Role of pathogenic natural antibodies and complement in a murine model of spinal cord injury (P4051)

Abstract

Abstract Traumatic spinal cord injury (SCI) results in complement activation and inflammation, which are implicated in a secondary injury that determines the extent of functional recovery. SCI has similar pathophysiological characteristics to ischemia reperfusion injury (IRI), and IRI in some organs is initiated by the binding of “natural” self-reactive IgM to post-ischemic neoepitopes, with the subsequent activation of complement. We demonstrated that Ab deficient Rag1-/- mice are protected from SCI, and that injury can be restored by reconstitution with a self-reactive natural IgM mAb specific for annexin A4. Following SCI, IgM bound to the spinal cord in wt mice, and anti-annexin A4 mAb bound to the spinal cord in Rag1-/- mice. Furthermore, IgM and C3d (complement activation product) co-localized after injury. We constructed a single chain antibody (scFv) derived from the anti-annexin A4 hybridoma and investigated: 1. Its ability to block the binding of pathogenic self-reactive IgM after SCI and, 2. Its utility as a targeting vehicle for delivery of a complement inhibitor after SCI (by linking the scFv to the complement inhibitor, Crry). The scFv-Crry construct, and to a lesser degree scFv alone, were protective against SCI, as measured by improved functional recovery, tissue sparing and demyelination. Data indicate an important role for self-reactive IgM in initiating complement activation after SCI, and that post-SCI neoepitopes represent therapeutic targets.