Activated autologous macrophage implantation in a large-animal model of spinal cord injury

Abstract

<jats:sec> <jats:title>Object</jats:title> <jats:p>Axonal regeneration may be hindered following spinal cord injury (SCI) by a limited immune response and insufficient macrophage recruitment. This limitation has been partially surmounted in small-mammal models of SCI by implanting activated autologous macrophages (AAMs). The authors sought to replicate these results in a canine model of partial SCI.</jats:p></jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Six dogs underwent left T-13 spinal cord hemisection. The AAMs were implanted at both ends of the lesion in 4 dogs, and 2 other dogs received sham implantations of cell media. Cortical motor evoked potentials (MEPs) were used to assess electrophysiological recovery. Functional motor recovery was assessed with a modified Tarlov Scale. After 9 months, animals were injected with wheat germ agglutinin–horseradish peroxidase at L-2 and killed for histological assessment.</jats:p></jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Three of the 4 dogs that received AAM implants and 1 of the 2 negative control dogs showed clear recovery of MEP response. Behavioral assessment showed no difference in motor function between the AAM-treated and control groups. Histological investigation with an axonal retrograde tracer showed neither local fiber crossing nor significant uptake in the contralateral red nucleus in both implanted and negative control groups.</jats:p></jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>In a large-animal model of partial SCI treated with implanted AAMs, the authors saw no morphological or histological evidence of axonal regeneration. Although they observed partial electrophysiological and functional motor recovery in all dogs, this recovery was not enhanced in animals treated with implanted AAMs. Furthermore, there was no morphological or histological evidence of axonal regeneration in animals with implants that accounted for the observed recovery. The explanation for this finding is probably multifactorial, but the authors believe that the AAM implantation does not produce axonal regeneration, and therefore is a technology that requires further investigation before it can be clinically relied on to ameliorate SCI.</jats:p></jats:sec>

Acute Spinal Cord Injury

“…First, following the idea that inflammatory cells might help to clear debris inhibitory to axonal growth, 99,100 autologous transplants of activated macrophages were tested in a T13-L1 hemisection model. 101 This study first examined pilot data on 7 dogs (including 1 sham dog, 2 culture media-only dogs, and 4 cell transplant dogs) but found no motor or electrophysiologic benefit of the transplant over a 9-month period, and the experiment was terminated. In 4 other studies a positive effect of the transplant, composed of MSCs derived from adipose tissue, bone marrow, Wharton jelly, or umbilical cord blood, was found.…”

Inflammation and axon regeneration

“…However, a second surgery might also eliminate nerve fibers that had been spared initially and cause sufficient trauma to reduce the effects of local circuit activity. A single attempt to replicate this approach in a dog model failed to demonstrate axon growth-promoting effects of autologous macrophage transplantation [57]. In a phase I clinical trial begun in 2000, surgical implantation of autologous macrophages was found to be feasible in acute SCI patients and without adverse effects [58].…”

Treatment of penetrating brain injury in a rat model using collagen scaffolds incorporating soluble Nogo receptor

“…The resulting increase in functional recovery relative to untreated animals was suggested to be related to the bridging of the defect by nerve fibres. While the data of that study and others provided the basis for a Phase I clinical trial (Knoller et al, 2005), a subsequent animal study in dogs failed to demonstrate a benefit of implanting macrophages into a spinal cord injury (Assina et al, 2008). Clearly, macrophages play a role of considerable complexity that is continuing to be elucidated.…”