Neuro-inflammation following Human Traumatic Brain Injury

Lead Research Organisation: University of Cambridge
Department Name: Neurosurgery

Abstract

Head injury is an important health issue as it is the commonest cause of death in those aged under 40 years in the developed world. The treatments that are used in patients with severe head injury are largely supportive. Studies in animals have shown us that inflammation in the brain after it is injured can make the injury worse. This study will look at the levels of inflammatory molecules, called cytokines, in the brain and see if blocking these molecules‘ action reduces the damage to nerve cells.
The study will be carried out in the Division of Neurosurgery in the University of Cambridge. We will use a monitoring technique called microdialysis to enable us to measure the levels of cytokines in the brains of patients with severe head injuries. We will go on to see if the levels of these cytokines are associated with activation of inflammatory cells within the brain called microglia.
We will also test to see whether these cytokines are toxic to human nerve cells (neurons) when these cells are grown outside the body.

Technical Summary

Traumatic Brain Injury (head injury, TBI) is a common cause of death and disability in both the developed and developing world. The potentially damaging role of cerebral inflammation following TBI has been demonstrated in many animal models. However, this data is yet to be replicated in humans. In particular, the interleukin-1 family of cytokines has been heavily implicated in potentiating neuronal injury. Our aim is to characterise the cytokine response following human TBI using cerebral microdialysis, a technique for sampling the brain extracellular space.
The first objective will be to develop a robust microdialysis methodology for the recovery of cytokines. Initially, this has taken the form of in vitro testing of the microdialysis catheters already employed in clinical use to determine the relative recovery for each cytokine of interest and to investigate the effect of albumin in the perfusate on relative recovery. The two types of perfusate will then be compared directly in vivo using paired catheters in the same patient.
The microdialysis methodology from these initial studies will be used in an observational study of the temporal course of cytokine expression following human TBI focusing on the following cytokines IL-1?, IL-1?, IL-1receptor antagonist, IL-6, IL-8 and TNF-?.
The next objective will be to carry out a randomised interventional study using IL-1receptor antagonist in human patients following severe TBI. The primary outcome will be safety however we will also incorporate cerebral microdialysis to determine whether the drug crosses the blood brain barrier and whether it alters the pattern of cytokine expression.
We also intend to elucidate the relationship between cytokine expression and microglial activation using a combined PET-microdialysis study, using the PK11195 ligand. It is hypothesised that activated microglia are the source of cytokine expression following trauma.
Finally, we will test the putative neurotoxic effects of the microdialysate recovered from the human brain following TBI on human neuronal cell culture. Our objective is to develop an in vitro neurotoxicity assay that can then be utilised to investigate which, if any, of the components of the microdialysate is toxic to neurons.
Taken together these studies will further our understanding of the molecular mediators of injury following human TBI by replicating and furthering many of the findings from animal models. In addition, attenuating the inflammatory response following TBI may provide a novel therapeutic approach for the treatment of human TBI.

Publications

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Helmy A (2014) Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: a phase II randomized control trial. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

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Helmy A (2016) Recombinant human interleukin-1 receptor antagonist promotes M1 microglia biased cytokines and chemokines following human traumatic brain injury. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

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Guilfoyle MR (2010) Spinal intradural haemorrhage in a patient with Wegener's Granulomatosis. in Clinical neurology and neurosurgery

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Helmy A (2011) The cytokine response to human traumatic brain injury: temporal profiles and evidence for cerebral parenchymal production. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

 
Description MRC Project Grant: 'Cerebral Energy Metabolism in Injured and Uninjured Brain'
Amount £408,068 (GBP)
Funding ID G1002277 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start  
 
Description Mechanism of action of Tranexamic Acid in isolated traumatic brain injury
Amount £360,101 (GBP)
Funding ID EME/14/205/01 
Organisation National Institute for Health Research 
Department NIHR Biomedical Research Centre
Sector Public
Country United Kingdom
Start 02/2016 
End 02/2019
 
Description Royal College of Surgeons Pump Priming Award
Amount £10,000 (GBP)
Funding ID Personal Award 
Organisation Royal College of Surgeons of England 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2017 
End 06/2018
 
Title Dose ranging study of IL1ra in Human Traumatic Brain Injury 
Description Interleukin-1 receptor antagonist is an immunomodulatory agent that we are developing with therapeutic intent in human traumatic brain injury. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
Impact We have utilised microdialysis methodology to confirm drug penetration into the central nervous system and modify the cerebral inflammatory response. 
URL https://clinicaltrials.gov/show/NCT02997371
 
Description Interview and Video for BBC 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Our group has been using computer aided design and 3D printing in medical quality titanium to manufacture cranial plates for human use. I was approached to carry out an interview and filming in the operating theatre and with a patient. This was distributed on BBC digital (http://www.bbc.co.uk/news/av/entertainment-arts-41325582/brain-surgery-revolution), and broadcast three times on the regional BBC network (Look East) reaching an audience of approximately 2.6 million people. I was also interviewed in person on the live evening broadcast.
Year(s) Of Engagement Activity 2017
URL http://www.bbc.co.uk/news/av/entertainment-arts-41325582/brain-surgery-revolution