Researchers from the Massachusetts General Hospital (MGH) are the first to show that a chemical signal controlling the movement of immune system cells can repel those cells as well as attracting them. The study in the May issue of Nature Medicine opens up the possibility of developing new ways of manipulating the immune system that might be applied in the treatment of autoimmune disease, organ transplantation and other critical areas.
The research team found that a protein called SDF-1, which is known to attract immune cells, also can repel T cells (one of the key types of immune cells) when present at high concentrations. When the body needs to summon immune cells to deal with an injury or infection, these cells are induced to move to the site where they are needed by proteins called chemokines. More than 50 chemokines have been identified; they can be produced in any cell of the body and are critical to proper functioning of the immune system.
The inspiration for the current study came when Mark Poznansky, MD, PhD, the study's first author, made a key observation while working in the laboratory of David Scadden, MD, at the MGH Cancer Center and the MGH AIDS Research Center. Poznansky was using a system developed in the laboratory to induce the primitive blood cells called stem cells to mature into T cells, a process that usually takes place in the thymus. After developing for several weeks on a three-dimensional grid of small wells containing thymus tissue, the mature T cells moved toward the outer edges of the culture chambers while the immature cells remained within the grid. It appeared as if something in the thymus tissue medium was repelling the mature T cells. "Mark's observation was unprecendented," says Scadden, the paper's senior author.
Poznansky theorized that perhaps one of the chemokines produced in the thymus that normally attracted T cells might repel the cells at higher concentration, such as might be present in the experimental system. To investigate this theory, the research team -- including Andrew Luster, MD, PhD, Ivona Olszak, BSc, Russell Foxall, MSc, and Richard Evans, MD -- conducted a number of experiments focused on a chemokine called SDF-1. Known to be the most basic chemokine, SDF-1 is produced in signficant quantities by both the thymus and the bone marrow.
The team measured the movement of T cells across a membrane separating areas with varying concentrations of SDF-1 and found that, while T cells moved toward low levels (10 to 100 nanograms per milliliter) of the chemokine, the cells moved away from higher concentrations (1 microgram -- the equivalent of 1,000 ng -- per ml). Similarly, when different concentrations of SDF-1 were injected into sites on lab plates containing T cells evenly suspended in a semi-solid matrix, time-lapse video microscopy showed T cells moving away from high-concentration sites and toward low concentration sites. Injections of a control substance onto the plates produced no cell movement.
Another experiment addressed whether the effects of SDF-1 might explain a known mystery in blood cell development: why bone marrow, which produces significant amounts of chemokines, contains very few T cells. The team exposed T cells to a medium containing bone marrow at various concentrations and found that the undiluted medium, which would contain the highest levels of SDF-1, repelled the T cells, while dilute concentrations of medium attracted T cells. Other tests showed that the processes of T-cell attraction and repulsion, although induced by the same protein, seem to involve different signalling pathways within the cells.
Lastly, the investigators ran a test to see whether high concentrations of SDF-1 might be able to halt an existing immune response in living animals. A group of mice was initially immunized against a protein from another animal, in order to "prime" their immune systems. Then samples of the same protein were injected into the peritoneal cavities of the mice, where they would be expected to produce an immune response characterized by the migration of T cells into the area. A day after receiving the injections, the mice received injections into the peritoneal cavity of either low or high concentrations of SDF-1 or an inert control substance. From 3 to 24 hours later, measurements were taken of T cells in the peritoneal cavities. Mice receiving either low-dose SDF-1 or the inert control had elevated T cell levels, indicating a continuing immune response against the foreign protein; but mice receiving the high-dose SDF-1 had low T cell levels, suggesting that the protein had halted their localized immune response.
While this test does imply that SDF-1 injections can halt an existing immune response in an animal, the authors caution that it's far too soon to know whether the protein has this effect naturally. "We could expect that there might be a natural feedback system that shuts down immune cell recruitment when levels of SDF-1 reach a certain point, but we don't currently know if it really happens that way. We're now investigating that question, as well as whether other chemokines might have similar effects," says Poznansky.
The authors believe that an ability to control the movement of immune cells might someday be applied to the treatment of autoimmune diseases like arthritis, diabetes or multiple sclerosis and may lead to new ways of protecting transplanted organs against rejection. They also conjecture that this newly discovered property of repelling T cells could play a role in the ability of certain infections or cancers to evade detection and attack by the immune system.
This study was supported by grants from the National Institutes of Health, the Defense Advanced Research Projects Administration and the Richard Saltonstall Charitable Foundation.
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