Researchers report effective immune suppression therapy following traumatic brain injury

November 11, 2015 by Christopher Packham report
White matter fiber architecture of the brain. Credit: Human Connectome Project.

(Medical Xpress)—The growing awareness of traumatic brain injury (TBI) in professional, collegiate and amateur sports has resulted in legal pressures, media coverage and medical research related to the pathology of head injuries. The problem is particularly acute in contact sports such as U.S. football, but even lower-impact sports have produced examples of the disabilities induced by even minor head trauma.

The pathology of TBI is produced not only by the initial injury, but during the body's protective immune response. The body's complement system is an auxiliary, innate immune system that helps phagocytes and antibodies to clear pathogens. Unlike the adaptive immune system, the complement system is not adaptive, unable to produce counters to novel infections.

In the event of traumatic , complement is a key contributor to neuropathology and disability. Deployed to the site of injury to fight infections, the complement system's membrane attack complex (MAC) induces inflammation and inflammasome activation and causes lysis in brain cells. Thus, researchers view inhibiting MAC and preventing complement-mediated lysis as a goal in the prevention of TBI disability.

A group of researchers in the U.K. and the Netherlands have now collaborated on a study, published in the Proceedings of the National Academy of Sciences, describing an anti-complement agent that targets brain damage and promotes recovery in mice with . Crucially, the agent demonstrated effectiveness post-injury, implying the existence of a therapeutic window following for the prevention of secondary neuropathological effects and associated disability.

The researchers sought an agent that would inhibit MAC from inducing lysis while preserving its anti-infection properties. The complement inhibitor they used combined the so-called complement receptor of the lg superfamily (CRIg) with complement regulator CD59a. This construct was designed to inhibit MAC assembly only at sites of injury by targeting deposition of essential complement components C3bi and C3b, thereby suppressing detrimental effects of the complement system while maintaining its upstream anti-infection functions.

They report that the CD59-2a-CRIg construct reduces posttraumatic neurologic disability and weight loss symptoms, which were monitored as an additional clinical outcome. The mice in the study demonstrated a 50 percent reduction of the neurological severity score after four hours, by comparison with untreated controls. Further, the authors note that the construct reduces inflammation, mitochondrial stress and axonal injury after incidents of TBI. By inhibiting inflammosome activation post-TBI, it regulates secondary inflammatory processes that contribute to brain injury.

And importantly, as the injured mice were treated 30 minutes post-TBI, the authors suggest that a window exists for anti-complement therapy to be administered by emergency responders: "The data suggest a therapeutic window of opportunity for effective intervention after TBI to prevent secondary neurological damage, raising the prospect that such strategies may work when administered postinjury in humans, perhaps by first responders at the scene or in the ambulance, as currently happens with thrombolytics with a reported 4.5-hour window," the authors write.

Explore further: Africa faces rising rates of traumatic brain injury

More information: An anticomplement agent that homes to the damaged brain and promotes recovery after traumatic brain injury in mice. PNAS 2015 ; published ahead of print November 2, 2015, DOI: 10.1073/pnas.1513698112

Activation of complement is a key determinant of neuropathology and disability after traumatic brain injury (TBI), and inhibition is neuroprotective. However, systemic complement is essential to fight infections, a critical complication of TBI. We describe a targeted complement inhibitor, comprising complement receptor of the Ig superfamily (CRIg) fused with complement regulator CD59a, designed to inhibit membrane attack complex (MAC) assembly at sites of C3b/iC3b deposition. CRIg and CD59a were linked via the IgG2a hinge, yielding CD59-2a-CRIg dimer with increased iC3b/C3b binding avidity and MAC inhibitory activity. CD59-2a-CRIg inhibited MAC formation and prevented complement-mediated lysis in vitro. CD59-2a-CRIg dimer bound C3b-coated surfaces with submicromolar affinity (KD). In experimental TBI, CD59-2a-CRIg administered posttrauma homed to sites of injury and significantly reduced MAC deposition, microglial accumulation, mitochondrial stress, and axonal damage and enhanced neurologic recovery compared with placebo controls. CD59-2a-CRIg inhibited MAC-induced inflammasome activation and IL-1β production in microglia. Given the important anti-infection roles of complement opsonization, site-targeted inhibition of MAC should be considered to promote recovery postneurotrauma.

Related Stories

Africa faces rising rates of traumatic brain injury

October 5, 2015
New research reveals that the projected estimates of traumatic brain injury (TBI) in Africa are high, with a burden of anywhere between approximately 6 to 14 million new cases in 2050. Most cases will result from motor vehicle ...

Researchers use neuroimaging to measure early cognitive improvement after mild TBI

September 21, 2015
Researchers published results of a novel study of the functional activation patterns of working memory after mild traumatic brain injury (TBI). This study, the first to enroll subjects during their initial evaluation in the ...

TBI triggers liver to produce protein tied to inflammation; hypertension drug blocks it

September 21, 2015
A new animal study shows that traumatic brain injury (TBI) affects the body as well as the brain and that treatment with hypertension drugs blocks the production of proteins related to inflammation.

Study finds association between people who have had a traumatic brain injury and ADHD

August 20, 2015
A new study has found a "significant association" between adults who have suffered a traumatic brain injury at some point in their lives and who also have attention deficit hyperactive disorder.

Traumatic brain injury linked to criminal activity

October 28, 2015
Experiencing a traumatic brain injury (TBI) may increase the likelihood of an individual criminally offending by 60 per cent, according to latest research.

Brain imaging reveals possible depression signature in traumatic brain injury

November 5, 2015
Approximately half of individuals who experience a traumatic brain injury (TBI) experience depression within a year. Those with TBI and depression are prone to poorer recovery, reductions in cognitive performance, greater ...

Recommended for you

Study explores whole-body immunity

November 21, 2017
Over the next few months, millions of people will receive vaccinations in the hope of staving off the flu—and the fever, pain, and congestion that come with it.

Drug could cut transplant rejection

November 21, 2017
A diabetes drug currently undergoing development could be repurposed to help end transplant rejection, without the side-effects of current immunosuppressive drugs, according to new research by Queen Mary University of London ...

Atopic eczema—one size does not fit all

November 21, 2017
Researchers from the UK and Netherlands have identified five distinct subgroups of eczema, a finding that helps explain how the condition can affect people at different stages of their lives.

Breast milk found to protect against food allergy

November 20, 2017
Eating allergenic foods during pregnancy can protect your child from food allergies, especially if you breastfeed, suggests new research from Boston Children's Hospital. The study, published online today in the Journal of ...

Zika-related nerve damage caused by immune response to the virus

November 20, 2017
The immune system's response to the Zika virus, rather than the virus itself, may be responsible for nerve-related complications of infection, according to a Yale study. This insight could lead to new ways of treating patients ...

How a poorly explored immune cell may impact cancer immunity and immunotherapy

November 17, 2017
The immune cells that are trained to fight off the body's invaders can become defective. It's what allows cancer to develop. So most research has targeted these co-called effector T-cells.


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.