Immune System Disorders

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A healthy immune system is the body’s best ally–an automated engine of biological warfare capable of destroying almost any microbial parasite it encounters. But, like all agents of destruction, when it spirals out of control it can be as deadly to friend as it is to foe.

Fifteen million Americans 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’s own tissues. Ailments as diverse as psoriasis, multiple sclerosis and Type I diabetes are all caused by an immune system run amok. No one knows what initiates any of these chronic diseases or how they might be cured, but researchers have nonetheless made significant headway in developing new drugs to treat them–drugs that represent the first substantial advancement in the field in 50 years.

Most of these new drugs are genetically engineered biological molecules, and the majority are designed to treat rheumatoid arthritis and its close clinical relative, lupus. Like all 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’s a catch: the treatments are nearly as harsh on the body as the diseases themselves. Steroids, for example–a mainstay of lupus therapy–shut down the immune system and suppress painful inflammation, but can also promote hardening of the arteries, bone loss, psychosis and obesity. Steroids, in fact, are among of the leading causes of death and morbidity for patients with chronic lupus.

But things may be looking up, thanks to advances in molecular immunology that have spurred the creation of new generation of drugs. It is becoming clear that a cell called CD4+, or helper T cell, is a central player in both the healthy and the pathological immune response. "The activation of the T cell–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 onto a helper T cell and "presents" it with the target molecule, instructing the T cell to prepare its troops for war. This activation is tightly controlled. It cannot occur without the lock-step interaction of a several proteins on the surface of both cells–one of which is known as CD4.

Once activated, the T cell transforms itself into a sort of commander-in-chief of immunity, activating the B cell–which secretes antibodies–and prompting the release of a farrago of molecular signals that lead to inflammation.

Autoimmune responses follow a similar course, except that the cells targeted belong to the body. "Biological response modifiers," as the latest drugs are known, tamp down that response by disrupting communication between the immune system’s soldiers.

The first and most famous of these are Wyeth-Ayerst’s Enbrel, and Remicade, manufactured by a subsidiary of Johnson and Johnson, which have been in use now for roughly two years. Both Enbrel and Remicade inhibit a key messenger in the inflammatory cascade known as the tumor necrosis factor (TNF). The drugs are both more effective than traditional medications, and more likely to slow down joint degradation. "The idea that biologics could prove effective against autoimmune diseases 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, Calif., for example, has zeroed in on the interactions between helper T cells and APCs to develop antibody drugs against lupus and RA. Their anti-RA antibody selectively switches off T cells involved in autoimmune responses by binding the CD4 molecule on their surfaces. Amgen, of Thousand Oaks, Calif., has developed a drug that works by blocking 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, helps 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.