Immune blockade impedes blood poisoning

Each year, roughly a half million people in the United States come down with sepsis-blood poisoning that is usually caused by bacteria. The consequences can be dire: One-third to one-half of these patients die from the disease, despite massive doses of antibiotics.

 The body doesn't handle sepsis well in part because key white blood cells called neutrophils, whose job it is to destroy bacteria in the blood, tend to shut down when it strikes. Researchers have now engineered an antibody that blocks this neutrophil deactivation in rats with sepsis, extending their survival. The research, reported in the July Nature Medicine, suggests that a similar antibody might work in human disease.

 Sepsis, also called septicemia, is a blood infection that can arise from trauma or disease. In past centuries, plagues, battle wounds, and unsanitary surgery caused many cases.

 Neutrophil deactivation in sepsis stems from a tragic misfire in the complement system, a complex cascade of protein interactions that guides many immune responses. In a normal immune response, some complement proteins activate neutrophils to combat bacteria.

 Scientists became curious, however, when they found large amounts of a complement-protein fragment called C5a attached to neutrophils in blood from people with sepsis. While C5a normally incites neutrophils to do battle, too much of it shuts them down, says study coauthor Peter A. Ward, a pathologist at the University of Michigan in Ann Arbor.

 Despite the complement system's apparent role in sepsis, many scientists have hesitated to tamper with these proteins because their immune functions are critical, if poorly understood, he says. Changing or blocking one protein risks upsetting the balance of the system.

 Nonetheless, by devising an antibody that blocks the action of C5a, Ward and his colleagues have ventured into the complement realm. C5a breaks off from a complement protein called C5. The antibody that the researchers engineered recognizes C5a and binds to it-preventing the overload of C5a that would deactivate neutrophils. However, the antibody doesn't recognize C5a until it splits from C5 and so doesn't interfere with that protein's normal function.

"We developed an antibody that turned out [to be] very fortuitous," Ward says.

 Preserved neutrophil function greatly aided rats in the study. The researchers perforated the large intestine in 43 rats, causing sepsis to develop. Of 10 rats getting the new antibody that blocks C5a, half survived beyond 10 days, Ward says. Nineteen of 21 rats receiving another antibody died within 8 days, and 12 rats getting no antibody all died within 5 days.

"The data in this paper are very impressive," says Kevin J. Tracey, a neurosurgeon at North Shore University Hospital in Manhasset, N.Y. "It's an important study that could lead to ... development of new therapeutics for sepsis." Indeed, Ward and his colleagues are now trying to devise an antibody to use against human sepsis.