Through experiments using mice, researchers have developed a method to successfully transplant a particular kind of protective brain cells without the use for life long anti-rejection drugs. The team at Johns Hopkins Medicine, have selectively circumvented the immune response against foreign cells which allows for transplanted cells to survive and even thrive and protect brain tissue after immune suppressing drugs have been discontinued.
A significant obstacle to the ability to replace brain cells is the mammalian immune system. The immune systems works by quickly identifying non self or self tissues and then mounting attacks to destroy foreign or non self invaders. This is beneficial when targeting viruses and bacteria, however it is a significant hurdle for transplanted organs, tissues or cells which are also flagged for destruction.
Traditional anti rejection medications that unspecifically and broadly tamp down the immune system at once frequently work to fend off tissue rejection. This leaves the patient vulnerable to infection and a variety of other side effects. Patients need to continue with these drugs indefinitely.
The Johns Hopkins Medicine team sought out ways to manipulate T cells which are the immune system’s elite infection fighting force that goes after foreign invaders. Specifically, they focused on a series of so called costimulatory signals that T cells must encounter in order to start an attack.
These particular signals are in place to help ensure the immune system cells don’t go rogue by attacking the body’s own healthy tissues. The idea is to exploit the normal tendencies of these signals as a means of training the immune system to eventually accept transplanted cells as self permanently.
To accomplish this, the team used two antibodies, CTLA4-lf and anti-CD154 which keep T cells from initiating an attack when they encounter foreign particles by binding to the surface of the T cell which essentially blocks the go signal. This particular combination was previously used successfully to block the rejection of solid organ transplants in animals, however had not been tested for cell transplants to repair the myelin in the brain.
In a significant set of experiments, the team injected the brains of mice with the protection glial cells which produce the myelin sheath that surrounds neurons. These very specific cells were genetically engineered to glow so that the team could keep track of them.
The glial cells were transplanted into three mice types. This included mice that were genetically engineered to not form the glial cells which create the myelin sheath, normal mice and mice that were bred to be able to mount a response of the immune system. They used the antibodies to block an immune response, concluding treatment after six days.
Each day the team used a specialized camera that could detect the glowing cells and capture pictures of the mice brains. They were particularly looking for the relative absence or presence of the transplanted glial cells. Cells that had been transplanted in the control mice that had not received the antibody treatment immediately started to die off. Their glow was no longer seen by the camera by day 21.
The mice which had received the antibody treatment were able to maintain significant levels of the transplanted glial cells for more than 203 days. This indicated they were not killed by the mouse’s T cells even in treatment absence.
The fact that any glow had remained showed the team that cells had survived the transplantation even long after stopping the treatment. This was interpreted as a success in selectively blocking the immune system’s T cells from killing the cells that had been transplanted.
The next step for the team was to see whether the transplanted glial cells would survive well enough to do what glial cells typically do in the brain which is create the myelin sheath. To accomplish this, the team looked for key structural differences between the mouse brains which contained thriving glial cells and those without using MRI imaging. The team discovered in the images the cells in the treatment mice were indeed populating the appropriate portions of the brain.
The results confirmed that the cells that had been transplanted had the ability to thrive and assume their normal function which is to protect the brain neurons. The results are preliminary, however the team was able to deliver these cells and allow them to thrive in a localized part of the mice brains.
For the future, the teams hopes to combine their findings with additional studies on cell delivery methods to the brain to help in repairing the brain on a more global scale.
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