Harnessing the Immune System to Treat Traumatic Brain Injury

Summary: A new mouse study identifies a targeted delivery method system that increases the number of specialized anti-inflammatory immune cells in the brain in areas restricted by inflammation and brain damage. The system has helped protect against apoptosis associated with brain injury, stroke, and multiple sclerosis.

Source: Babraham Institute

A therapeutic method to harness the body’s immune system to protect against brain damage is published today by researchers from the Babraham Institute’s Immunology Research Program.

The collaboration between Prof. Adrian Liston (Babraham Institute) and Prof. Matthew Holt (VIB and KU Leuven; i3S-University of Porto) has produced a targeted delivery system to increase the number of anti-inflammatory immune cells specialized specifically in the brain to limit inflammation and damage.

Their brain-specific delivery system protected against brain cell death following brain injury, stroke, and in a model of multiple sclerosis.

The research is published today in the journal Natural immunology.

Traumatic brain injuries, such as those caused in a car crash or fall, are a leading cause of death worldwide and can lead to long-lasting cognitive impairment and dementia in those who survive.

One of the main causes of this cognitive impairment is the inflammatory response to injury, with swelling of the brain causing permanent damage.

While inflammation in other parts of the body can be treated therapeutically, but in the brain it is problematic due to the presence of the blood-brain barrier, which prevents common anti-inflammatory molecules from reaching the site. of the trauma.

Professor Liston, Senior Group Leader of the Babraham Institute’s Immunology Program, explained their approach: “Our body has its own anti-inflammatory response, regulatory T cells, which have the ability to sense inflammation and to produce a cocktail of natural anti-inflammatories. . Unfortunately, there are very few of these regulatory T cells in the brain, so they are overwhelmed by inflammation following injury.

“We sought to design a new therapeutic to stimulate the population of regulatory T cells in the brain, so that they can manage inflammation and reduce the damage caused by traumatic injury.”

The research team found that the number of regulatory T cells was low in the brain due to a limited supply of the crucial survival molecule interleukin 2, also known as IL2. IL2 levels are low in the brain compared to the rest of the body because it cannot pass the blood-brain barrier.

Together, the team designed a new therapeutic approach that allows brain cells to manufacture more IL2, thereby creating the conditions necessary for the survival of regulatory T cells. An adeno-associated virus (AAV) vector-based ‘gene delivery’ system was used: this system can actually cross an intact blood-brain barrier and deliver the necessary DNA to the brain to produce more IL2.

Commenting on the work, Professor Holt, from VIB and KU Leuven, says that “For years, the blood-brain barrier seemed to be an insurmountable obstacle to the effective delivery of biologicals to the brain.

“Our work, using the latest viral vector technology, proves that this is no longer the case; in fact, it is possible that under certain circumstances the blood-brain barrier may prove therapeutically beneficial, serving to prevent the “leakage” of therapeutics into the rest of the body.

The new therapy designed by the research teams was able to increase levels of the survival molecule IL2 in the brain, up to the same levels found in the blood. This allowed the number of regulatory T cells to accumulate in the brain, up to 10 times higher than normal.

To test the efficacy of the treatment in a mouse model that closely resembles traumatic brain injury accidents, the mice were given carefully controlled brain impacts and then treated with the IL-2 gene delivery system.

The scientists found that the treatment was effective in reducing the amount of brain damage following the injury, assessed by comparing both the loss of brain tissue and the mice’s ability to perform cognitive tests.

Lead author Dr Lidia Yshii, associate professor at KU Leuven, explained: “Seeing the brains of the mice after the first experiment was a ‘eureka moment’ – we could immediately see that the treatment reduced the size of the lesion.”

Recognizing the broader potential for a drug to control brain inflammation, the researchers also tested the effectiveness of the approach in 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 a stroke model, mice treated with the IL2 gene delivery system after a primary stroke were partially protected against secondary strokes occurring two weeks later.

In a follow-up study, still under peer review, the research team also demonstrated that the treatment was effective in preventing cognitive decline in aging mice.

Traumatic brain injuries, such as those caused in a car crash or fall, are a leading cause of death worldwide and can lead to long-lasting cognitive impairment and dementia in those who survive. Image is in public domain

“By understanding and manipulating the immune response in the brain, we were able to develop a gene delivery system for IL2 as a potential treatment for neuroinflammation.

“With tens of millions of people affected each year and few treatment options, this has real potential to help those in need. We hope this system will soon enter clinical trials, which are essential for testing whether the treatment also works in patients,” said Professor Liston.

See also

This shows a diagram of the study

Dr Ed Needham, consultant in neurocritical care at Addenbrooke’s Hospital who was not part of the study, commented on the clinical relevance of these findings: “There is an urgent clinical need to develop treatments that can prevent secondary injuries that occur after trauma. cerebral lesion – brain-damage. Importantly, these treatments must be safe to use in critically ill patients who are at high risk of life-threatening infections.

“Current anti-inflammatories act on the entire immune system and can therefore increase the susceptibility of patients to such infections.

“The exciting advancement of this study is that not only can the treatment successfully reduce brain damage caused by inflammation, but it can do so without affecting the rest of the body’s immune system, thus preserving the natural defenses needed to survive. to a serious illness. ”

About this TBI and immune system research news

Author: Press office
Source: Babraham Institute
Contact: Press Office – Babraham Institute
Picture: Image is in public domain

Original research: Free access.
Astrocyte-targeted interleukin-2 gene delivery specifically increases the number of resident regulatory T cells in the brain and protects against pathological neuroinflammation” by Matthew Holt et al. Natural immunology


Summary

Astrocyte-targeted interleukin-2 gene delivery specifically increases the number of resident regulatory T cells in the brain and protects against pathological neuroinflammation

The ability of immunomodulatory biological agents to prevent and reverse pathology has transformed recent clinical practice. However, full utility in the field of neuroinflammation requires the identification of both effective targets for local immune modulation and a delivery system capable of crossing the blood-brain barrier.

The recent identification and characterization of a small population of T regulators (Tregister) resident in the brain present such a potential therapeutic target.

Here, we identified brain interleukin 2 (IL-2) levels as a limiting factor for brain-resident Tregister cells.

We have developed a gene delivery approach for astrocytes, with a small molecule switch to allow temporal control and enhanced production in responsive astrocytes to spatially direct delivery to inflammatory sites. Mice with brain-specific IL-2 delivery were protected in models of traumatic brain injury, stroke, and multiple sclerosis, with no impact on the peripheral immune system.

These results validate the administration of the brain-specific IL-2 gene as an effective protection against neuroinflammation and provide a versatile platform for the delivery of various biologics to neuroinflammatory patients.