Charles A.
Dinarello, MD
Anti-cytokine-based Therapies: Basic and
Clinical Studies.
Abstract: Cytokines regulate inflammation and host responses to infection and trauma. Whereas some cytokines make disease worse, others reduce inflammation and promote healing. Attention has focused on blocking cytokines that are harmful to the host, particularly during overwhelming infection. Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are proinflammatory cytokines that produce fever, inflammation, tissue destruction, and in some cases shock and death. Reducing the biological activities of IL-1 and TNF is accomplished by several different but highly specific strategies: neutralizing antibodies, soluble receptors, receptor antagonists, and inhibitors of the proteases that convert inactive precursors to active molecules. Blocking IL-1 or TNF has been highly successful in patients with rheumatoid arthritis, inflammatory bowel disease, and graft-versus-host disease, but distinctly not successful in patients with sepsis.
Agents such as TNF-neutralizing antibodies, soluble TNF receptors, and IL-1 receptor antagonists have been administered to over 13,000 septic patients in double-blind, placebo-controlled trials. Although there has been a highly consistent small (two to three percent) increase in 28-day survival with anti-cytokine therapy, the effect has not been statistically significant. However, certain patient subgroups, such as those with disseminated intravascular coagulation, show remarkable improvement in survival with anti-TNF therapy. A large meta-analysis of anti-cytokine therapy in sepsis concluded that the benefit of such therapy appeared small because the sample size of each trial was small. Ideally, anti-cytokine therapy should "rescue" the patient who continues to deteriorate in the face of considerable support efforts. Although it remains difficult to identify those patients who may benefit from anti-cytokine therapies in septic shock, anti-cytokine therapies for local inflammation are entering clinical practice.
Biographical sketch: Charles A. Dinarello is Professor of Medicine at the University of Colorado School of Medicine in Denver. Until 1996, he was Professor of Medicine and Pediatrics at Tufts University School of Medicine and a staff physician at the New England Medical Center Hospital in Boston. Dr. Dinarello received his medical degree from Yale University and his clinical training at the Massachusetts General Hospital. From 1971 to 1974, he was a clinical associate and from 1975 to 1977 a senior investigator at the National Institutes of Health in Bethesda. Dr. Dinarello serves on the editorial board of several scientific journals and has published over 450 original research articles on cytokines, particularly interleukin-1. The Institute for Scientific Information lists him as the world's thrid most cited life scientist (1981-1994). He has trained over 25 young investigators, many of whom are recognized experts in their fields. Dr. Dinarello is presently a member of the Board of Scientific Advisors of the National Institutes of Allergy and Infectious Diseases. He was Vice President of the American Society of Clinical Investigation (1989-1990) and President of the International Cytokine Society (1995-1996). The recipient of several awards for his contributions to the field of infectious diseases and cytokines, he received Germany's Ernst Jung Prize in Medicine in 1993. He donated the entire prize money ($125,000) to universities and research institutes in the United States and Israel, and established the Sheldon M. Wolff Professorship at Tufts University to honor his late mentor. In 1996, he received the Ludwig Heilmeyer Gold Medal of the Society for Internal Medicine (Germany, Austria, and Switzerland) for his contributions to progress in internal medicine. In 1997, the University of Marseille (France) conferred upon Dr. Dinarello the degree Doctor Honoris Causa. He was elected into the National Academy of Sciences in 1998.
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