Traumatic spinal cord injury (SCI) initiates a cascade of pathophysiological events that cause secondary injury and determine the extent of functional recovery. Although the processes that occur following SCI are complex, inflammation is considered to play a key role in the progressive degenerative events and repair mechanisms that take place. The complement system plays a key role in the pathogenesis of many inflammatory and ischemic conditions, and recent evidence shows that it also plays a central role in SCI. The long term goals of this research are to define complement-dependent mechanisms involved in secondary neuronal injury and neuroregeneration after SCI. More specifically, the goal is to determine how complement is activated following SCI and how different complement activation products and pathways modulate the progression of injury and repair following traumatic injury and influence functional recovery. In association with mechanistic studies, a further goal is to develop and characterize novel targeted complement inhibitory strategies that can be safely applied several hours after traumatic injury. The working hypothesis is that complement plays a key role in SCI and that understanding complement-dependent mechanisms involved in secondary injury and neuroregeneration after traumatic injury will allow the development of an effective and safe therapeutic strategy based on complement inhibition. We further hypothesize a key role for naturally circulating IgM in initiating complement activation after SCI, and propose that targeting the IgM-binding epitopes that become exposed after SCI with a complement inhibitor will provide significant improvements in the efficacy and safety of currently available complement inhibitors.
Specific aims : Our data show an important role for naturally occurring IgM antibodies in activating complement and promoting SCI. Using a panel of recently isolated self reactive IgM mAbs, we propose to investigate the proximal events involved in complement activation by characterizing the expression of neoepitopes that are temporarily expressed at the site of SCI. Based on these analyses, we will select a neoepitope specificity for the targeted delivery of complement inhibitors, using antibody fragments (scFv) derived from the appropriate IgM hybridoma as targeting vehicle. We will utilize different types of complement inhibitor to determine which complement pathways and which complement activation products are involved in secondary injury, and which type of targeted complement inhibition provides optimal protection when applied after traumatic injury.
Aim 1. To characterize neoepitope expression following SCI, and the role of self-reactive naturally occurring IgM antibodies in complement activation and secondary damage. We will investigate neoepitope expression qualitatively, quantitatively and temporally in spinal cords following traumatic SCI using our panel of IgM mAbs of known specificities by direct binding studies and by determining how each mAb reconstitutes inflammation and injury in IgM deficient mice.
Aim 2. To determine complement effector mechanisms involved in secondary injury and develop a novel therapeutic strategy. Based on data from aim 1, we will select the most appropriate targeting vehicle (a single chain antibody fragment derived from appropriate hybridoma) and explore its use as: i. a potential competitor for the binding of pathogenic IgM and, ii. as a targeting vehicle for delivering different complement inhibitors. To better understand complement effector mechanisms, we will target complement inhibitors that block either early or late complement activation products, or that block a specific pathway of activation. Efficacies and outcomes will be determined in terms of how the different complement inhibitors/pathways/activation products effect injury, inflammation, neuroregeneration and recovery.
US soldiers are returning in greater numbers with head traumas and spinal cord injuries for which we are still incapable of providing adequate therapies. In our studies we will use a mouse model of SCI that will replicate combat related injuries. The model will study injuries related to IEDs, blast (high pressure waves), landmines and explosive fragments. Injury and repair mechanisms will be investigated using clinically relevant pharmacologic agents (complement inhibitors) as investigative tools, and the work is thus also expected to elucidate mechanisms as well as lead to development of a therapeutic strategy. The approach/strategy would consist of treatment with a specific and targeted anti-inflammatory agent applied within several hours of receiving traumatic injury in order to modulate secondary inflammatory injury and improve cord repair, thus improving clinical outcome as injury progresses from acute to chronic.
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