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Maternal infection is consistently identified as a major contributor to pregnancy complications and premature birth. Listeria infected mice have revealed that an aggressive immune respnse can be stopped, allowing the pregnancy to continue.

A method for blocking pregnancy loss?

Maternal infection is consistently identified as contributing to pregnancy complications and premature birth. The same small immune molecules are also implicated in other pregnancy losses. Now, research finds mom's immune cells can be be stopped from attacking her fetus and save the pregnancy.

Scientists at Cincinnati Children's Hospital Medical Center suggest restricting a pregnant mother's immune cells from the placenta can protect against pregnancy complications during maternal infection. The study sheds new light on the challenge of premature birth and the related complications of preeclampsia, spontaneous abortion and stillbirth.

The work was published March 9, 2015 in the Journal of Clinical Investigation.

One of every 9 infants in the United States is born premature, or before 37 weeks of pregnancy, according to the U.S. Centers of Disease Control. There remains no effective therapy for these pregnancy complications, and babies born too early are highly vulnerable to death or long-term developmental abnormalities.

Maternal infection is consistently identified as an important contributor to pregnancy complications and premature birth according to senior author Sing Sing Way MD PhD, a pediatrician with the Division of Infectious Diseases at the Cincinnati Children's Perinatal Institute.

"Pregnant women are especially susceptible to infection. So it might seem counter intuitive to prevent their immune cells from properly penetrating placental tissues," said Way. "However, we found that pregnancy complications largely stem from harmful maternal immune cells that recognize and attack the placenta and other immunologically foreign tissues derived from the fetus. Restricting the access of harmful immune cells to developmentally delicate fetal tissue represents a highly innovative therapeutic strategy."

The immune system of a pregnant mother has a delicate balancing act to perform. It must protect against infection while trying not to harm the baby from a mother's over-reactive immune responses. Any proposed therapy to modify a pregnant mother's immune system, therefore, must be extremely precise.

Along with first author and Cincinnati Children's researcher Vandana Chaturvedi PhD, the research team used mice to model human pregnancy and thus evaluate pregnancy outcomes after laboratory induced infection manipulated the maternal immune system to respond.

Using a bacterium commonly found in the environment and food supply, Listeria monocytogenes, researchers infected pregnant mice. In humans, Listeria causes a severe invasive infection in the mother often with fatal consequences for the fetus.

Listeria infected pregnant mice attracted neutrophils and macrophages (specialized first-responder immune cells) carrying the protein CXCL9 — which rapidly infiltrated the placenta. These neutrophils and macrophages in turn attracted T cells that specifically recognized any paternal antigens in the uterus thus attacking the fetus as foreign. Typically, placental cells are programmed not to call signaling proteins (chemokines) and attract toxic proteins like CXCL9. But infection with Listeria broke the protective placental barrier.

However, the researchers discovered they could neutralize CXCL9 by blocking its receptor protein located on the T cells surface — CXCR3. Blocking CXCR3 kept CXCL9 proteins from infiltrating the placenta. Way and colleagues experimentally blocked CXCR3 multiple ways. One way was to genetically delete the CXCR3 chemokine receptor in female mice altogether, so it was not present during pregnancy or during infection with Listeria. In a second complementary approach, a protein or antibody with CXCR3 neutralizing properties was administered to the pregnant mice which, remarkably, provided protection against CXCL9 even after infection.

Regardless of methodology, blocking CXCR3 effectively eliminated fetal resorption and restored healthy, live offspring to Listeria infected mice.

Researchers also tested to see if blocking CXCR3 would apply to pregnancy complications not caused by infection. The team caused fetal injury by depleting the protective maternal regulatory T cells. These cells naturally expand in women during healthy pregnancies, but not in pregnancies complicated by preeclampsia or spontaneous abortion. Surprisingly, they found that blocking CXCR3 prevented fetal loss by depleting the maternal regulatory T cells.

Dr. Way says therapeutically preventing harmful immune cells from entering the placenta targets the most common root of fetal injury. He believes this strategy can have broad applicability for infectious as well as non-infectious causes of pregnancy complications. In fact, the small molecule inhibitors blocking CXCR3, and related chemokines, are currently being tested for treatment of other human autoimmune and inflammatory disorders.

"We hope the findings from this study will spark renewed interest across the biomedical community in establishing the underlying causes of pregnancy complications, and development of new therapeutic strategies for ensuring healthy pregnancy and healthy children."

Sing Sing Way MD PhD, pediatrician, Division of Infectious Diseases, Cincinnati Children's Perinatal Institute.

Abstract
Mammalian pregnancy requires protection against immunological rejection of the developing fetus bearing discordant paternal antigens. Immune evasion in this developmental context entails silenced expression of chemoattractant proteins (chemokines), thereby preventing harmful immune cells from penetrating the maternal-fetal interface. Here, we demonstrate that fetal wastage triggered by prenatal Listeria monocytogenes infection is driven by placental recruitment of CXCL9-producing inflammatory neutrophils and macrophages that promote infiltration of fetal-specific T cells into the decidua. Maternal CD8+ T cells with fetal specificity upregulated expression of the chemokine receptor CXCR3 and, together with neutrophils and macrophages, were essential for L. monocytogenes–induced fetal resorption. Conversely, decidual accumulation of maternal T cells with fetal specificity and fetal wastage were extinguished by CXCR3 blockade or in CXCR3- deficient mice. Remarkably, protection against fetal wastage and in utero L. monocytogenes invasion was maintained even when CXCR3 neutralization was initiated after infection, and this protective effect extended to fetal resorption triggered by partial ablation of immune-suppressive maternal Tregs, which expand during pregnancy to sustain fetal tolerance. Together, our results indicate that functionally overriding chemokine silencing at the maternal-fetal interface promotes the pathogenesis of prenatal infection and suggest that therapeutically reinforcing this pathway represents a universal approach for mitigating immune-mediated pregnancy complications.

Funding support for the study came from the National Institute of Allergy and Infectious Diseases (grants R01-AI087830, R01-AI100934, R21-AI112186), and an Investigator in the Pathogenesis of Infectious Disease award from the Burroughs Wellcome Fund.

Cincinnati Children's Hospital Medical Center ranks third in the nation among all Honor Roll hospitals in U.S. News and World Report's 2014 Best Children's Hospitals. It is also ranked in the top 10 for all 10 pediatric specialties. Cincinnati Children's, a non-profit organization, is one of the top three recipients of pediatric research grants from the National Institutes of Health, and a research and teaching affiliate of the University of Cincinnati College of Medicine. The medical center is internationally recognized for improving child health and transforming delivery of care through fully integrated, globally recognized research, education and innovation. Additional information can be found athttp://www. cincinnatichildrens. org. Connect on the Cincinnati Children's blog, via Facebook and on Twitter.

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