With its army of cells and myriad antibodies, our immune system is well designed to repel attacks by harmful bacteria, viruses, and other microbes. But it may also hold a key to a longstanding mystery-how to treat spinal-cord injuries that each year leave thousands of people paralyzed. A well-known example is the unfortunate outcome of actor Christopher Reeve’s fall from a horse.
The hope for new treatments stems from recent research on macrophages-immune cells that are among the first to arrive on the scene when the body suffers a wound or infection. Drawn by chemicals released at the damaged area, macrophages rush to sites of inflammation and act like cellular vacuum cleaners, ingesting invading microorganisms, dead or dying cells, and any other debris.
This clean-up work is essential because it allows the body to repair a wound efficiently. If you think of a wound site as a pothole in the street, the job of macrophages is to remove any pieces of crumbled pavement before the hole gets filled in.
Yet growing evidence suggests that the human central nervous system-the brain and spinal cord-denies itself the healing touch of these immune cells. While macrophages do not normally exist in the central nervous system, they should seemingly be able to migrate there when beckoned by inflammatory chemicals. Several years ago, however, researchers began to show that few macrophages respond to brain or spinal-cord injuries.
Following up on that lead, a research team led by Michal Schwartz of Israel’s Weizmann Institute of Science has recently found that the mammalian central nervous system secretes a molecule that inhibits the recruitment and activity of macrophages. According to Schwartz, the molecule, which the researchers have yet to name, also restrains microglia-cells in the brain that appear to closely monitor the health of neurons and transform themselves into macrophages in response to certain stimuli.
Why would our central nervous system possess the means to inhibit the normally helpful immune system? Schwartz speculates that exerting control over macrophages is vital if the mammalian brain is to prevent inadvertent destruction of its intricate neural circuits. She notes that macrophages are indiscriminate eaters, sometimes devouring healthy cells at a wound site as easily as bacteria and dead cells. In most tissues, that’s a reasonable tradeoff to guarantee that a wound is properly cleaned. In the brain and spinal cord, however, any loss of cells might be disastrous. So Schwartz believes that the central nervous system eliminated the risk that macrophages might mistakenly harm it by developing agents that suppress the cells. “It’s a benefit for the healthy brain,” she says, “but it’s a drawback when there’s an injury.”
Schwartz contends that the suppression of these immune cells underlies the well-documented inability of the human spinal cord to repair itself. In a spinal cord injury, a person remains paralyzed because the cord’s axons, the long cables that link one nerve cell to another, do not regenerate when crushed or severed. Damaged nerve cells do send out new extensions, but growth of these fledgling axons quickly stalls.
Why spinal cord axons in humans fail to fully regenerate, while axons in arms and legs and elsewhere in our peripheral nervous system do so with relative ease, has long been a frustrating mystery. For decades, scientists simply thought mammalian spinal cords did not have the ability to repair axons. A consensus has recently emerged that axons in the central nervous system can indeed regenerate but that substances in their environment actively thwart their complete regrowth. For example, besides Schwartz’s macrophage-inhibiting molecule, the central nervous system contains a type of myelin-the fatty insulation surrounding axons-that includes at least one protein that directly stops a regenerating axon in its tracks. Curiously, myelin from the peripheral nervous system does not contain this protein.
Schwartz maintains that macrophages are needed to efficiently clean up loose myelin, which harbors the axon-inhibitory protein, and other materials that pervade the site of a spinal cord injury. In recent experiments on rats, Schwartz’s group tested the therapeutic powers of macrophages on severed optic nerves, the thick bundles of axons that transmit information between the eye’s retina and the brain. Investigators work with optic nerves because they match spinal cords in their inability to regenerate axons after an injury and can be monitored more easily. Last fall, Schwartz’s group reported that macrophages placed at the site of a rat’s severed optic nerve spurred the regrowth of new axons across the lesion.
The challenge was to trigger the macrophages, which normally exist in a quiescent state, to enter their wound-healing vacuum-cleaner mode. The researchers found that when the immune cells were first grown in the laboratory with tissue from the rats’ central nervous system, the macrophage transplants failed, presumably because the immune-suppressing molecule discovered by Schwartz’s group prevented the activation of the cells. But when macrophages were grown with peripheral nerve segments, transplants of the cells stimulated axons to regenerate.
Scientists who have conducted similar experiments on the crushed spinal cords of rats have also obtained encouraging results. “We took activated macrophages, put them in the injured spinal cord, and found enhanced regeneration,” says Wolfgang Streit, a neuroscientist at the University of Florida Brain Institute. Streit proposes that the macrophages, in addition to their clean-up functions, may prepare paths for growing axons by laying down components of the extracellular matrix, a mesh of proteins and other molecules that fills in the space between cells.
Though the early findings have been tantalizing, using macrophage transplants to treat spinal cord injuries is a strategy still in its infancy. The next critical step is to prove that the spinal-cord axons that regenerate after macrophage therapy can actually restore function to paralyzed limbs. Both Streit and Schwartz are already conducting animal studies to explore that question.
Although such evidence is not yet in hand, researchers are optimistic that macrophage-transplant therapy will become part of the arsenal physicians use to treat damaged spines. “The question is no longer whether spinal cord axons can regenerate,” says Wise Young, a spinal-cord injury investigator at New York University, “but how we can get them to regrow much more efficiently.”