Blocking an immune response in the brain improves stroke recovery in mice

Mature neuron
After a stroke, the complement system flags salvageable neurons for destruction before they have a chance to recover. (UCSD)

Treating an ischemic stroke clears the blood clot and restores blood flow, but this approach ignores an immune response in the brain that can continue to damage neurons. Researchers at the Medical University of South Carolina treated mice with a compound that curbed this response locally, improving their recovery without affecting immune function in the rest of the body. 

Neurons in the stroke core, the area most severely affected by oxygen loss, are irreparably damaged and die, but cells outside the core can still be saved, said principal investigator Stephen Tomlinson, Ph.D., professor and vice chair for research and faculty development in MUSC's Department of Microbiology & Immunology, in a statement. The problem occurs when the complement system gets involved, flagging these salvageable cells for destruction before they can recover. 

"When cells at the stroke core die, they release damaging toxins into the surrounding brain tissue," said first author Ali Alawieh, an M.D./Ph.D. candidate in the Department Microbiology & Immunology. "Neurons in these nearby areas respond by temporarily shutting down. An immune recognition system consisting of natural antibodies sees stressed, nonfunctioning cells and assumes they're about to die and release their own damaging toxins, so it activates the complement system to start clearing out the damaged cells. It's all part of the body's normal homeostatic processes but, in stroke, complement becomes pathological and inappropriately labels live neurons for elimination." 

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Tamping down the complement response is a potential stroke therapy, but the challenge is figuring out how to achieve that without compromising the immune system's other functions, including protecting the body from infections. 

The researchers discovered that stressed but salvageable neurons present neoepitopes, the part of an antigen where antibodies can bind to their cell membrane. This attracts a protein called complement C3d, which tags them for clearance by microglia, a type of immune cell in the central nervous system. That causes neuron loss and post-stroke inflammation. 

The team attached an antibody fragment that recognizes these epitopes to a complement blocker dubbed B4Crry. Rodents given a single dose of the treatment had less C3d in their brains, improved neurological symptoms and less dead tissue 24 hours after a stroke, compared to control animals. Over a 15-day recovery period, the treated animals had fewer neurological deficits and smaller lesions than the controls. 

"This therapy also allows more time to intervene and only requires a simple injection," Alawieh said. "It breaks the inflammatory response cycle and prevents chronic inflammation from occurring in the brain, which we know can continue for many years after a stroke." The findings are published in Science Translational Medicine. 

The researchers have studied complement's role in other conditions, such as cardiovascular disease and will examine how inhibiting complement might change outcomes in traumatic brain injury. Tomlinson is a consultant to AdMIRx, a startup founded to develop anticomplement treatments for inflammatory and autoimmune diseases. 

AdMIRx joins Jena, Germany-based InflaRx, which recently raised $55 million to back a phase 2b trial of its anticomplement antibody, and Apellis, which is developing a complement inhibitor for the rare blood disorder paroxysmal nocturnal hemoglobinuria. In the opposite approach, Grid Therapeutics is working on a complement-activating drug to treat late-stage solid tumors.

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