Nature Medicine, 4:814-821 (1998).

Abstract
Postinjury recovery in most tissues requires an effective dialog with macrophages; however in the mammalian central nervous system this dialog may be restricted (possibly due to its immune-privileged status), which probably contributes to its regeneration failure. We circumvented this by implanting pre-exposed ex vivo to peripheral nerve segments, into transected rat spinal cord. This stimulated tissue repair and partial recovery of motor function, manifested behaviorally by movement of hind limbs, plantar placement of the paws and weight support, and electrophysiologically by cortically-evoked hind-limb muscle response. We substantiated these findings immunohistochemically by demonstrating continuity of labeled nerve fibers across the transected site and by tracing descending fibers distally to it by anterograde labeling. In recovered rats, retransection of the cord above the primary transection site led to loss of recovery, indicating the involvement of long descending spinal tracts. Injection of macrophages into the site of injury is relatively non-invasive and, as the cells are autologous, it may be developed into a clinical therapy.

Glia, 24:329-337 (1998).

Abstract
We have previously demonstrated that the failure of the mammalian central nervous system (CNS) to regenerate following axonal injury is related to its immunosuppressive nature, which restricts the ability of both recruited blood-borne monocytes and CNS-resident microglia to support a process of repair. In this study we show that transected optic nerve transplanted with macrophages stimulated by spontaneously regenerative nerve tissue, e.g., segments of peripheral nerve (sciatic nerve), exhibit axonal regrowth at least as far as the optic chiasma. Axonal regrowth was confirmed by double retrograde labeling of the injured optic axons, visualized in their cell bodies. Transplanted macrophages exposed to segments of CNS (optic) nerve were significantly less effective in inducing regrowth. Immunocytochemical analysis showed that the induced regrowth was correlated with a wide distribution of macrophages within the transplanted-transected nerves. Concomitantly, it was correlated with enhancement of clearance of myelin, known to be inhibitory for regrowth and poorly eliminated after injury in the CNS. These results emphasize that healing of the injured mammalian CNS, like healing of any other injured tissue, requires the partnership of the immune system, which is normally restricted, but that the restriction can be circumvented by transplantation of peripheral nerve-stimulated macrophages.

Neurosurgery, 44:1041-1046, (1999).

Abstract
The failure of the adult mammalian central nervous system (CNS) to regenerate after injury has long been viewed as a unique phenomenon resulting from the specific nature of this system. The finding that some CNS axons could be induced to regrow if provided with a permissive environment suggested that this failure is a result, at least in part, of the nature of the post injury neuronal environment. It was further shown that the involvement of inflammatory cells, particularly macrophages, in postinjury processes in the CNS is limited. We have suggested that, to achieve recovery after injury, the adult mammalian CNS may require the assistance of the same postinjury factors as those involved in the recovery of spontaneously regenerating systems but that its accessibility to such assistance is restricted. Accordingly, we proposed that it might be possible to circumvent the restriction, allowing regeneration to occur. We showed that the implantation of autologous macrophages, which had been prestimulated by exposure to a regenerative (sciatic) nerve, into completely transected spinal cords of adult rats led to partial motor recovery. This treatment intervenes in the postinjury process by simulating in the axotomized CNS the events that occur naturally in spontaneously regenerating systems.