JANUARY 22, 2001 VOL. 157 NO. 3

The Hunt for Cures

Autoimmune Diseases
New ways to intervene when the body attacks itself
By UNMESH KHER

ALSO
The Future of Drugs
Now that our DNA has been decoded, the search for better, faster and more effective medications begins in earnest
• Inside the Brave New Pharmacy: At a leading genomics firm, the star of the show is a robot
• DNA Microarrays: The workhorse of genomic medicine
• Bioinformatics: How to design a molecule
• The Search for Cures: The fight against aids, cancer, mental illness, obesity, Alzheimer's

A healthy immune system is the body's best ally—an automated engine of biological warfare that can destroy almost any microbial parasite it encounters. But, like all other agents of destruction, when it spirals out of control, it is as deadly to friend as it is to foe.

Millions of people around the world know this in their bones. They are victims of a group of more than 40 disorders that arise when the immune system launches a sustained attack against the body. Ailments as diverse as psoriasis, multiple sclerosis and Type I diabetes are all caused by an immune system run amuck. No one knows what initiates any of these chronic diseases or how they might be cured, but researchers have lately made significant headway in developing drugs to treat them—drugs that arguably represent the first substantial advancement in the field in 50 years.

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Most of these drugs are genetically engineered biological molecules, and the majority are designed to treat rheumatoid arthritis and its close clinical relative, lupus. Like many other autoimmune diseases, both disorders strike women disproportionately. In RA, the immune system attacks the joints and eventually weakens the bones, causing excruciating pain, fatigue and daily bouts of fever. With lupus, the attack is far more generalized, affecting blood vessels, joints, skin and several internal organs. In severe cases, it can be lethal.

Both can be treated, but there is a catch: the treatments are nearly as harsh as the diseases. Steroids, for example—a mainstay of lupus therapy—shut down the immune system and suppress inflammation, but they can also promote hardening of the arteries, bone loss, obesity and even psychosis. Steroids are, in fact, among the leading causes of death and morbidity for patients with chronic lupus.

But things are looking up, thanks to advances in immunology that have spurred the creation of a new generation of drugs. It is becoming clear that a cell called CD4, or helper T cell, is a key player in both healthy and autoimmune responses. "T-cell activation—like the branches of government—is controlled by a series of checks and balances," explains Dr. C. Garrison Fathman, a clinical immunologist at Stanford University.

One of those checks is the T cell's dependence on another cellular player: the antigen-presenting cell. The APC is an omnivorous creature whose job, among other things, is to gobble up microbial invaders. To initiate the immune response, the apc coughs up a molecule from the bug it has eaten, latches on to a helper T cell and "presents" it with a target molecule, instructing the T cell to prepare its troops for war. This activation is tightly controlled; it cannot occur without the lockstep interaction of several proteins on both cells—one of which is known as CD4.

Once activated, the T cell becomes a sort of commander in chief of immunity, activating the B cell—which secretes antibodies—and prompting the release of a farrago of inflammatory molecular signals.

Autoimmune responses follow a similar course, but the cells targeted belong to the body. "Biological-response modifiers," as the new drugs are known, tamp down that response by blocking communication between the immune system's soldiers.

The most famous of these are Wyeth-Ayerst's Enbrel, and Remicade, made by a subsidiary of Johnson & Johnson, which have been in use for roughly two years. Both inhibit a messenger in the inflammatory cascade known as the tumor necrosis factor (TNF). The drugs are more effective than traditional medications, and more likely to retard joint degradation. "The idea that biologics could prove effective against autoimmune disease has been firmly established by the TNF story," says Dr. H. Michael Belmont of the Hospital for Joint Diseases in New York City.

That story, in fact, has inspired trials of nearly two dozen new biotech medicines. IDEC Pharmaceuticals in San Diego, U.S., for example, has zeroed in on the interactions between CD4 T cells and APCS to make antibody drugs against lupus and RA. The company's anti-RA antibody selectively switches off T cells involved in autoimmune responses by binding the CD4 molecule on their surfaces. Amgen, of Thousand Oaks, U.S., has a drug that blocks Interleukin-1, another molecule that promotes inflammation.

Thanks to technologies spawned by genomics, the list of potential drug targets is growing rapidly. Human Genome Sciences and Seattle-based ZymoGenetics, for instance, are independently developing drugs to inhibit a newly discovered factor that stimulates B cells and is produced copiously in RA and lupus patients.

Encouraged by these successes, drug companies are starting to turn to the lesser known autoimmune diseases. Remicade, for example, is used to alleviate the intestinal inflammation caused by Crohn's disease, and drugs against the potentially systemic disorders scleroderma and Sjogren's syndrome are well along in clinical trials. None of these treatments is a cure, of course, but anything that can put the brakes on a runaway immune system has to be considered a good start.

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