Johns Hopkins Medicine research may have developed a way to transplant certain protective brain cells without the need for lifelong anti-rejection drugs, as published in the journal Brain; the approach selectively circumvents responses from the immune system against foreign cells to allow the transplanted cells to survive and thrive to protect brain tissues long after stopping immunosuppressive drugs.
“Because these conditions are initiated by a mutation causing dysfunction in one type of cell, they present a good target for cell therapies, which involve transplanting healthy cells or cells engineered to not have a condition to take over for the diseased, damaged or missing cells,” says Piotr Walczak, M.D., Ph.D., associate professor of radiology and radiological science at the Johns Hopkins University School of Medicine.
The researchers are working on developing ways to stop the immune system responses without side effects, and investigated ways to manipulate T cells which are the immune system’s infection fighting force that attack foreign invaders, specifically focussing on a series of costimulatory signals that T cells must encounter in order to begin attack.
“These signals are in place to help ensure these immune system cells do not go rogue, attacking the body’s own healthy tissues,” says Gerald Brandacher, M.D., professor of plastic and reconstructive surgery and scientific director of the Vascularized Composite Allotransplantation Research Laboratory at the Johns Hopkins University School of Medicine and co-author of this study.
To exploit natural tendencies of these costimulatory signals that train the immune system to accept the transplanted cells as being part of self the researchers used CTLA4-lg and anti-CD154 antibodies to keep the T cells from beginning an attack by blocking signals.
Protective glial cells that produce myelin sheath that surrounds neurons that were genetically engineered to glow were injected into mice brains so they could be studied. Glial cells were transplanted into three types of mice: those engineered to not for glial cells that create myelin sheath; normal mice; and those engineered not to be able to mount an immune response.
Antibodies were used to block an immune response, stopping treatment after six days, and specialized cameras were used to detect the glowing cells and pictures of the mice brains to look for the presence or absence of the transplanted cells. Cells transplanted into control mice without antibody treatment began to die off immediately and was no longer detected after 21 days; while those receiving antibody treatment maintained significant levels of transplanted cells for over 203 days even in the absence of treatment.
“The fact that any glow remained showed us that cells had survived transplantation, even long after stopping the treatment,” says Shen Li, M.D., lead author of the study. “We interpret this result as a success in selectively blocking the immune system’s T cells from killing the transplanted cells.”
To see whether the transplanted glial cells survived well enough to create the myelin sheath key structural differences were looked at between mice brains with and without thriving glial cells using MRI imaging; cells in the treated animals were found to be populating the appropriate parts of the brain. Results confirm the transplanted cells were able to thrive and assume normal function to protect neurons.
Although results are preliminary the cells were delivered to thrive in a localized portion of the mouse brain. Researchers hope to combine findings with studies on cell delivery methods to the brain in the future to help repair the brain more globally.
