Anti-cytokine therapeutics and infections

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Vaccine. 2003 Jun 1;21 Suppl 2:S24-34.

Anti-cytokine therapeutics and infections.

Dinarello CA.

Department of Medicine, University of Colorado Health Sciences

Center, Denver, CO 80262, USA.

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.

Publication Types:

Review

Review, Tutorial

PMID: 12763679 [PubMed - indexed for MEDLINE]