title: Anti-cytokine therapeutics and infections.
abstract: In view of the increasing use of anti-cytokine-based therapies to treat autoimmune diseases, the role of specific cytokines in host defense against infection has become a highly relevant area of investigation. There are over 300,000 patients worldwide being treated with agents that specifically block the biological activities of interleukin-1 (IL-1) or tumor necrosis factor (TNF) for reducing the severity of autoimmune diseases such as rheumatoid arthritis, Crohn's disease or psoriasis. Those patients receiving anti-TNF-alpha or IL-1 blocking therapies are treated on a chronic basis. Studies suggest that other chronic inflammatory diseases will benefit from anti-cytokine therapies. However, there is a growing body of clinical evidence that neutralization of TNF-alpha is associated with an increased risk of opportunistic infections, including mycobacterial diseases. Blockade of IL-1 activity with the IL-1 receptor antagonist (IL-1Ra) appears, at present, to be relatively safe. However, because of physician under reporting (some estimates of reporting being less than 5% of these infections), the true incidence of infections, both serious and non-serious, will remain unknown. Does the increase in infections associated with anti-cytokine-based therapies come as a surprise? Of the two components of host defense, the innate and the acquired responses, which are affected by anti-cytokine therapies? From a wealth of rodent studies using live infection models, the following conclusions can be drawn: (1) neutralization or gene deletion for TNF-alpha is frequently associated with reduction of host defense in models of live Gram-positive or Gram-negative infections as well as infection by intracellular microbes such as Salmonella and Listeria; (2) absence of the IL-1 receptor can also result in decreased resistance to Listeria or Gram-positive bacteria and (3) TNF-alpha and IFN-gamma are required for defense against infection caused by Mycobacterium tuberculosis.
authors.affiliation: Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
mesh_terms: D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D007239:Infections / Q000209:etiology*; D007371:Interferon-gamma / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology; D018410:Pneumonia, Bacterial / Q000209:etiology; D012480:Salmonella Infections / Q000209:etiology; D012772:Shock, Septic / Q000276:immunology; D014376:Tuberculosis / Q000209:etiology
chemical_list: D016207:Cytokines; D009569:Nitric Oxide; D007371:Interferon-gamma