Imagine a war in which one of the armies becomes so dominant that it starts to attack its own country. An overactive immune system works much like that – attacking the body it is designed to protect. Medical School Prof. Peter Ward who works in the University’s Pathology Department, is researching the inflammatory response to better understand how to control an overblown response.

Jessica Boullion
Inside the lungs
Jessica Boullion
Ward

The immune system, specifically the inflammatory response, is often called the “first line of defense” against invading bacteria and viruses. Inflammation is the movement of fluid, important proteins and white blood cells to the site of infection. But when inflammation becomes uncontrollable, it sometimes attacks a patient’s own body. Many illnesses are caused by a hyperactive immune system. One such illness is sepsis, an exaggerated immune response to a bacterial or viral infection, which can lead to loss of limbs, shut down organs and may even lead to death. An overactive inflammatory response can also result in rejection of organ transplants

Ward’s work focuses on inflammation in the lungs, which are more susceptible to an overactive inflammatory response than other organs.

One of the main areas of his research is the role of cytokines and chemokines, small protein “messengers” that trigger the inflammatory response, in the immune response pathway. Ward said very little is known about the origin of these protein messengers, or which ones are important.

Other key players in the inflammatory response are complement proteins, a system of 30 proteins that interact to control the immune system, and trigger the inflammatory response. Complement proteins make a logical target for his research because by blocking them, scientists can cut off the chain reaction that triggers the inflammatory response at its initial stage.

One of Ward’s research projects concerns a complement protein called C5. This protein is likely to have a role in the cause of sepsis. Ward and his research team have found that by blocking C5 receptors, the inflammatory response is greatly reduced.

Ward said 600,000 to 800,000 people develop sepsis every year and around 30 to 50 percent of them die. Sepsis also takes a heavy economic toll, costing patients in the U.S. alone $18 to 20 billion per year.

So far the only effective drug to treat sepsis is produced by Eli Lilly, a leading pharmaceutical company. The drug, Xigris, uses a protein with anti-inflammatory effects, called Activated Protein C.

According to the company, Xigris is much more cost-effective than traditional sepsis therapy. But Ward criticized the effectiveness of Xigris, pointing out that use of the drug caused the mortality rate to improve only marginally, falling to a rate of 28 to 32 percent. The company is currently continuing research on the effects of Activated Protein C.

According to Medical School Prof. Theodore Standiford, about 325 to 350 patients were diagnosed with sepsis at the University’s hospital last year. Standiford also noted that while the incidents of sepsis were increasing because of an aging population, more invasive medical procedures and more aggressive immunosuppressive therapy, the mortality rate for sepsis was decreasing.

Some University doctors prescribe Xigris to treat patients with severe sepsis. In 2005, 16 patients received the treatment. University doctors have strict guidelines to follow when prescribing Xigris. It can only be given to patients who are at a severe stage of sepsis. In the milder stage, Xigris can actually harm the patient rather than help. Studies have shown that in less severe patients Xigris is correlated with a two-fold increase in intercranial bleeding, Standiford said.

In the face of diseases such as sepsis, Ward said better understanding of the inflammation pathway and the immune system seems urgent.

Researchers have come a long way since the discovery of chemokines 20 years ago, but that there is still progress to be made. Ward said he hopes the scientific community will be able to provide effective drugs within the next five to 10 years to battle sepsis and other overactive inflammatory diseases.

Fast facts about the immune system

– The inflammatory response is the movement of fluid, important proteins and white blood cells to the site of infection.
– An overactive inflammatory response can cause damage to the body.
Sepsis, an exaggereated immune response to a bacterial or viral infection, can cause the loss of limbs, organ malfunction and even death.
Diseases like those shown in the lung on the right, can trigger an overactive inflammatory response. Lungs are more susceptible to an overactive inflammatory response than other organs.

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