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Developmental biology - Premature Birth

Can Calming Immune System Halt Premature Birth?

A potential treatment that could stop many cases of premature labor and birth in their tracks...


Premature birth is the leading cause of infant death and disability in the U.S., and costs billions in dollars and heartache every year. Now, University of Connecticut (UConn) researchers report in the journal Reproductive Sciences a potential treatment that could stop many cases of premature labor and birth in their tracks. Their target - our immune system.

UConn Health's Christopher Nold, an obstetrician who practices maternal-fetal medicine at Hartford Hospital, and Anthony Vella, an immunologist, were curious about the immune system's role in premature birth. Most pregnancies last about 40 weeks.
Babies born before 37 weeks can be too small to regulate their body temperature or breathing. They can suffer from brain bleeds and other organ crises, which can impact long-term development and/or intellectual ability.

In the United States about 337,000 babies were born prematurely in 2016. But in other mammals premature birth is quite rare, and usually happens only if there is an infection or inflammation.

Researchers knew that cytokines, small proteins that alert the body to infection and cause inflammation, are found in the amniotic fluid of many women who give birth prematurely. That made the researchers wonder, as the fetus is different enough from its mother the immune system ought to attack it — but something blocks that from happening during pregnancy. What if that protection stopped for some women and caused premature labor?
"There are a lot of anti-inflammatory mechanisms that prevent the fetus from being rejected. So maybe dangerous inflammation, that can break down the tolerance barrier, could mediate the start-up of birth."

Anthony T. Vella PhD, Department of Pediatrics, University of Connecticut School of Medicine, Farmington, Connecticut, USA.

To investigate, Nold and Vella took cells from female reproductive tracts and amniotic fluid surrounding a fetus in the womb. They then exposed these samples to pieces of bacteria back in their lab. As expected, the collected cells produced lots of cytokines - equivalent to shouting "invaders!"

But, these cytokines weren't the inflammation-causing kind they expected. Instead, they were granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokines. GM-CSF is a kind of cytokine which causes cells to mature quickly and become bacteria-eating macrophages. Macrophages in pregnant women tend to increase right before a woman gives birth. It was now unclear if the increase was directly connected to birth, or from another process.
Nold and Vella's finding that GM-CSF is released in response to perceived bacterial infection in mice is intriguing. There is already a drug available that can block GM-CSF. Treating pregnant mice with this drug sharply reduced preterm birth in those exposed to pieces of dangerous bacteria. If preventing premature births in humans could become this straightforward, it would be a game changer. Nold and Vella have filed for a provisional patent on the technology.

But first, they need to figure out if GM-CSF is also cause of premature birth in women. Nold has many collected samples from early human pregnancies still untested. He wants to test them to see if anything detectable could inform risk for human premature birth — such as a high GM-CSF level. "We're hoping to do more immune mechanism studies in mice. And in the not-too-distant future, we hope to start looking at human studies," Nold adds. Hartford Hospital has already given the two researchers a small grant, and the men are looking for more funding to pursue human research further.

Abstract

Objective
A multitude of factors promotes inflammation in the reproductive tract leading to preterm birth. Macrophages peak in the cervix prior to birth and their numbers are increased by the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). We hypothesize GM-CSF is produced from multiple sites in the genital tract and is a key mediator in preterm birth.

Study Design
Ectocervical, endocervical, and amniotic fluid mesenchymal stem cells were treated with lipopolysaccharide (LPS), and the concentration and expression of GM-CSF was measured. Pregnant CD-1 mice on gestational day 17 received LPS and an intravenous injection of either anti-mouse GM-CSF or control antibody. After 6 hours, the preterm birth rate was recorded.

Results
Treatment with LPS increased the GM-CSF concentration and messenger RNA expression after 24 hours in all 3 cell lines (P < .01). Mice treated with LPS and the GM-CSF antibody had a preterm birth rate of 25%, compared to a 66.7% preterm birth rate in controls, within 6 hours (P < .05, x2). Treatment with the anti-mouse GM-CSF antibody decreased the concentration of GM-CSF in the mouse serum (P < .01) but did not alter the number of macrophages or collagen content in the cervix.

Conclusion
These studies demonstrate that GM-CSF is produced from multiple sites in the genital tract and that treatment with an antibody to GM-CSF prevents preterm birth. Curiously, the anti-mouse GM-CSF antibody did not decrease the number of macrophages in the cervix. Further research is needed to determine whether antibodies to GM-CSF can be utilized as a therapeutic agent to prevent preterm birth.

Authors
Christopher Nold MD, Julie Stone MD, Kathleen O’Hara, Patricia Davis MD, Vladislav Kiveliyk, Vanessa Blanchard, Steven M. Yellon PhD and Anthony T. Vella PhD.


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Oct 19, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




Mice produce cytokines in response to uterine bacterial infection, predicting premature delivery. If the same cytokines appear in human maternal blood collections and can be paired to early births, a treatment might be possible to stop early deliveries. Image Credit: Jessica Florence



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