Towards IVIg mimetics: Understanding the interplay between complement and Fc receptor signalling in secondary injury after SCI
Funded in: 2017, 2018, 2019
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Problem: Our limited understanding of the complex inflammatory response to spinal cord injury, and its relationship to recovery
Target: Macrophages and other phagocytic cells that can harm the inflamed spinal cord
Goal: To find new anti-inflammatory therapies that promote better outcomes from spinal cord injury
Introduction: Traumatic insults to the spinal cord cause immediate and irreversible tissue damage, followed by a subsequent phase of secondary injury during which more nerve cells are lost. Driven by biological processes, the secondary injury phase is amenable to therapeutic intervention and thus an important target for improving recovery.
Problem statement: A contribution of inflammation to secondary pathology and tissue loss after spinal cord injury (SCI) is well established, however, effective treatment options are currently lacking. We recently showed that intravenous immunoglobulin (IVIG - a potent immunomodulatory treatment in which patients get administered a high dose of antibodies) successfully attenuates inflammation and secondary tissue damage after experimental SCI. What we do not yet know is how IVIG changes the inflammatory responses to one that is more beneficial for functional recovery.
Methods and expected results: Immunoglobulin molecules can modulate the inflammatory response by binding to specific receptors on the surface of macrophages and other immune cells. To determine if this interaction is key to IVIG’s effectiveness, we will treat SCI mice with just the specific portion of the immunoglobulin molecule that binds these receptors (i.e. the Fc domain). We will also employ transcriptomic analysis to determine how macrophages and other immune cells are changed by IVIG treatment in terms of the molecules that they produce, and then plan to test some of these in relation to SCI recovery. Overall, we expect to find the working mechanism how IVIG improves the neurological outcome from SCI, and to discover novel targets that could mimic its actions.
Potential application: Development of IVIG-based therapies for treating acute SCI.