Immunoglobulin G (IgG) attenuates neuroinflammation and improves neurobehavioral recovery after cervical spinal cord injury

Abstract

BackgroundEvidence suggests that the inflammatory events in the acute phase of spinal cord injury (SCI) exacerbate the initial trauma to the cord leading to poor functional recovery. As a result, minimizing the detrimental aspects of the inflammatory response after SCI is a promising treatment strategy. In this regard, immunoglobulin G (IgG) from pooled human serum is a promising treatment candidate. Due to its putative, though poorly characterized immuno-modulatory effects, IgG has been used clinically to treat neuroinflammatory disorders such as Guillain-Barré syndrome, but its effects in neurotrauma remain largely unexplored.MethodsThis study examines the potential neuroprotective effects of IgG in a well-characterized cervical model of SCI. Female Wistar rats were subject to moderate-severe clip compression injury at the C7-T1 level. IgG (0.4 g/kg) or saline was injected intravenously to randomly selected animals at 15 min post SCI. At several time points post SCI, biochemical assays, histology and immunohistochemistry analyses, and neurobehavioral assessments were used to examine the neuroprotective effects of IgG at the molecular, cellular, and neurobehavioral levels.ResultsWe found that intravenous treatment of IgG following acute clip-compression SCI at C7-T1 significantly reduced two important inflammatory cytokines: interleukin (IL)-1β and IL-6. This early reduction in pro-inflammatory signaling was associated with significant reductions in neutrophils in the spinal cord and reductions in the expression of myeloperoxidase and matrix metalloproteinase-9 in the injured spinal cord at 24 h after SCI. These beneficial effects of IgG were associated with enhanced tissue preservation, improved neurobehavioral recovery as measured by the BBB and inclined plane tests, and enhanced electrophysiological evidence of central axonal conduction as determined by motor-evoked potentials.ConclusionThe findings from this study indicate that IgG is a novel immuno-modulatory therapy which shows promise as a potential treatment for SCI.

Bilateral Contusion-Compression Model of Incomplete Traumatic Cervical Spinal Cord Injury

“…16 Based on this work, lesional tissue was distinguished from surrounding unlesioned tissue by intense eosin staining and a fibrous, irregular appearance. As recovery proceeds, the volume of lesional tissue decreases (Fig.…”

“…24 The Rivlin-Tator aneurysm clip was originally designed for use in the thoracic cord; our lab has developed modified protocols for its use at the C6-C7 and C7-T1 spinal levels. 16,18,25 The current study represents one of the first detailed characterizations of the consequences of clipcompression injury at the C6 level in rats. Neuroanatomical analysis at multiple time points post-injury has provided important insights into the pathophysiology of secondary injury after acute impact and sustained compression in the cervical cord.…”

Characterization of the Antibody Response after Cervical Spinal Cord Injury

“…Indeed, this ''paradox'' of coexisting immune suppression and autoimmunity is a common concept in systemic autoimmune diseases, 65 and is now recognized as part of SCI pathology. 66 Intravenous immunoglobulin G administration could address this duality of the immune response after SCI, 67,68 given that it is successfully used both as an immune replacement for immunosuppressed individuals, and as an immunosuppressant for autoimmune diseases. 69 Despite the increased antibody levels in the lesioned spinal cord and the splenic autoreactive response in vitro during the subacute phase of cSCI, we did not find increased levels of serum autoantibodies against spinal cord proteins by ELISA.…”

Human immunoglobulin G reduces the pathogenicity of aquaporin-4 autoantibodies in neuromyelitis optica

“…hIgG decreased IL-1β and IL6 production in a spinal cord injury model (Nguyen et al, 2012). IL6 is elevated in NMO and promotes NMO-IgG secretion by plasmablasts, and IL6 receptor block by the monoclonal antibody tocilizumab has been shown to be beneficial in NMO (Chihara et al, 2011).…”