A therapeutic method of using the body’s immune system to protect against brain damage is published today by researchers from the Babraham Institute’s immunology research program. A collaboration between Professor Adrian Liston (Babraham Institute) and Professor Matthew Holt (VIB and KU Leuven; i3S-University of Porto) has created a targeted delivery system to increase the number of specialized anti-inflammatory immune cells in the brain to limit brain function. inflammation and damage. Their specific system of delivery to the brain protected against brain cell death after brain injury, stroke and in the multiple sclerosis model. The study is published today in the Journal Nature immunology.
Traumatic brain injury, similar to trauma during a car accident or fall, is a significant cause of death worldwide and can cause long-term cognitive impairment and dementia in survivors. The main cause of this cognitive impairment is an inflammatory response to trauma in which cerebral edema causes irreversible damage. While inflammation in other parts of the body can be eliminated therapeutically, but in the brain it is problematic due to the presence of a blood-brain barrier that prevents common anti-inflammatory molecules from reaching the site of injury.
Professor Listan, senior head of the Babraham Institute’s immunology team, explained their approach: “Our body has its own anti-inflammatory response, regulatory T cells that have the ability to feel inflammation and make a cocktail of natural anti-inflammatory drugs. Unfortunately, there are very few such regulatory T cells in the brain, so they are affected by inflammation after injury. We sought to develop a new therapeutic tool to increase the number of regulatory T cells in the brain so that they could manage inflammation and reduce the damage caused by traumatic injuries. ”
The research team found that the number of regulatory T cells in the brain was low due to limited supply of the essential to survival molecule interleukin 2, also known as IL2. The level of IL2 in the brain is low compared to the rest of the body because it cannot cross the blood-brain barrier.
Together, the team has developed a new therapeutic approach that allows brain cells to produce more IL2, thereby creating the conditions necessary for regulatory T cells to survive. A “gene delivery” system based on the engineered adeno-associated viral vector (AAV) has been used: this system can actually cross the intact blood-brain barrier and deliver the DNA needed for the brain to produce more IL2.
Commenting on the work, Professor Holt of VIB and KU Leuven said: “Over the years the blood-brain barrier has seemed an insurmountable barrier to efficient delivery of biologics to the brain. Our work using the latest viral vector technology proves this to be no longer the case; that under certain circumstances the blood-brain barrier may be therapeutically useful to prevent “leakage” of therapeutic agents to the rest of the body ”.
A new therapeutic tool developed by research teams has been able to increase the level of IL2 survival molecule in the brain to the same level in the blood. This allowed the accumulation in the brain of regulatory T-cells, which is 10 times higher than normal. To test the effectiveness of treatment in a mouse model that is very reminiscent of a traumatic brain injury, the mice received carefully controlled strokes and then treated with the IL-2 gene delivery system. The researchers found that the treatment was effective in reducing the amount of brain damage after injury, assessed by comparing brain tissue loss and the ability of mice to work in cognitive tests.
The lead author, Dr. Lydia Ishi, an associate professor at KU Leuven, explained: “Seeing the brains of mice after the first experiment was a ‘eureka moment’ – we immediately saw that the treatment reduced the size of the injury.”
Recognizing the broader potential of a drug capable of controlling brain inflammation, the researchers also tested the effectiveness of the approach on experimental mouse models of multiple sclerosis and stroke. In the multiple sclerosis model, treating mice during early symptoms prevented severe paralysis and allowed mice to recover faster. In the stroke model, mice receiving the IL2 gene delivery system after the primary stroke were partially protected from secondary strokes that occurred two weeks later. In a subsequent study that is still undergoing peer review, the research team also demonstrated that the treatment was effective in preventing cognitive decline in aging mice.
By understanding and manipulating the immune response in the brain, we have been able to develop a gene delivery system for IL2 as a potential treatment for neuroinflammation. Tens of millions of people suffer each year and several treatment options have real potential to help people in need. the system will soon begin the clinical trials needed to test whether the treatment is effective in patients as well. ” Said Professor Liszt.
Dr Ed Needham, a neurocritical consultant at Addenbrook Hospital who was not involved in the study, commented on the clinical significance of these results: “There is an urgent clinical need to develop treatments that can prevent secondary damage that occurs after brain injury. that these treatments should be safe for use in critically ill patients who are at high risk of life-threatening infections.Modern anti-inflammatory drugs act on the entire immune system and thus may increase patients’ susceptibility to such infections. this study is that treatment can not only successfully reduce brain damage caused by inflammation, but it can do so without affecting the rest of the body’s immune system, thereby maintaining the natural defenses needed to survive a serious illness. ”