International Collaboration On Neuroinflammation in Traumatic Brain Injury (ICON-TBI)

Traumatic brain injury (TBI) is commonly thought of as an acute self-limited problem. However, in many patients, it can result in chronic disability. In a sizeable minority, such disability can be progressive. Indeed, we now know that either a single severe TBI, or repeated mild TBI, can substantially increase the risk of late dementia. It is believed that a substantial part of these late effects of TBI may be driven by brain inflammation. Indeed, we have known for a long time that patients who suffer a severe TBI have significant acute inflammation in the brain. However, there is increasing evidence that this process may also be important in milder forms of TBI, and that it can become a chronic process. Intriguingly, there are suggestions from animal models of TBI that some of this chronic inflammation may be because the body develops an immune response against the brain, but it is not clear whether this process is beneficial or harmful to patients. We plan to investigate this issue by studying 175 patients with a range of TBI severity. We will look at the levels of inflammatory cells and molecules in both blood and brain fluids, and compare this with a technique called positron emission tomography (PET), which uses small doses of radioactive tracers to image brain inflammation, and with serial magnetic resonance imaging to map the impact of such inflammation. These clinical studies will be underpinned by a portfolio of animal studies which will obtain more detailed information on the types of brain inflammation that occur after TBI, understand what drives it to produce harm or benefit, and investigate the effect of novel drugs in improving this process. We believe that our research may allow us to identify patients who develop chronic inflammation, differentiate those who experience harm from those who benefit from this process, and provide drugs that might be used to control this process in specific subgroups of patients. This holds the promise that we may be able to identify drugs that act more precisely, and match them to the needs of specific patients. This would represent a substantial advance on the present context, where we use drugs that have very wide actions on inflammation across an entire population of patients, and run the risk that many of these patients may not experience any benefit from the drug, but still be at risk of harm from its side effects.

There is growing acceptance that traumatic brain injury (TBI) can result in long-lasting physical, psychiatric and psychological disability. TBI may also be progressive, with worsening neuroimaging findings and neurology over months and years, and/or increased risk of late dementia. The mechanisms underpinning these late processes are uncertain, but may involve neuroinflammation, which is known to occur in acute severe TBI. However, neuroinflammation may also occur in mild TBI, and may include an adaptive immune response with autoantibody production and chronic microglial activation. These have been investigated in animal models, but there are limited clinical data. ICON-TBI will address this through complementary clinical and experimental research, involving 175 patients with a range of TBI severity. We will bank serial blood, CSF and brain microdialysis samples, obtain serial MRI (including diffusion tensor imaging), and undertake serial imaging of microglial activation with [11C]PK11195 PET in a subgroup of patients to understand the time course of and consequences of microglial activation following TBI. Peripheral and CNS immunocytes will be characterised using immunophenotyping and expression profiling, and we will measure autoantibody responses, and their modulation by the acute alarmin response, immunocyte profile, and CD8 T cell exhaustion. Clinical studies will be underpinned by studies in experimental models of diffuse and focal TBI, which will investigate the role of severity, age and gender in modulating neuroinflammation, and explore novel immunomodulatory therapies, including a selective TNFR1 antagonist. We will characterise microglial polarisation states after TBI, explore whether variations in this process could explain varying outcome impact of neuroinflammation, and examine the effect of immunomodulatory events on microglial phenotype and subsequent outcome.

ICON-TBI seeks to use complementary clinical and experimental research to characterise the innate and adaptive immune response in TBI, and identify the beneficial and/or harmful effects of these processes on outcome. Our research outputs could lead to a better understanding of how an initial acute biomechanical injury is converted into chronic and/or progressive pathology, provide a knowledge base for precision medicine approaches to dealing with this transition following TBI, and take the initial in translating a novel, clinically applicable, immunomodulatory interventions to human TBI treatment..

The strong research portfolio and multidisciplinary research team in ICON-TBI promise highly productive outputs in terms of publications and follow through grant funding. We will be addressing novel biology in the context of our studies, and it is likely that we will find biomarkers that indicate whether a continuing neuroinflammatory process exists and is likely to be harmful or beneficial in any given patient. These will allow patient stratification and supports precision medicine approaches to management of TBI. This may identify patient subsets in whom immunomodulation is helpful - providing a more refined use of specific therapies (such as the TNFR1 dAb) in specific patients, rather than the past use of broad spectrum anti-inflammatory agents such as corticosteroids across the board, which led to worse outcomes. In other instances our outputs may allow identification of patients who might benefit from vaccination against neural antigens, to promote protective autoimmunity - a revolutionary concept. As an intermediate step, we will be able to identify enriched populations of TBI patients who would be candidates for trials of these interventions, and specify clinical imaging and molecular biomarkers that could be used in such trials. Perhaps the first candidate for such an intervention would be the TNFR1 dAb that is being studied in the experimental WP in ICON-TBI - the agent has already undergone extensive safety testing in humans, and is already in trial as an inflammation modulator in other clinical settings.

The research in this application will provide the substrate for several non-clinical and clinical graduate studentships leading to higher degrees. Some of the posts that support such graduate study have been specified in an earlier section, but is likely that many more will be identified after funding is secured. Perhaps equally importantly, the ICON-TBI research program will provide a substrate for scientific and professional development of young PIs who have been identified in an earlier section, and provide a basis for a network of researchers interested in neuroinflammation after TBI.

More specifically, the autoantibody and imaging biomarkers that emerge from ICON-TBI can be further developed and/or validated within the 5400 patient CENTER-TBI study as part of a Work Package that includes Prof Menon and Prof Wang. Additional opportunities for validation and implementation will come from other InTBIR portfolio studies.