“One of the fascinating characteristics of MIF is its capacity to counter-regulate the inflammatory and immunosuppressive effects of glucocorticoid hormones.”

There are two main reasons. One is that severe sepsis and septic shock are life-threatening complications of infections with unmet medical needs. Indeed, until recently all experimental anti-sepsis therapies targeting either the microbes or the host inflammatory response (i.e., cytokines) had failed to reduce mortality of severe sepsis and septic shock, which is still in the range of 30 to 60%. Identification of novel therapeutic targets for patients with severe sepsis therefore remains imperative.

The other reason has to do with the molecular target of the intervention described in this article—macrophage migration inhibitory factor (MIF). Identified in the late 1960s as one of the first cytokines ever described, MIF has emerged recently to be a critical mediator of innate immunity and sepsis. Studies published in the late 1990s indicated that MIF played an important role in the pathogenesis of inflammatory diseases, including sepsis, hence the renewed interest in this cytokine.

Yes, indeed. We have reported that elevated MIF concentrations are circulating in the bloodstream of patients with severe sepsis and septic shock. We also showed that neutralization of the activity of this pro-inflammatory cytokine was associated with reduced morbidity and mortality in experimental models of bacterial sepsis. Importantly, unlike previous experimental anti-sepsis therapies, anti-MIF therapy was found to be efficacious when given therapeutically (i.e., after the onset of infection) and not only when given prophylactically (i.e., before the onset of infection). These results also opened new prospects for the treatment of acute and chronic inflammatory and autoimmune diseases, such as rheumatoid arthritis and bowel inflammatory diseases.

The immune system, especially the natural defenses against infection—often designated under the name of "innate immunity"—plays a fundamental role in the host defenses against microbes. At the core of our natural anti-microbial defenses, a subset of white blood cells called macrophages play a crucial role in the defenses again invasive microbes. The detection of these microorganisms occurred via molecules expressed at the surface of the macrophages that function as microbial sensors. Binding of microbes or microbial products to these receptors results in the activation of macrophages that release soluble molecules aimed at activating the inflammatory response necessary to eradicate or wall off invasive microorganisms. Because inflammation is a central feature of host defenses, it needs to be kept on tight control. Lack of an inflammatory response may be detrimental as it may promote the growth of microorganisms.

But the incidence of overwhelming inflammatory reactions, such as occurs in severe sepsis and septic shock, is also dangerous for the host. The cytokines, a group of effector molecules of inflammation, play an important role in host defenses against infection. Yet, when released in large quantities—as is the case in severe sepsis and septic shock—they contribute to an overabundant inflammatory response leading to multiple organ dysfunctions, and, all too often, even death. One of these molecules, MIF, has been shown to play an important part in the pathogenesis of severe sepsis and septic shock. The results presented in this article showed that the concentrations of MIF were elevated in patients with septic shock and also in animals with experimental sepsis. Neutralization of MIF activity was associated with improved survival even when treatment was started after the onset of shock.

In 1991, I joined the group of Dr. Richard Bucala at The Picower Institute for Medical Research in Manhasset, NY, who was investigating the stress response to infection and who had just discovered the unanticipated presence of MIF in the pituitary gland. For many years, the lack of biologically active recombinant MIF proteins and of neutralizing antibodies had been a serious obstacle in the investigations of the biology of MIF. Unraveling the biological properties of MIF was much easier once these reagents became available and significant progress occurred in a short period of time. These included the finding that macrophages were an important source of MIF—and not only a target cell, which had been the prevailing concept for many years—and that MIF was a pro-inflammatory cytokine.

Competition between endogenously produced native MIF and exogenous added recombinant MIF also proved to be a challenge in MIF research and the subtracting experiments with anti-MIF antibodies was often more instructive. Subsequent work showed that this constitutively expressed protein was swiftly released by immune cells upon exposure to microbial products. One of the fascinating characteristics of MIF is its capacity to counter-regulate the inflammatory and immunosuppressive effects of glucocorticoid hormones.