Anticytokine therapies for acute inflammation and the systemic inflammatory response syndrome: IL-10 and ischemia/reperfusion injury as a new paradigm

The results of recent anticytokine trials for sepsis syndrome have been dis appointing. Several Phase II and Phase III clinical trials have shown a mod est benefit in various subsets of patients; however, there has been no repo rted benefit in the primary endpoint of 28-day all-cause mortality. The fai lure of these trials is clearly multifactorial, and causes include the over all complexity of the inflammatory response, heterogeneity of the patient p opulations, absence of a hypercytokine response at the time of drug treatme nt, and the relatively short half-life of the administered drugs. The failu re of anticytokine therapies may represent inadequate application of the tr eatment modality rather than any inherent weakness of the treatment itself. We have recently initiated a Phase I clinical trial examining the role of the anti-inflammatory cytokine IL-10 during surgical repair of a thoracoabd ominal aortic aneurysm. This study may overcome some of the design limitati ons of previous anticytokine trials in sepsis, and serve as a paradigm for future anticytokine therapy trials. Although the incidence of thoracoabdomi nal aortic aneurysms is relatively low, the patient population is homogeneo us and the surgical injury associated with its repair reproducible. Additio nally, postoperative mortality and morbidity rates are significant. Most im portantly, the operative repair is associated with an obligatory visceral i schemia and reperfusion injury that appears to be associated with a proinfl ammatory cytokine response and postoperative organ dysfunction. IL-10 is a pleuripotent anti-inflammatory cytokine that both inhibits TNF alpha and IL -1 synthesis, and antagonizes their actions through upregulation of cytokin e antagonists. Furthermore, IL-10 administration has been associated with o nly minimal adverse side effects during Phase I and Phase II trials.