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Impact of brain injury, stroke and MS reduced in mice by scientists at Babraham Institute and KU Leuven



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Scientists have shown they can reduce the impact of brain injury, stroke and multiple sclerosis in mice using a targeted therapeutic treatment that they hope could soon enter human clinical trials.

After what they described as a “eureka moment”, they were able to restrict brain inflammation and prevent the death of brain tissue, enabling the mice to perform better in cognitive tests.

Prof Adrian Liston, of the Babraham Institute
Prof Adrian Liston, of the Babraham Institute

It was achieved by increasing the number of regulatory T cells - which mediate the immune system’s anti-inflammatory response - in the brain.

The research was a collaboration between Prof Adrian Liston, of the Babraham Institute, and Prof Matthew Holt, of the VIB-KU Leuven Centre for Brain and Disease Research in Belgium and i3S at the Univeristy of Porto.

Prof Liston, a senior group leader in the Babraham Institute’s immunology programme, said: “Our bodies have their own anti-inflammatory response, regulatory T cells, which have the ability to sense inflammation and 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 the inflammation following an injury.

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

The top image shows an untreated mouse brain after a controlled impact, the site of damage can be seen by the dark circular impact site. The bottom brain is from a treated mouse 14 days after the impact, the absence of a visible impact site shows the success of the treatment in preventing brain tissue loss. Image: Babraham Institute
The top image shows an untreated mouse brain after a controlled impact, the site of damage can be seen by the dark circular impact site. The bottom brain is from a treated mouse 14 days after the impact, the absence of a visible impact site shows the success of the treatment in preventing brain tissue loss. Image: Babraham Institute

Such brain injuries, caused for example by car accidents or falls, are a significant cause of death and can lead to long-term cognitive impairment and dementia in those who survive.

Key to the cognitive impact is the inflammatory response to the injury, which can lead to swelling of the brain, causing permanent damage.

The challenge in addressing this with drugs in the way it would be treated elsewhere in the body is that the blood-brain barrier prevents common anti-inflammatory molecules from reaching the site of trauma.

The researchers found regulatory T cell numbers were low in the brain due to the limited supply of a critical survival molecule called interleukin 2, or IL2.

These immunofluorescence staining images show how the treatment has reduced the amount of damage after traumatic brain injury when mice were pre-treated with the IL2 treatment. The top layer of brain tissue is visibly thicker in the bottom right image compared to top right. Each row shows the uninjured brain hemisphere (left) and the injured hemisphere (right). The top row shows an untreated brain while the bottom row shows a treated brain, with less damage occurring in the injured hemisphere. Image: Babraham Institute
These immunofluorescence staining images show how the treatment has reduced the amount of damage after traumatic brain injury when mice were pre-treated with the IL2 treatment. The top layer of brain tissue is visibly thicker in the bottom right image compared to top right. Each row shows the uninjured brain hemisphere (left) and the injured hemisphere (right). The top row shows an untreated brain while the bottom row shows a treated brain, with less damage occurring in the injured hemisphere. Image: Babraham Institute

Levels of this are lower in the brain because it cannot pass the blood-brain barrier.

But the team designed a new approach that allows more IL2 to be made by brain cells.

This created the conditions needed by regulatory T cells to survive.

They deployed a gene delivery system, based on an engineered adeno-associated viral vector (AAV). This system is able to cross an intact blood brain barrier and deliver the DNA needed for the brain to increase its IL2 production, up to levels normally seen in blood.

Prof Holt, who studied for his PhD at the MRC Laboratory of Molecular Biology in Cambridge, said: ”For years, the blood-brain barrier has seemed like an insurmountable hurdle to the efficient delivery of biologics to the brain.

“Our work, using the latest in 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 actually prove to be therapeutically beneficial, serving to prevent ‘leak’ of therapeutics into the rest of the body.”

The result was a tenfold increase in the number of regulatory T cells in the brain than usual.

Mice were given carefully controlled brain impact and treated with the IL-2 gene delivery system to test the treatment’s efficacy.

It reduced the amount of brain damage, with less brain tissue lost, and the mice performed better in cognitive tests.

Dr Lidia Yshii, associate professor at KU Leuven
Dr Lidia Yshii, associate professor at KU Leuven

Dr Lidia Yshii, associate professor at KU Leuven and lead author of the research paper published in Nature Immunology, 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 injury lesion.”

The researchers then tested the approach in experimental mouse models of multiple sclerosis (MS) and stroke.

Treating mice during early symptoms of MS prevented severe paralysis and allowed the mice to recover faster.

Prof Liston explained: “In a model of stroke, mice treated with the IL2 gene delivery system after a primary stroke were partially protected from secondary strokes occurring two weeks later. In a follow-up study, still undergoing peer review, the research team also demonstrated that the treatment was effective at preventing cognitive decline in ageing mice.

“By understanding and manipulating the immune response in the brain, we were able to develop a gene delivery system for IL-2 as a potential treatment for neuroinflammation.

A magnetic resonance imaging (MRI) scan of the brains of two mice after a controlled impact to create a traumatic brain injury. The arrow shows there the impact was made, the grey area below the arrow shows the size of the lesion. The amount of brain swelling is visibly reduced in the brain of the treated mouse (bottom). Image: Babraham Institute
A magnetic resonance imaging (MRI) scan of the brains of two mice after a controlled impact to create a traumatic brain injury. The arrow shows there the impact was made, the grey area below the arrow shows the size of the lesion. The amount of brain swelling is visibly reduced in the brain of the treated mouse (bottom). Image: Babraham Institute

“With tens of millions of people affected every year, and few treatment options, this has real potential to help people in need. We hope that this system will soon enter clinical trials, essential to test whether the treatment also works in patients.”

Dr Ed Needham, a neurocritical care consultant at Addenbrooke’s Hospital who was not a part of the study, said the results were encouraging.

“There is an urgent clinical need to develop treatments which can prevent secondary injury that occurs after a traumatic brain injury,” he said.

“Importantly, these treatments have to be safe for use in critically unwell patients who are at high risk of life-threatening infections.

“Current anti-inflammatory drugs act on the whole immune system, and may therefore increase patients' susceptibility to such infections.

“The exciting progress in this study is that, not only can the treatment successfully reduce the brain damage caused by inflammation, but it can do so without affecting the rest of the body's immune system, thereby preserving the natural defences needed to survive critical illness.”



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