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 disappointing. Several Phase II and Phase III clinical trials have shown a modest benefit in various subsets of patients; however, there has been no reported benefit in the primary endpoint of 28-day all-cause mortality. The failure of these trials is clearly multifactorial, and causes include the overall complexity of the inflammatory response, heterogeneity of the patient populations, absence of a hypercytokine response at the time of drug treatment, and the relatively short half-life of the administered drugs. The failure of anticytokine therapies may represent inadequate application of the treatment 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 thoracoabdominal aortic aneurysm. This study may overcome some of the-design limitations of previous anticytokine trials in sepsis, and serve as a paradigm for future anticytokine therapy trials. Although the incidence of thoracoabdominal aortic aneurysms is relatively low, the patient population is homogeneous and the surgical injury associated with its repair reproducible. Additionally, postoperative mortality and morbidity rates are significant. Most importantly, the operative repair is associated with an obligatory visceral ischemia and reperfusion injury that appears to be associated with a proinflammatory cytokine response and postoperative organ dysfunction. IL-10 is a pleuripotent anti-inflammatory cytokine that both inhibits TNFalpha and IL-1 synthesis, and antagonizes their actions through upregulation of cytokine antagonists. Furthermore, IL-10 administration has been associated with only minimal adverse side effects during Phase I and Phase II trials.
Huber
T S
TS
Department of Surgery, University of Florida College of Medicine, Gainesville 32610-0286, USA.
Gaines
G C
GC
Welborn
M B
MB
Rosenberg
J J
JJ
Seeger
J M
JM
Moldawer
L L
LL
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D017544:Aortic Aneurysm, Abdominal / Q000601:surgery; D017545:Aortic Aneurysm, Thoracic / Q000601:surgery; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors; D016753:Interleukin-10 / Q000502:physiology / Q000627:therapeutic use*; D007511:Ischemia / Q000473:pathology*; D015201:Meta-Analysis as Topic; D051379:Mice; D009102:Multiple Organ Failure / Q000209:etiology; D011183:Postoperative Complications / Q000188:drug therapy; D011323:Primates; D011446:Prospective Studies; D015427:Reperfusion Injury / Q000473:pathology*; D012377:Rodentia; D016019:Survival Analysis; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy; D017211:Treatment Failure; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014781:Viscera / Q000098:blood supply*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10