Complement Plays an Important Role in Spinal Cord Injury and Represents a Therapeutic Target for Improving Recovery following Trauma

Abstract

Initiation of an inflammatory cascade following traumatic spinal cord injury (SCI) is thought to cause secondary injury and to adversely impact functional recovery, although the mechanisms involved are not well defined. We report on the dynamics of complement activation and deposition in the mouse spinal cord following traumatic injury, the role of complement in the development of SCI, and the characterization of a novel targeted complement inhibitor. Following traumatic injury, mice deficient in C3 had a significantly improved locomotor score when compared with wild-type controls, and analysis of their spinal cords revealed significantly more tissue sparing, with significantly less necrosis, demyelination, and neutrophil infiltration. Wild-type mice were also treated with CR2-Crry, a novel inhibitor of complement activation that targets to sites of C3 deposition. A single intravenous injection of CR2-Crry 1 hour after traumatic injury improved functional outcome and pathology to an extent similar to that seen in C3-deficient animals. CR2-Crry specifically targeted to the injured spinal cord in a distribution pattern corresponding to that seen for deposited C3. As immunosuppression is undesirable in patients following SCI, targeted CR2-Crry may provide appropriate bioavailability to treat SCI at a dose that does not significantly affect systemic levels of serum complement activity.

B cells produce pathogenic antibodies and impair recovery after spinal cord injury in mice

“…Recently, a deficiency in C1q was shown to be neuroprotective and promote functional recovery after SCI or traumatic brain injury (34)(35)(36). C3 deficiency also confers neuroprotection with reduced inflammation and improved functional recovery after SCI (37). Further support for our hypothesis comes from our studies showing that injection of pathogenic SCI antibodies into the spinal cord of complement-deficient mice is benign, unlike identical injections into WT spinal cord.…”

Crystal Structure of C5b-6 Suggests Structural Basis for Priming Assembly of the Membrane Attack Complex

“…A large number of other complement-mediated disorders are known, and in many situations indications were found for the importance of the MAC. They include inflammation caused by trauma (49), rheumatoid arthritis (50), macular degeneration (51,52), hemolytic anemias (53,54), nephritis (55,56), and demyelinating neuropathies such as multiple sclerosis and Guillain-Barré syndrome (57,58). In rodent models, MAC formation increased the severity of rheumatoid arthritis, whereas a CD59 derivative decreased it (59,60).…”

Targeted complement inhibition and microvasculature in transplants: a therapeutic perspective

“…A benefit of this therapy is that it only attaches to deposited long-lived C3 cleavage fragments, iC3b, C3dg and C3d and does not affect circulating C3; because of this property, therapy does not increase susceptibility to infection [50]. CR2-Crry is a wellcharacterized complement inhibitor [50][51][52][53][54] which has demonstrated benefit in preclinical models of acute lung injury following intestinal ischaemia-reperfusion injury [50], spinal cord injury [52], ischaemic stroke [51], arthritis [53] and autoimmune renal disease [54]. Taken together, these findings suggest that treating acute rejection with complement inhibition while avoiding CD8…”