Teaching Tolerance to T Cells

By Sarah Richardson|Saturday, July 01, 1995
Autoimmune diseases result from a cruel mistake: the patient’s immune defenders, notably the T cells, attack the very tissues they should protect. In rheumatoid arthritis, it’s the joints; in diabetes, the pancreas; and in multiple sclerosis, the brain and spinal cord. For some reason the immune cells botch their central mission, which is to distinguish self from nonself. Now researchers at a number of institutions are testing a novel approach to restraining the traitorous T cells. It’s based on a simple principle: You are what you eat.

When you eat food, you ingest proteins that are unfamiliar to the body. But immune cells in the gut don’t attack those proteins; they allow them to be absorbed. Because we need to take in food, the gut’s immune cells have evolved to be more tolerant of foreign proteins. Furthermore, they apparently communicate this tolerance to immune cells elsewhere in the body. If you inject a foreign protein into a person or an animal, you normally get a strong immune response. But if a small amount of the protein is eaten before or after the injection, the immune response is weaker. The phenomenon is called oral tolerance.

In the 1980s neurologist Howard Weiner of Harvard Medical School was one of the first researchers to recognize the potential of oral tolerance as a treatment for autoimmune disease. As I was reading and thinking, says Weiner, I said to myself, wait a minute, we don’t normally react to proteins that come into the gut, because of the way we evolved. But in multiple sclerosis, we’re reacting to a protein in the brain--a self protein. Could we reset the immune system? What if I fed MS patients a brain protein? Would it help?

Weiner and his colleagues first tested this idea by injecting mice with one of the proteins that make up myelin--the material that forms a protective sheath around nerve fibers and that in multiple sclerosis is attacked by T cells. After the injections, the mice contracted the mouse equivalent of MS. But when Weiner gave the animals the myelin protein to eat, the number of myelin-attacking T cells in their bodies decreased substantially.

Why? When the gut absorbs myelin, says Weiner, regulatory T cells are released that migrate out of the gut and are distributed through the bloodstream. It’s like an immunization in the gut, where you induce these regulatory immune cells that then go to the brain and suppress inflammation, he explains. Although the regulatory T cells appear to be structurally identical to T cells that attack myelin, they don’t secrete the same chemical signals. Instead of releasing signals that escalate the immune attack, they release signals that suppress the activation of harmful T cells.

More recently, Weiner and his colleagues conducted a yearlong study of 30 human MS patients. Half were fed myelin pills every day, while the other half got a placebo. Those fed the myelin suffered fewer of the abrupt neurological attacks that characterize MS (the cumulative effect of which is a degeneration of the legs, eyes, and other parts of the body). A different research group is now testing the treatment in a full-scale clinical trial involving 504 MS patients.

Clinical trials of oral tolerance are also under way on patients with rheumatoid arthritis and uveitis, an autoimmune disease of the eyes, and a trial is planned for juvenile diabetes. One day oral tolerance may even be used to prevent the rejection of transplanted organs. Before receiving the donor organ, the recipient would eat synthetic proteins that match crucial proteins in the organ, thus blunting the immune response. This idea has been successfully tested in animals.

Oral tolerance is not likely, however, to become a cure for autoimmune diseases; it merely restrains the autoimmune response, rather than eliminating whatever causes the response. And a lot remains to be learned about how oral tolerance works. But Weiner thinks it is already clear that oral tolerance can yield effective treatments--and without the side effects that accompany some of the drugs that are now used to treat autoimmune disease. The amazing thing is, it’s not toxic, he says. It stimulates the body’s own regulatory systems.

Ten years ago, he adds, there weren’t many people working on this approach. Now they realize how powerful a mechanism oral tolerance is.
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