Immune response to human embryonic stem cells in mice suggests human therapy may face challenge

August 18, 2008

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," said Joseph Wu, MD, PhD, assistant professor of 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."
-end-
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 Study and Research Grant. 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.stanford.edu.

PRINT MEDIA CONTACT: Krista Conger at (650) 725-5371 (kristac@stanford.edu)

BROADCAST MEDIA CONTACT: M.A. Malone at (650) 723-6912 (mamalone@stanford.edu)

Stanford University Medical Center

Related Stem Cells Articles from Brightsurf:

SUTD researchers create heart cells from stem cells using 3D printing
SUTD researchers 3D printed a micro-scaled physical device to demonstrate a new level of control in the directed differentiation of stem cells, enhancing the production of cardiomyocytes.

More selective elimination of leukemia stem cells and blood stem cells
Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia.

Computer simulations visualize how DNA is recognized to convert cells into stem cells
Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.

First events in stem cells becoming specialized cells needed for organ development
Cell biologists at the University of Toronto shed light on the very first step stem cells go through to turn into the specialized cells that make up organs.

Surprising research result: All immature cells can develop into stem cells
New sensational study conducted at the University of Copenhagen disproves traditional knowledge of stem cell development.

The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.

Healthy blood stem cells have as many DNA mutations as leukemic cells
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ.

New method grows brain cells from stem cells quickly and efficiently
Researchers at Lund University in Sweden have developed a faster method to generate functional brain cells, called astrocytes, from embryonic stem cells.

NUS researchers confine mature cells to turn them into stem cells
Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute at the National University of Singapore and the FIRC Institute of Molecular Oncology in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification -- by confining them to a defined geometric space for an extended period of time.

Researchers develop a new method for turning skin cells into pluripotent stem cells
Researchers at the University of Helsinki, Finland, and Karolinska Institutet, Sweden, have for the first time succeeded in converting human skin cells into pluripotent stem cells by activating the cell's own genes.

Read More: Stem Cells News and Stem Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.