IVIg attenuates complement and improves spinal cord injury outcomes in mice

Abstract

ObjectiveTraumatic spinal cord injury (SCI) elicits immediate neural cell death, axonal damage, and disruption of the blood–spinal cord barrier, allowing circulating immune cells and blood proteins into the spinal parenchyma. The inflammatory response to SCI involves robust complement system activation, which contributes to secondary injury and impairs neurological recovery. This study aimed to determine whether intravenous immunoglobulin (IVIg), an FDA‐approved treatment for inflammatory conditions, can scavenge complement activation products and improve recovery from contusive SCI.MethodsWe used functional testing, noninvasive imaging, and detailed postmortem analysis to assess whether IVIg therapy is effective in a mouse model of severe contusive SCI.Results IVIg therapy at doses of 0.5–2 g/kg improved the functional and histopathological outcomes from SCI, conferring protection against lesion enlargement, demyelination, central canal dilation, and axonal degeneration. The benefits of IVIg were detectable through noninvasive diffusion tensor imaging (DTI), with IVIg treatment counteracting the progressive SCI‐induced increase in radial diffusivity (RD) in white matter. Diffusion indices significantly correlated with the functional performance of individual mice and accurately predicted the degree of myelin preservation. Further experiments revealed that IVIg therapy reduced the presence of complement activation products and phagocytically active macrophages at the lesion site, providing insight as to its mechanisms of action.InterpretationOur findings highlight the potential of using IVIg as an immunomodulatory treatment for SCI, and the value of DTI to assess tissue damage and screen for the efficacy of candidate intervention strategies in preclinical models of SCI, both quantitatively and noninvasively.

Disease-modifying effect of intravenous immunoglobulin in an experimental model of epilepsy

“…The present findings therefore strongly suggest that IVIg might alleviate epileptogenesis through modulation of the complement cascade. This is consistent with a proposed mechanism for the effect of IVIg in experimental stroke2133 and spinal cord injury34 although causality remains to be proven. Hippocampal sclerosis, a common pathological change in TLE patients, is characterized by selective loss of neurons, pathological proliferation of interneuron networks and a severe glial reaction35.…”

“…We used a dose of 2 g/kg IVIg as this dose is used clinically and was also previously shown to be neuroprotective in animal models of stroke21 and spinal cord injury34. A summary overview of the experimental design is shown in Fig.…”

Potential immunotherapies for traumatic brain and spinal cord injury

“… 209 , 210 IVIG has been also examined for neuroprotective effects in ischemia-type insults. 210 , 211 , 212 In animal studies, IVIG administration acutely after SCI 213 or TBI 214 significantly improves neural functional recovery. IVIG not only suppresses the excessive immune responses via inhibiting inflammatory cytokine production, immune cell invasion/activation and complement activation in the CNS, but also reverses the concomitant immunosuppression against invading pathogens after CNS injury.…”

Elevated Autoantibodies in Subacute Human Spinal Cord Injury Are Naturally Occurring Antibodies

“…Indeed, intravenous IgG (IVIg) preparations, which are used to treat both immunedepression and autoimmune disorders, are manufactured by pooling the serum IgGs from more than 1,000 healthy donors and are loaded with AAbs against a wide range of antigens ( 52 ). In this regard, a commercial human IVIg preparation containing IgG AAbs that bind to astrocytes, oligodendrocytes, microglia and neurons is therapeutic in experimental SCI ( 53 ), suggesting that endogenous naturally occurring AAbs might have a protective role immediately after SCI as well. A strong parallelism has been reported to occur in stroke, where pre-existing anti-NMDAR1 autoantibodies normally present in healthy subjects have an acute protective role if the blood brain barrier (BBB) is competent before occurrence of the ischemia ( 54 , 55 ).…”