Cholera toxin fights autoimmune disease.

The many cells and chemicals that make up the body's elaborate immune system are supposed to hunt down and vanquish invaders -- largely bacteria, viruses, and foreign tissues that threaten health. But for reasons no one quite understands, immune system components sometimes get confused and begin attacking familiar, benign elements of the body.

Researchers in Sweden have begun harnessing a fragment of the cholera toxin in a novel approach to thwarting autoimmune disease -- the general term for immune attacks against the body's own tissue. The new therapy, described in Atlanta last week at the annual meeting of the American Association of Immunologists, held as part of Experimental Biology '95, promotes tolerance of a substance that the immune system had previously recognized as foreign by attaching it to a cholera toxin fragment.

When fed to animals, a single, small dose of this combo permanently shut down either of two experimentally induced autoimmune diseases, reported study leader Cecil Czerkinsky of the University of Goteborg in Sweden.

Of the two primary components of cholera toxin, only the A chain is actually poisonous. The B chain not only anchors the molecule to the intestine, it also stimulates the immune system. Drawing on the idea that individuals can sometimes develop a tolerance to antigens -- substances that cause an immune reaction -- by eating them, Czerkinsky's team fed its animals sample antigens linked to B chains.

In the intestines, the strategy "induced a very strong antibody response to the [antigen]," Czerkinsky notes. "But at the same time, these animals developed a profound state of tolerance in the periphery -- the blood and lymph nodes." And that led his group to investigate the B chain for blunting undesirable immune responses in animals.

They began by "gluing" the B chain to myelin basic protein, a material that sheathes nerves and falls under immune attack in multiple sclerosis (MS). In rats experiencing MS-like autoimmunity, Czerkinsky says, a single dose of the remedy "cured them."

Other researchers have headed off MS-like diseases in animals by

administering this protein. However, Czerkinsky says, that "only worked with huge amounts and before disease induction."

His team also prevented the joint swelling and tissue destruction normally seen in mice with autoimmune arthritis. The treatment, another B-chain-linked antigen, began weeks after the disease had been induced.

Most recently, the researchers gave B-chain-linked antigens from heart grafts to mice following tissue transplants. Immune reaction against these antigens would normally lead to rejection of the deliberately mismatched tissue in 11 or 12 days. But treated animals accepted the tissue for 22 days, which suggests that rejection might be avoided with better tissue matching and multiple follow-up doses of the B-chain-modified antigen, says Czerkinsky.

"The data look very interesting -- and convincing," says Charles O. Elson, director of gastroenterology at the University of Alabama in Birmingham. Indeed, says immunologist Judith A. Kapp of Emory University in Atlanta, "I think people are pretty excited about it."

Though no one knows yet how the therapy works, Kapp suspects that the B chain somehow obstructs the precursors of a class of white blood cells known as T cells from making those

T cells that produce tissue-damaging inflammatory agents.

But the big question, Elson notes, is whether humans will derive similar benefits. Hoping to find answers, he says, "we're talking about doing some studies here with them [Czerkinsky's team]" to test how well people tolerate the toxin-modified antigen. "So we should know within a year or two if this works in humans."