Mother's Immune System May Block Fetal Treatments for Blood Diseases

--However, Animal Study Also Points Toward Strategies for Success--

PHILADELPHIA, Aug. 17 /PRNewswire-USNewswire/ -- Pediatric researchers have
resolved an apparent contradiction in the field of prenatal cell
transplantation -- a medical approach that holds future promise in correcting
sickle cell disease and other serious congenital blood disorders. In a new
study in animals, the researchers showed that the mother's immune response
interferes with the offspring's earlier ability to tolerate transplanted donor
cells.

The study team concludes that focusing on transplant techniques that avoid the
maternal immune response may allow scientists to take advantage of fetal
tolerance to achieve a long-sought goal of treating blood diseases prenatally.

While cautioning that much work must be done to understand how these animal
findings apply to humans, the current findings are "surprising but
reassuring," said study leader Alan W. Flake, M.D., of the Children's Center
for Clinical Research at The Children's Hospital of Philadelphia.

The study appeared online August 3 in the Journal of Clinical Investigation.

For over 50 years, explained Flake, it has been a fundamental precept of
immunology that a fetus tolerates foreign antigens in a window-of-opportunity
period before its immune system fully develops the capacity to mount an immune
response. Scientists assumed that by carefully introducing donor cells and
stimulating a fetus to develop tolerance to those cells, one could set the
stage for a later organ or cellular transplant that would not be rejected by a
more mature immune system.

As prenatal diagnosis has continued to become available for a greater number
of congenital diseases, scientists have considered the possibility of
correcting blood disorders such as sickle cell disease or thalassemia. After
first transplanting a small number of healthy cells in an early-stage fetus to
establish tolerance, a second dose of transplanted cells later in gestation
would proliferate, and treat the blood disorder before birth. Researchers use
hematopoietic cells -- stem cells that that develop into blood cells -- in
this technique, in utero hematopoietic cell transplantation (IUHCT).

However, over the years, Flake's team and other research groups found that
IUHCT studies in animal models yielded inconsistent results, ranging from no
tolerance to transplants to full tolerance and every degree of tolerance in
between. Contrary to the concept of fetal tolerance, an immune barrier seemed
to be acting against transplanted cells.

The current study, done in mice, solves the puzzle of an apparent immune
barrier. Newborn mice (pups) that received cell transplants in utero were
divided into two groups. Mice nursed by their biological mothers lost the
transplanted donor cells, while mice nursed by foster mothers retained those
donor cells.

The mothers whose fetuses received the donor cells transplants had developed
antibodies against those cells, and subsequently transmitted those antibodies
to their pups through breast milk. "Those antibodies in the breast milk
triggered rejection of the transplanted blood cells in the pups," said Flake.
"But in the absence of a maternal immune response, we confirmed that immune
tolerance does occur in the early-gestation fetus 100 percent of the time."

Of course, mouse biology is not the same as human biology, and Flake added,
"Mouse time is not the same as human time." Because mice have such a brief
gestational period, the mother's immune response didn't develop until after
the birth of her pups, and was therefore transferred by breastfeeding. In
large animals and humans, said Flake, the more likely route of
maternal-to-fetal transmission would be through the placenta late in
pregnancy, and not through postnatal breastfeeding.

However, it remains an open question whether the mouse findings are applicable
to larger mammals and especially to humans. Flake's study team is continuing
their investigations in larger animal models.

Looking forward to techniques to avoid maternal immune reactions to prenatal
cell transplants, Flake proposed two possibilities. One would be use the
mother as a source of donor cells, which would not stimulate an unwanted
immune response. Another strategy could involve inducing the generation of
increased numbers of T regulatory cells; those cells normally act to prevent
the fetus from inappropriately reacting against maternal cells.

The ultimate goal, said Flake, is to develop IUHCT as a prenatal treatment for
any congenital blood disorder that may currently be treated with postnatal
bone marrow transplants. That would include sickle cell disease, thalassemia,
and some inherited immunodeficiency diseases. Currently such postnatal
transplants are risky and relatively rare.

"Our current finding is not a clinical breakthrough," added Flake. "But it
does offer new potential to the field of cellular transplantation."

Funds from the National Institutes of Health, the Ruth and Tristram C. Colket
Jr. Chair of Pediatric Surgery at The Children's Hospital of Philadelphia and
the Albert M. Greenfield Foundation supported this study.

About The Children's Hospital of Philadelphia: The Children's Hospital of
Philadelphia was founded in 1855 as the nation's first pediatric hospital.
Through its long-standing commitment to providing exceptional patient care,
training new generations of pediatric healthcare professionals and pioneering
major research initiatives, Children's Hospital has fostered many discoveries
that have benefited children worldwide. Its pediatric research program is
among the largest in the country, ranking second in National Institutes of
Health funding. In addition, its unique family-centered care and public
service programs have brought the 430-bed hospital recognition as a leading
advocate for children and adolescents. For more information, visit
http://www.chop.edu.

SOURCE The Children's Hospital of Philadelphia

Rachel Salis-Silverman of The Children's Hospital of Philadelphia,
+1-267-426-6063, Salis@email.chop.edu