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Transplanted Brain Stem Cells Survive in Mice Without Anti-rejection Drugs

Johns Hopkins Medicine researchers say that in experiments with mice, they have developed a method to successfully transplant specific protective brain cells without the need for a lifetime of anti-rejection drugs.

A report on their research was published in the journal Brain on Sept. 16 and describes the new approach which selectively escapes the immune response against foreign cells, permitting transplanted cells to survive, thrive and protect brain tissue long after discontinuing immune-suppressing drugs.

This ability to effectively transplant healthy cells into the brain without the necessity for conventional anti-rejection drugs could promote the search for treatments that help children born with a rare but devastating type of genetic diseases in which the protective coating myelin around neurons that helps them transmit messages, does not form normally. About 1 of every 100,000 children born in the U.S. are estimated to have one of these diseases like Pelizaeus-Merzbacher disease. This syndrome is characterized by infants missing developmental milestones like sitting and walking, experiencing involuntary muscle spasms, and potentially suffering partial paralysis of the arms and legs, all due to a genetic mutation in the genes that generate myelin.

Piotr Walczak, M.D., Ph.D., associate professor of radiology and radiological science at the Johns Hopkins University School of Medicine, says, “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”.

The mammalian immune system is a major obstacle to our ability to replace these defective cells. It works by rapidly identifying ‘self’ or ‘nonself’ tissues and attacking to destroy nonself or “foreign” trespassers. Even though this is beneficial when targeting bacteria or viruses, it poses a major hurdle for transplanted organs, tissue or cells, which also get flagged for destruction. Traditional anti-rejection drugs that largely and unspecifically tamp down the immune system in total frequently help fend off tissue rejection but leave patients defenseless to infection and other side effects. Patients end up needing these drugs indefinitely.

In an attempt to stop the immune response without any side effects, the Johns Hopkins Medicine team pursued ways to manipulate T cells, the system’s elite infection-fighting force that fights foreign invaders.

Walczak and his team specifically focused on the series of purported “costimulatory signals” that T cells must encounter to begin an attack.

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, explains “These signals are in place to help ensure these immune system cells do not go rogue, attacking the body’s own healthy tissues. The idea was to exploit the natural tendencies of these costimulatory signals as a means of training the immune system to eventually accept transplanted cells as ‘self’ permanently”.

To do this, the investigators used two specific antibodies, CTLA4-Ig and anti-CD154, which stop T cells from beginning an attack whenever they encounter foreign particles by binding to the T cell surface to basically block the ‘go’ signal. Walczak says this combination has formerly been used successfully to block rejection of solid organ transplants in animals but had yet not been tested for cell transplants to repair myelin in the brain.

In a vital series of experiments, Walczak and his team injected brains of test mice with the protective glial cells that form the myelin sheath that surrounds neurons. These precise cells were genetically engineered to glow so the researchers could track them. They then transplanted the glial cells into three types of mice: first were the genetically engineered mice who could not form the glial cells that create the myelin sheath, second was normal mice and third were mice that were bred to be incapable of mounting an immune response.

Now the researchers used the antibodies to block an immune response and stopped treatment after six days. Every day, the researchers tracked the glowing cells with a specialized camera that could detect them and captured pictures of the mouse brains searching for the relative presence or absence of the transplanted glial cells. Cells transplanted into the control mice that did not get the antibody treatment immediately began to die off with their glow becoming undetectable by the camera by day 21. The mice that got the antibody treatment upheld significant levels of transplanted glial cells for more than 203 days, showing that they were not destroyed by the mouse’s T cells even in the absence of treatment.

Shen Li, M.D., lead author of the study, said, “The fact that any glow remained showed us that cells had survived transplantation, even long after stopping the treatment. We interpret this result as a success in selectively blocking the immune system’s T cells from killing the transplanted cells.”

The ensuing step was to check whether the transplanted glial cells survived adequately enough to function normally in the brain and create the myelin sheath. For this check, the researchers investigated for key structural differences between mouse brains having thriving glial cells and those without via MRI images. These images showed that the cells in the treated mice were indeed populating the proper parts of the brain.

Their results thus confirmed that in mice, the transplanted cells were able to thrive and undertake their normal function of protecting neurons in the brain. Walczak noted that these results are preliminary as the team was able to deliver these cells and let them to thrive in a very localized portion of the mouse brain. In the coming days, they intend to combine their findings with research on cell delivery methods to the brain to help repair the brain on a larger scale.

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