Pivotal Protein: Inhibiting immune compound slows sepsis

By restraining the action of an immune system protein that can run amok, scientists experimenting on mice have reversed the course of severe sepsis, an often-lethal blood infection that shuts down vital organs. The work suggests that neutralizing this protein would halt the disease in some people, but researchers acknowledge that a human trial is still years away.

Sepsis arises as a complication of pneumonia, appendicitis, burns, infections, trauma, or other factors. Cell damage, either by microbial toxins or injury, sets off the immune reaction that leads to severe sepsis. As the body lurches into a self-defense mode, it mass-produces inflammatory proteins, such as tumor necrosis factor alpha (TNF-alpha) and high-mobility group

box 1 (HMGB1).

Some patients die when their blood pressure crashes and organs fail, a combination of phenomena known as septic shock. This inflammatory spiral is orchestrated by TNF-alpha, says Kevin J. Tracey, a neurosurgeon at North Shore–Long Island Jewish Research Institute in Manhasset, N.Y.

However, many people who die from severe sepsis have few signs of inflammation in their tissues, autopsy data show. Tracey suspected that HMGB1 is the major culprit in such patients. In earlier work, he and his team had found that HMBG1 undermines the linings of body cavities, such as the abdomen, making them leaky. The chemical imbalance that results probably leads to organ failure, he says.

Tracey and his colleagues recently tested two anti-HMGB1 agents in mice with severe sepsis. The researchers had induced the condition by perforating the large intestines of 36 mice. Twenty-four hours later, they gave half the animals antibodies against HMGB1, and the other mice received unrelated antibodies. After 2 weeks, 13 of the mice getting anti-HMGB1 treatment had survived, compared with only 5 of the others. Giving an HMGB1-inhibiting drug called A-box achieved similar results in another batch of mice, the researchers report in the Jan. 6 Proceedings of the National Academy of Sciences.

In severe sepsis, dying cells release compounds that attract immune cells called macrophages, which then produce HMGB1. Anti-HMGB1 antibodies act by surrounding HMGB1 molecules, keeping them from binding to healthy cells. The A-box compound works by stalling HMGB1 production in macrophages.

The new study “underscores the potential of HMGB1 as a therapeutic target in the future treatment of sepsis,” says Mark Perrella, a pulmonologist at Harvard Medical School and Brigham and Women’s Hospital in Boston. But Perrella notes that sepsis is an unpredictable disease. While HMGB1 is apparently the problem in some patients, death occurs in others because anti-inflammatory proteins compromise immunity and leave a person vulnerable to further infection. Eventually, doctors might use genetic profiling to choose the best antisepsis therapy, Perrella says.

Doctors might also determine a patient’s immune status by measuring HMGB1 concentrations in the blood, Tracey notes.

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