Researchers report effective immune suppression therapy following traumatic brain injury

November 11, 2015 by Christopher Packham, Medical Xpress report

brain
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

Abstract
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

A bad influence—the interplay between tumor cells and immune cells

October 16, 2018
Research at Huntsman Cancer Institute (HCI) at the University of Utah (U of U) yielded new insights into the environment surrounding different types of lung tumors, and described how these complex cell ecosystems may in turn ...

New immunotherapy targeting blood-clotting protein

October 15, 2018
Normally, the blood protein fibrin does not enter the brain. But in several neurological disorders, the blood-brain barrier—which keeps large molecules in the blood from entering the brain—becomes abnormally permeable, ...

Function of neutrophils during tumor progression unraveled

October 15, 2018
Researchers at The Wistar Institute have characterized the function of neutrophils, a type of white blood cells, during early stages of tumor progression, showing that they migrate from the bone marrow to distant sites and ...

Immune health maintained by meticulously ordered DNA

October 15, 2018
Walter and Eliza Hall Institute researchers have revealed how immune health is maintained by the exquisite organisation skills of a protein called Pax5.

Enzyme that triggers autoimmune responses from T-cells in patients with MS found

October 11, 2018
A team of researchers from Switzerland, the U.S. and Spain has isolated an enzyme that triggers an autoimmune response from T-cells in patients with MS. In their paper published in the journal Science Translational Medicine, ...

Scientists reveal new cystic fibrosis treatments work best in inflamed airways

October 11, 2018
A new UNC School of Medicine study shows that two cystic fibrosis (CF) drugs aimed at correcting the defected CFTR protein seem to be more effective when a patient's airway is inflamed. This is the first study to evaluate ...

0 comments

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.