Cytokine therapeutics for the treatment of sepsis: why has nothing worked?

Several clinical trials have attempted to treat sepsis by blocking certain aspects of the inflammatory response. Tumor necrosis factor and interleukin 1 have been specific targets for inhibition but none of the trials have been successful. These trials were started on the basis of preclinical trials that suggested these would be effective. There were three lines of evidence to support the idea of cytokine inhibition. First, patients with increased levels of cytokines are more likely to die. Second, experimental animal models demonstrated that blocking the cytokines would improve outcome. Third, injection of purified, recombinant cytokines would cause both organ injury and death in experimental animals. Several additional aspects of the inflammatory response have been discovered since these trials were initiated. Included among these potential new targets are interleukin 18 and HMG-1. However, before new clinical trials are started there must be careful consideration of why previous interventions were not effective. The concept of blocking a single elevated cytokine may be too simple to deal with the complex problem of sepsis. As patients move through different phases of the septic response, there may be intervals when it is appropriate to inhibit multiple cytokines while at other times it may be appropriate to augment the immune response.