Immune response to human embryonic stem cells in mice suggests human
therapy may face challenge
STANFORD, Calif. - Human embryonic stem cells trigger an immune
response in mice, researchers from the Stanford University School of
Medicine report. The finding suggests that the effectiveness of human
therapies derived from the cells could be limited unless ways are
found to dampen the rejection response.
The researchers found the immune response in mice could be mitigated
by the use of common antirejection medications. Overall, the work
indicated that, contrary to previous suggestions, the immune system
is not blind to the presence of foreign embryonic stem cells.
"It's getting harder and harder to believe that these cells are
immunoprivileged,
cardiovascular medicine and of radiology. "In fact, the rejection of
these cells confirms our suspicions that they do cause an immune
response."
Embryonic stem cells form all cells in an embryo. Many researchers
have suggested that these cells may receive a kind of "free pass"
from the normally vigilant immune system in order to allow the growth
of a fetus that contains both maternal and paternal genetic material.
Such an immunological exemption could alleviate many concerns about
using cells for therapy that don't exactly match the recipient's
immune system - such as existing embryonic stem cell lines that are
not directly derived from the recipient.
"We all want to know what's going to happen if you transplant these
stem cells into a person," said Mark Davis, MD, PhD, the Burt and
Marion Avery Family Professor and professor of microbiology and
immunology. But because unmodified embryonic stem cells can cause
cancer, the researchers transplanted the cells into mice rather than
people.
Davis, who is also an investigator for the Howard Hughes Medical
Institute, is a co-author of the paper, which will be published Aug.
18 in the online early edition of the Proceedings of the National
Academy of Sciences. Wu is the senior author of the research.
Wu, Davis and their colleagues injected human embryonic stem cells
into the leg muscles of mice with either normal or compromised immune
systems. They followed the fate of the transplanted cells with a
novel molecular imaging technique that can visualize whole, living
animals. Previous studies of this type relied on microscopic
examination of tissue samples from sacrificed animals, but this new
approach allows researchers to watch the life or death of cells in
real time.
Although the cells died within about seven to 10 days in mice with
functioning immune systems, they survived and proliferated in the
immunocompromised mice. Repeated injections of cells into the immune-
normal mice led to more rapid cell death, indicating that the immune
system was becoming more efficient at recognizing and rejecting the
cells.
"The data is quite convincing," said Wu. "Based on these results, we
believe that transplanting these cells into humans would also cause
an immune response."
It's not known what triggers the immune system to attack the
embryonic stem cells, but the scientists believe it may be a protein
that begins to appear on the surface of the cells as they
differentiate into more-specialized tissues. Once the immune system
has been primed to recognize the foreign molecules, it responds even
more quickly to repeated invasion.
"That's the beauty of this kind of noninvasive imaging system," said
Wu. "It allows us to assess the response of one animal to a variety
of conditions and gives us much more valuable information.
Because the aggressive reaction of the immune system somewhat mimics
the way the body reacts to transplanted organs, the researchers
wondered if common antirejection medications would increase cell
survival. They found that a combination of two compounds - tacrolimus
and sirolimus - allowed the cells to survive for up to 28 days in the
mice with normal immune systems.
Wu and his colleagues will continue to investigate whether different
combinations can more effectively mitigate the immune response in
mice. They also plan to conduct similar experiments in a mouse model
that more closely approximates what would happen in humans.
"A lot of research efforts are devoted to the basic science of stem
cells," said Davis. "This work is focused on the immediate
practicalities of actually using these cells therapeutically.
###
Other Stanford authors include postdoctoral scholars Rutger-Jan
Swijnenburg, MD; Johannes Govaert, MD; Feng Cao, MD, PhD, and Ahmad
Sheikh, MD; as well as Sonja Schrepfer, MD, PhD, clinical instructor
of cardiothoracic surgery; Katie Ransohoff, undergraduate; Andrew
Connolly, MD, PhD, associate professor of pathology, and Robert
Robbins, MD, professor and chair of cardiothoracic surgery.
The work was supported by the National Institutes of Health, the
Burroughs Wellcome Foundation, the California Institute of
Regenerative Medicine, the Howard Hughes Medical Institute, the
International Society for Heart & Lung Transplantation and a European
Society for Organ Transplantation-
Astellas Pharma US, Inc. manufactures tacrolimis, which was used in
this study.
Stanford University Medical Center integrates research, medical
education and patient care at its three institutions - Stanford
University School of Medicine, Stanford Hospital & Clinics and Lucile
Packard Children's Hospital at Stanford. For more information, please
visit the Web site of the medical center's Office of Communication &
Public Affairs at http://mednews.
PRINT MEDIA CONTACT: Krista Conger at (650) 725-5371
(kristac@stanford.
BROADCAST MEDIA CONTACT: M.A. Malone at (650) 723-6912
(mamalone@stanford.
Public release date: 18-Aug-2008
Contact: Krista Conger
kristac@stanford.
650-725-5371
Stanford University Medical Center
http://www.eurekale
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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