro-inflammatory cytokines in sera and amniotic fluids at 2hrs, indicating successful maternal response to poly(I:C). In contrast, PBS-injected dams showed neither sickness behavior nor increased cytokine levels. In heterozygous IL-6+/- matings, pregnant IL-6 KO dams showed significant levels of IL-6 in amniotic fluids but not in their sera after poly(I:C) injection, indicating a fetal source of this cytokine. Additionally the presence of IL-6 in supernatants from cultured placental cell preparations from these IL-6 KO dams confirmed cytokine production from the heterozygous (IL-6+/-) fetal component.
In vitro activated spleen cells from offspring of poly(I:C)- (vs PBS)-injected dams showed preferential differentiation toward Th17 cell development. Pro-inflammatory cytokines such as IL-6, MCP-1, and TNF- were also present in these in supernatants from these in vitro activated spleen cells of offspring from poly(I:C)-injected dams. Together, these data suggested a pro-inflammatory phenotype of these offspring. Moreover, in comparison to offspring of PBS-injected dams, adult offspring of poly(I:C)-injected dams mounted heightened acute inflammatory responses as shown by significantly greater accumulation of neutrophils in the peritoneal cavity, and pro-inflammatory cytokines in serum and peritoneal cavity fluid after zymosan injection. Finally, offspring of poly(I:C)- (vs. PBS)-injected dams exhibited a significantly higher frequency and earlier onset of clinical symptoms of EAE following MOG35-55 immunization.
Overall, these data demonstrate that offspring of poly(I:C)-injected pregnant dams exhibit a pro-inflammatory phenotype due to developmental programming of the immune system. As a result, these offspring manifest altered responses to subsequent immune stimuli, which have profound consequences on health and disease.

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