Traumatic brain injury is the leading cause of death and disability of young adults in the developed world.
There is evidence that the body’s immune response to a severe traumatic brain injury compounds the initial damage in some patients, leading to a worse outcome. Professor Menon aims to improve understanding of this immune response, how it might impact on recovery, and how it could be prevented or treated to improve outcomes for patients.
This project is based on extensive pilot data and, following rigorous assessment as part of our competitive grant round, it was recommended for funding on the basis of its strong potential to advance understanding of the role of the immune system in the body's response to traumatic brain injury and how the immune response might be redirected to promote healing.
Traumatic brain injury (TBI) is damage to the brain caused by an external physical force – most commonly the result of an accident, assault or fall.
It is the leading cause of death and disability of young adults in the developed world. On top of the initial, direct injury, subsequent brain swelling in the days after the injury causes further damage to the brain.
Additionally, one in three brain-injured patients develop progressive loss of brain cells over the years following the injury.
Although little except prevention can influence the initial injury, these two secondary phenomena could theoretically be prevented with medication, thereby improving outcomes.
Whilst the underlying causes of these two phenomena are not understood, there is some evidence that the body’s immune system is contributing to both the acute swelling and the long-term brain cell loss.
The immune system is usually responsible for fighting infection and healing damage but, in certain circumstances, it can mistake the body’s own cells for invaders and attack them as if they were an infection. This process is called autoimmunity.
Professor Menon has found evidence that some TBI patients develop antibodies (defensive weapons produced by the immune system) directed against brain cells. In a pilot study, patients who developed these “autoantibodies” appeared to have an outcome that was worse than was predicted using well-recognised factors such as age and depth of coma. This suggests that the autoantibodies might be contributing to brain damage.
The team has also seen that patients treated with an immune-modulating medicine following TBI were less likely to develop autoantibodies, suggesting that the process can be prevented with medicines.
And furthermore, they have found that blood samples from patients who had suffered a TBI six months previously still had autoantibodies to brain cells, raising the possibility that these antibodies could be contributing to the ongoing brain cell loss seen years later.
The team is now carrying out a larger study to look for the development of autoimmunity to brain cells, using blood samples, brain scans and memory tests from a large cohort of TBI patients. They will screen 500 patients for the development of autoantibodies during the first week following severe TBI, and 100 patients who have blood samples and brain scans repeated serially between six months and two years post-injury.
They will see how the development of autoantibodies correlates with early outcome, and whether persistence of autoantibodies correlates with evidence of ongoing brain cell loss. And they will further investigate the underlying mechanisms of autoantibody production, to get a deeper understanding of how to target the immune system with drugs that could prevent the development of autoimmunity and promote its healing role.
The University of Cambridge hosts leading groups in the fields of traumatic brain injury, neurocritical care and neuroinflammation, and Addenbrooke’s Hospital in Cambridge has one of the very few dedicated trauma/ neurocritical care units in the UK. Additionally, Cambridge is one of two co-ordinating centres for the €30 million, 4,500 patient CENTER-TBI study – a pan-European initiative that aims to improve care for patients with TBI, bringing many of the world’s leading TBI experts together in an international and multi-disciplinary effort to revolutionise treatment, and providing crucial access to a large set of samples and data.
This projects brings together Professor David Menon, a world-leader in TBI research, and co-chair of CENTER-TBI; Professor Alasdair Coles, an expert in the mechanisms of autoimmunity in the brain; Dr Edward Needham, who will carry out the immunological laboratory work, and has been instrumental in bringing the research this far; and Dr Virginia Newcombe, an expert in neuro-imaging and TBI.
This outstanding team is ideally positioned to conduct this research, and has a strong track record of previous collaboration.
Traumatic brain injury is the leading cause of death and disability in young adults in the developed world. There is great and inexplicable variability in outcome between individuals with overtly similar injuries and, despite significant advances in technology, it remains difficult to predict outcomes.
Secondary injury compounds the original brain damage and is thought to be a major contributor to this variability in outcome. Professor Menon's research will allow us to understand the variability caused by secondary injury and to clarify the effect of autoimmunity on patient outcome. This research will also help guide the selection of medicines for future clinical trials, with the hope of improving outcomes.
I think the project's strength lies in its exceptionally strong preliminary data, the logical hypothesis and importance of the expected results, which are likely to be directly applicable in treatment of TBI patients, and the superb environment and research team, which is a guarantee of feasibility.
- External reviewer
Acquired brain and spinal cord injury (including stroke) is one of our current research priorities, reflecting the large unmet need in this area. Our aim is to fund research to advance understanding of how to promote repair of the brain and spinal cord following injury.
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