Poster at 7th International Neurotrauma Symposium, Adelaide, Australia, 12-16 September 2004

The phenotype of activated macrophages associated with spinal cord repair.

Yonit Bomstein, Ina Sarel, Marina Bubis, Karen Vitner, Keren Bressler, Barak Yahalom, Ronit Bakimer, Jonathan Marder, and Eti Yoles,  Proneuron Biotechnologies, Ness -Ziona 74101, Israel

Severe spinal cord injury (SCI) results in primary tissue destruction that leaves the environment hostile to tissue survival and healing, causing secondary damage. Though repair mechanisms, like neurogenesis, axonal sprouting and activation of cellular immunity, have been demonstrated in the injured CNS, they fail to restore function.  Recently we showed that controlled tissue-specific immune activity induces functional recovery after SCI. Implantation of rat blood-derived macrophages co-incubated with skin improved functional recovery of severely contused rats. Human skin-coincubated macrophages are now in phase II clinical study in patients with acute, complete SCI. We have compared human skin-co-incubated macrophages to known types of macrophage activations: classical (incubated with lipopolysaccharide) and alternative (incubated with interleukin-4), for their immunological phenotype and biological activity on neuronal survival and neurite outgrowth in vitro.

Conditioned media from cultures of lipopolysaccharide-activated macrophages adversely affected the neuronal growth and survival of cultured rat cortical neurons. In contrast, conditioned media from cultures of skin- or IL-4-activated macrophages had no such effect. Secretion of proinflammatory cytokines was high in lipopolysaccharide-activated macrophages but virtually absent in IL-4-activated macrophages. Skin-activated macrophages secreted intermediate levels of interleukin-1 and interleukin-6, but no TNF-alpha. The number of CD80-positive macrophages was elevated in cultures incubated with lipopolysaccharide as compared to macrophages incubated with skin or IL-4.

Skin-activated macrophages thus represent a unique cellular phenotype, distinct from "classically'" or "alternatively" activated macrophages. We propose that this phenotype supports an immune response that promotes neuronal cell survival and repair, resulting in wound-healing and functional recovery.