Strengthening newborns’ immune systems: A secret in the plasma

Blood cells
The immunosuppressant effect in newborns' blood comes not from blood cells themselves, but from the plasma that surrounds them (smaller.pathological.ca/Flickr)
There’s something different about newborns’ blood. In babies less than 28 days of age, the immune system still hibernates—making newborns more susceptible to life-threatening infections and less responsive to many vaccines. Ofer Levy, MD, PhD, and his colleagues at Boston Children’s Hospital have done extensive work toward understanding the newborn immune system, and now they’ve uncovered a mechanism to help explain why the system is so weak—and how it might be strengthened.

“If we can understand the molecular mechanisms causing the immune system to be different when we’re very young or very old, we can leverage that knowledge to develop new treatments,” says Levy.

Levy’s lab analyzed cord blood samples from newborns in Boston found that their plasma—the liquid that carries blood cells—differs from adult blood in two important ways. It has more of the enzymes that create adenosine, a small molecule that suppresses the immune system, and less adenosine deaminase (ADA), the enzyme that breaks adenosine down. (Interestingly, some people with severe combined immunodeficiency syndrome, better known as “boy in the bubble” disease, are ADA-deficient as well. In a way, their immune systems never “grew up.”)

“Previous work had indicated that newborns had higher adenosine in the blood,” says Matthew Pettengill, PhD, the study’s first author. “We were initially studying enzyme expression in blood cells, but we actually found that enzyme levels in the plasma played a more significant role than the enzymes in cells.”

Plasma hadn’t really been considered a player in the immune response before. The researchers needed to confirm their finding—which they did by taking plasma samples from large numbers of children in British Columbia, Canada and Gambia. Samples taken at different ages all pointed to an increase in plasma ADA activity over time.

“That makes it really generalizable,” Levy says. “We believe this relative ADA deficiency of early life is a global reality.”

Diagram showing adenosine in child and adult blood
Newborns have more of the enzymes that create adenosine and less of the one that breaks it down, leaving much more in the blood

In a test tube, blocking the enzymes that produce adenosine increased the newborn immune response to S. epidermidis, a bacterial infection often seen in the neonatal intensive care unit. That suggests a possibility for a therapeutic approach to enhance the ability of newborns to fight infection.

Alternatively, doctors could give newborns ADA to help break adenosine down. Levy notes that this approach is sometimes used in children with “boy in the bubble” disease to increase their immune response.

“This discovery gives us potential new tools for immunomodulation,” says Levy. “If we want to either increase the immune response or decrease it, we now know that the tools that modulate adenosine levels operate differently in newborns and adults, and that we have to choose therapies accordingly.”

In the case of newborns, Levy envisions decreasing the adenosine levels in a localized part of the body—the site where the vaccine would be injected—thereby boosting the local immune response to the vaccine.

The insight that plasma has an age-specific effect on the immune response will also make for better laboratory models of newborn immunity, in which to screen potential anti-infective drugs. “The focus on plasma is pretty unique to our group,” says Levy. “Most people look for differences in the cells. Things that are in plasma make good biomarkers—you can sample blood and test for them really quickly—and they can be readily added to blood. The more accurately we model a newborn in a test-tube, the better our drug screens will be.”

ResearchBlogging.orgCitation:Pettengill M, Robson S, Tresenriter M, Millán JL, Usheva A, Bingham T, Belderbos M, Bergelson I, Burl S, Kampmann B, Gelinas L, Kollmann T, Bont L, & Levy O (2013). Soluble ecto-5′-nucleotidase (5’NT), alkaline phosphatase, and adenosine deaminase (ADA1) activities in neonatal blood favor elevated extracellular adenosine. The Journal of biological chemistry PMID: 23897810