LONDON - Efforts to elucidate the cause of septic shock in humans, a condition that frequently is lethal, have so far drawn a blank. Disappointingly, studies using antibodies against tumor necrosis factor (TNF) and interleukin 1 (IL-1), despite early promise from animal studies, have shown no improvement in the survival of patients.

Researchers in Switzerland have now suggested a new strategy: antibodies to a cytokine called macrophage migration inhibitory factor (MIF). The study outlining the experiments on which they base this recommendation is published in the February Nature Medicine in a paper titled, "Protection from septic shock by neutralisation of macrophage migration inhibitory factor."

Thierry Calandra, of the Division of Infectious Diseases at the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, together with colleagues in Regensburg and Munich, Germany; Geneva, Switzerland; and Manhasset, N.Y., report they have determined a critical role for MIF in the pathogenesis of septic shock.

Septic shock can occur as a result of septicaemia, when toxins from the bacteria multiplying in the blood damage the capillaries. This leads to very low blood pressure, and organs such as the lungs and kidneys stop functioning. Death commonly follows.

Calandra and colleagues decided to investigate the role of MIF in this process. MIF is a cytokine produced by monocytes and macrophages once they have been exposed to bacterial toxins and other cytokines such as TNF and interferon gamma. Once released, MIF promotes inflammatory and immune responses. MIF also has the ability to combat the anti-inflammatory and immunosuppressive effects of hormones called glucocorticoids on macrophages and T cells.

The researchers used a mouse model of septic shock that involved inducing bacterial peritonitis either by injecting Escherichia coli into the peritoneum or by a procedure called cecal ligation and puncture (CLP). The latter is acknowledged to be a good model of how septic shock may follow surgery in human patients. Other groups had already shown that, following these procedures, proinflammatory cytokines such as TNF alpha or IL-1 beta would appear in the peritoneal cavity and in circulating blood of the mouse.

Calandra and his colleagues looked for MIF in the peritoneal cavity and the blood of the mice. They demonstrated that high concentrations were present in both. In Nature Medicine, they wrote: "Thus, an acute bacterial infection induced the release of abundant amounts of MIF, first at the primary site of infection and then in the systemic circulation when the infection disseminated."

The group then studied the role of MIF in sepsis, in mice lacking both copies of the gene for TNF alpha. These mice are susceptible to a type of bacterial peritonitis that is not normally lethal. The researchers also thought that the TNF alpha knock-out would allow them to see the role played by MIF in sepsis more clearly, in the absence of one of the key players in inflammation.

As they had seen previously, all the TNF alpha knock out mice died from septic shock after CLP. But when they added a dose of mouse monoclonal antibody against MIF, given immediately after CLP, survival of the animals shot up from zero to 62 percent. This finding provided "direct evidence for a critical part for MIF in the pathogenesis of sepsis as these results were obtained in the absence of TNF alpha," the authors wrote.

They also performed the reverse experiment, injecting a bolus of recombinant mouse MIF along with the E. coli. Mortality of those animals injected with E. coli alone was 21 percent, but rose to 62 percent in the group injected with both MIF and E. coli, confirming the harmful effect of an excessive amount of MIF.

The group also decided to measure levels of MIF in human patients with sepsis. They found a statistically significant increase in MIF levels in such patients. Plasma concentrations of MIF were 3 ng/ml in controls, 12.2 ng/ml in patients with severe sepsis and 17.8 ng/ml in patients with septic shock (p=0.001).

In conclusion, Calandra and his colleagues wrote, "In conjunction with our previous observations that MIF is an important mediator of lethal endotoxaemia and staphylococcal toxic shock, the results of the present study assign a critical part for MIF in the pathogenesis of septic shock. Given the central position of MIF in innate immune responses to microbial products and in the regulation of inflammatory responses, treatment with antibody against MIF may offer a new strategy for the management of patients with sepsis and septic shock."

Commenting on the paper in a News & Views article in the same issue of Nature Medicine, titled "MIF mediation of sepsis," Thomas Martin, of the Seattle VA Medical Center at the University of Washington in Seattle, said: "It is premature to conclude that MIF is the essential mediator of sepsis in humans. More information is needed about the cellular mechanisms by which MIF acts to understand where MIF fits in the complex network of events that occurs in sepsis." Studies in humans, he added, are under way and these will provide "a clinical perspective about the importance of MIF in sepsis and other human diseases."