If healthy cells are harvested from a patient and introduced into another individual as a therapy to replace diseased or damaged cells, an immune response will be triggered. White blood cells called T-cells recognize the cells as foreign and attack them. In order for such a therapy to work, anti-rejection drugs must be taken to suppress the immune response.
For instance, Pelizaeus-Merzbacher disease is a type of leukodystrophy, a hereditary disorder affecting the central nervous system in which there is a lack of myelin, the fatty substance that surrounds nerve fibers and promotes the rapid transmission of nerve impulses. Without sufficient levels of myelin, patients experience reduced neurological function. The condition affects around 1 in 100,000 children in the United States and causes involuntary muscle spasms, difficulty sitting and walking, and partial paralysis of the arms and legs. The disease is caused by a single mutation in the gene responsible for producing myelin.
Glial cells are responsible for producing myelin. By replacing these defective or missing glial cells, myelin will start to be produced; however, replacing those glial cells will trigger an immune response. T cells will attack the foreign cells when they are introduced so immunosuppressive drugs would need to be administered for life.
The problem with immunosuppressive drugs is while they will prevent introduced cells from being attacked, the drugs are not specific. That means patients’ immune systems will not be effective at killing bacterial and viral invaders, leaving patients at risk of potentially life-threatening infections.
Researchers at Johns Hopkins University have shown that treatment of Pelizaeus-Merzbacher disease through the introduction of healthy and functional glial cells may not require the use of immunosuppressive drugs.
The key to this technique is tricking the T-cells into thinking the introduced cells are native to the patient. The researchers studied the costimulatory signals required by T-cells to trigger an attack.
There are two signals required to activate T-cells. The first is an antigen-specific signal where the T-cell antigen receptor interacts with molecules on the membrane of antigen presenting cells (APCs). The second is an antigen nonspecific signal provided by interactions between co-stimulatory molecules on the membranes of APC and T-cells.
“These signals are in place to help ensure these immune system cells do not go rogue, attacking the body’s own healthy tissues,” explained Gerald Brandacher, professor of plastic and reconstructive surgery, scientific director of the Vascularized Composite Allotransplantation Research Laboratory at the Johns Hopkins School of Medicine.
By using these costimulatory signals, the researchers could train the immune system to accept transplanted cells, without the need for anti-rejection drugs.
Two antibodies were used – CTLA4-Ig and anti-CD154 –to prevent the T-cells from launching an attack against foreign glial cells by binding to the surface of the T-cells. This prevents the T-cells from commencing an attack. This technique has previously been used in organ transplantation, but never for cell transplants to repair myelin in the brain.
Healthy glial cells from one mouse were implanted into the brains of three types of mice: A mouse model that lacked the ability to produce glial cells, mice without a functional immune system, and normal mice. The antibodies were introduced to prevent an immune response and the treatment was stopped six days following transplantation. The introduced glial cells were identified with fluorescent markers to enable them to be tracked.
In normal mice, the introduced glial cells were killed off by the immune system and could not be detected after 21 days. Following the antibody treatment, the glial cells survived more than 203 days, demonstrating they were not killed off by the immune system. The researchers then used MRI scans to show the glial cells were populating appropriate areas of the brain and were producing myelin to protect neurons in the brain, as if the cells were native to those mice.
The study is detailed in the paper – Induction of immunological tolerance to myelinogenic glial-restricted progenitor allografts – which was recently published in the journal Brain. DOI: 10.1093/brain/awz275