January 2001

From Virginia Tech

Veterinary researchers seek secret to reversing birth defects

BLACKSBURG, VA, January 25, 2001--Fetal development is a highly choreographed process. But all too often it is disrupted when a mother is exposed to a teratogen – an agent known to cause a variety of birth defects. In the United States alone, 150,000 babies are born with defects like these, making birth defects the leading cause of infant mortality.

What if there was a way to reduce or even reverse these defects?

Call it unbelievable, call it magic, or call it — as toxicologist Steven Holladay does — "immunoteratology." The name comes from the influence the mother’s immune system can have in assuring fetal development remains on track.

Recognizing the tremendous impact this could have on the number of babies born with birth defects every year, Holladay and his team of researchers at Virginia-Maryland Regional College of Veterinary Medicine set out to discover just how this magic really works. Scientists have reported that injecting pregnant mice with enough of an inert substance will alert and set into action one of the body’s frontline immune cells called "macrophages." These macrophages essentially engulf and break down what they see as foreign – a process called phagocytosis.

In the past, other researchers had hypothesized that the macrophages were acting directly on the fetus. Under this scenario, the cells would cross the placenta from the mother, then find and eliminate abnormally developing cells in the fetus that were causing birth defects, such as cleft palates, digit anomalies, and neural tube defects affecting the brain and spinal cord. But that proved to be a dead end.

Holladay and colleague Lioudmila Sharova decided to turn down a different road. While their own tests clearly showed that immune stimulation did reduce birth defects in mice, they believed something other than maternal immune cells crossing the placenta was causing this phenomenon.

They knew that fundamental reproductive immunology suggests maternal immune cells don’t routinely traffic across the placenta. This is in part because the fetus is genetically different from the mother and will be recognized by her immune cells as foreign, resulting in what is known as a negative "graft-vs.-host" rejection response in the fetus.

So instead of a direct effect from maternal immune cells, they looked for an indirect effect.

Once set into action, immune cells secrete a vast array of proteins called cytokines or growth factors that regulate immune responses through cell-to-cell communication. Similar or sometimes identical growth factors are also required for the timed expression of cell-cycle genes. Cell-cycle genes control carefully orchestrated waves of cellular proliferation, differentiation, or cell death necessary for normal development. Consider development of the hand as an example. Cells proliferate, but at some point, some of the cells must undergo programmed cell death – apoptosis – to create separate digits.

To test this hypothesis, Holladay and Sharova looked at the expression of a limited panel of genes that regulate cell cycle and apoptosis during fetal development of the palate. Using laboratory animals, they found that when the mother is injected with a known teratogen like urethane, there is decreased expression of these critical development genes, resulting in cleft palates.

They also verified that stimulation of the maternal immune system has the opposite effect on activity of these cell cycle genes in the fetus, significantly increasing their expression level. So, while a chemical like urethane might reduce the growth factor in the fetus, immunostimulation of the mother may cause an increase in that same growth factor in the fetus. In this way, Holladay’s biomedical sciences team was able to reduce the incidence of clubbed digits from 20 percent to zero, and cut the number of cleft palates by half.

The implications of Holladay’s research could be enormous. Traditional thinking has long held that the fetus is a preprogrammed entity that derives nutrition from the mother, but otherwise directs its own development. But the observation that maternal immune stimulation causes altered expression of critical genes in the fetus indicates it’s time for another look.

Holladay says these observations may suggest that there is routine cross-talk between fetus and mother via chemical mediators, and that mothers may play a much greater role than once believed in fetal development. Not only does this indicate that optimal maternal immune health may be important for protection against agents or events that lead to many birth defects, but it also raises the question whether individuals with a compromised immune system are at greater risk for having babies with birth defects.

Answering these questions could help unlock some of the secrets to fetal development and a mother’s early role in ensuring things go right.

PR CONTACT: Jeffrey S. Douglas, APR 540-231-7911 jdouglas@vt.edu

Contact information for researchers:
Dr. Steven Holladay: holladay@vt.edu +1 540-231-3372
Dr. Lioudmila V. Sharova: ludmila@vt.edu 540-231-4825

Release written by Meg Conlan
The research has been published as follows:

Holladay SD, Sharova LV, Smith BJ, Gogal RM Jr. Ward DL, and Blaylock BL. Non-specific stimulation of the maternal immune system. I. Reduced teratogen-induced fetal malformations. Teratology 62:413-419, 2000.

Sharova LV, Sura P, Smith BJ, Gogal RM Jr., Sharov AA, Ward DL, and Holladay SD. Non-specific stimulation of the maternal immune system. II. Effects on fetal gene expression. Teratology 62:420-428, 2000.

Presentations have been made as follows:

Holladay SD (1998). New frontiers in immunotoxicology: 1. Environmental chemical exposure and human autoimmune disease- is there a relationship? 2. Immunoteratology- can maternal immune proteins protect against chemical-induced teratology? National Institute of Occupational Safety and Health (NIOSH), Morgantown, WV.

Holladay SD (1999). Immunoteratology: Does the maternal immune system play a role in directing embryogenesis? Washington State University, Pullman, WA.

Sharova L, Gogal RM, Smith BJ, Sura P, Luster MI, Heindel JJ, and Holladay SD (1999). Non-specific immune activation and prevention of chemical induced teratology. 14th Annual Symposium of the Foundation for Immunotoxicology, National Institute of Occupational Safety and Health (NIOSH), Morgantown, WV.

Holladay SD (1999). Altered fetal gene expression following non-specific stimulation of maternal immune function: A role in preventing cleft palate? National Institutes of Health (NIH): National Institute of Dental and Craniofacial Research (NIDCR) workshop: Prevention of Craniofacial Anomalies. Washington, D.C.

Holladay SD (1999). Development of the immune system: Immunotoxicants and Immunoteratology. Mid-West Annual Meeting of the Teratology Society, Kalamozoo, MI.











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