When it comes to the pain and debilitation of arthritis, the body can be its own worst enemy. The immune system which generally protects the body from the constant barrage of bacteria, viruses and assorted poisons presented by the world has become a prime suspect in the search for the cause of joint swelling and inflammation. An overactive immune reaction could lie at the heart of this condition, a defensive response which the body somehow fails to turn off.

Researchers at two American biotechnology companies are rapidly revealing the workings behind this on/off switch, with optimistic implications for arthritis sufferers. The proteins operating this switch should be manipulated by a new compound, which is expected to enter clinical trials this fall. Eventually, an entirely new class of agents could be available to treat the underlying causes of certain arthritic disorders rather than simply the obvious symptoms.

Moreover, arthritis is only one of many disorders which may be treated at its most fundamental level. Others include multiple sclerosis, diabetes, blood diseases and the ongoing problem of preventing the rejection of transplanted organs.

The excitement surrounds a protein called interleukin-1 or IL-1, one of several related proteins that the body manufactures for specific tasks. An IL-3 protein, for example, stimulates the production of platelets essential to blood clotting. Others control the behaviour of killer cells, the front-line troops waging the bodys battles with disease.

Proteins like IL-1 are relatively recent discoveries, products of new genetic technology enabling biochemists to isolate particular parts of complex organic molecules. Once isolated, these tiny strands of matter can be cloned, replicated in numbers large enough to fill test tubes and permit formal experiments.

Such work has been necessary to achieve any deeper understanding of the immune system, an intricate chemical network lacking any physically defined structure like the bodys circulatory or nervous systems.

What has emerged is a picture of a precision mechanism defining our very survival. Immunity is our defence against the less intrusion of foreign and often hostile organisms into the most intimate corners of our biological lives. Without our immune system we would fall prey to the simplest of maladies, such as the growth of microorganisms contained in the food we eat; with our immune system in place, however, we can muster strategies to repulse invaders the body has never before encountered.

Consider a venomous snake bite, injecting into the body some poison that destroys tissue or interferes with nerve signals vital to breathing or heartbeat. These effects can be countered by the introduction of antibodies, proteins specifically tailored to bind with venom molecules and neutralize them. Those antibodies can be cultivated in an animal by injecting small amounts of the venom and allowing the animals immune system to build up a set of antibodies; blood taken from the animal then serves as a snake-bite serum, so rich in antibodies that an injection into a bite victim counteracts the poison.

This procedure is perhaps nothing short of miraculous, given that neither animal nor human need to have previously encountered the snake venom to produce just the right antidote. The secret lies in the bodys remarkable variety of antibodies, a range of proteins so diverse as to combine with any set of invading molecules or antigens. Even more impressive, therefore, are the control mechanisms telling the various antibody-producing cells what to produce and when.

Such control begins with macrophages, white blood cells patrolling the body for foreign substances, consuming whatever does not belong and displaying various parts of it to attract antibody-producing cells.

Macrophages have a key a role in the immune response, says Cindy Jacobs, a staff scientist with Immunex, a Seattle-based biotechnology company. Theyre the beginning cell that takes something foreign and presents it to the immune system. It says, Here, see this? You better respond to this, and Im going to give you factors to respond to it, like IL-1.

IL-1 was discovered in 1984, in connection with this function of macrophages. The protein attaches itself to receptors on the surface of antibody-producing cells, directing those cells to attack whatever has been indentified as undesirable. Youcall it an immune response when the response is good, says Jacobs. The system sees a foreign substance, responds to it and removes it, then everything goes back to a normal condition. If, for whatever reason, this process gets out of control, or it cant get rid of the antigen, it can now start causing tissue injury. At that point, you stop calling it an immune response and start calling it an inflammatory response.

This inflammatory response serves as a model for arthritis, giving researchers fresh insight into the disease process and how it might be halted. If the root of the problem lies with a signal that continues long after it is needed, the solution is to stop the signal.

Just last year Immunex came up with one technique for stopping IL-1s immune signals. The company developed IL-1 receptors that remain in the solution around cells, competing with the receptors on the cell surface. Protein binding to cells can cause the cell to produce more of the enzymes generating inflammation; if the protein binds with the soluble receptors, then nothing happens. By adding these decoy receptors to an area where IL-1is active, the proteins call for immune activity can be muted.

The idea is to use the soluble IL-1 receptors to mop up the excess IL-1, says Jacobs, who views this approach as a precisely targeted method of getting the protein to interfere with itself. We found that these soluble receptors are naturally produced, she adds. This was very surprising. Youd think this is something that just came out of the lab, but when you go and look, you find soluble receptors. This maybe a way the body has of tuning down the immune response.

Synergen, a biotechnology firm based in Boulder, Colorado, has taken a different approach to the same goal. Rather than diverting IL-1, this group of researchers has isolated a substance that interferes with the binding process itself. This is a naturally occurring protein, which we believe just sits in the receptor and blocks IL-1 from docking with the receptor, says Synergen spokesperson Ken Collins. Were in the process of developing this as a therapy for inflammatory diseases, and rheumatoid arthritisis the first target were going after.

The blocking protein has been dubbed IL-1ra, the last two letters standing for receptor antagonist. Collins says Synergen expects a selected number of clinics to begin testing the medicaluse of IL-1ra this fall. Those tests represent the first step toward approval by the American Food and Drug Administration, which may be years away.

Ultimately, IL-1ra could take the form of an injection taken to alleviate recurring episodes of rheumatoid arthritis. While not a cure, this treatment would deal with the underlying causes of the ailment more directly than anything done so far. And because the active agent occurs normally within the body, few related problems are anticipated.

Its far better to treat our body with something thats naturally produced to turn off the immune system, rather than going with artificial chemicals that have a lot of side effects,says Jacobs.

By exploring the immune system in detail, scientists have now laid bare the manner in which the body protects each of us for a life time from a world that would otherwise prove fatal. IL-1and other proteins are crucial elements of that protection, which can turn against us or fail altogether. Knowing they are there, however, enables us to take immunity into our own hands and possibly overcome its apparent shortcomings.