CYTOKINES AND SEVERE INFECTIONS

In severe infections two factors play a part : the infectious agent an d the response of the host. The response of the host involves producti on of a large number of endogenous mediators including a number of cyt okines that are currently the focus of many studies : tumor necrosis f actor (TNFalpha), interleukins (IL-1 and IL-6), and interferon gamma ( IGNgamma). These cytokines are part of the body's normal defense mecha nisms but can have toxic effects when produced in excessive amounts. A lthough levels of these cytokines are often high in the blood of patie nts with sepsis, persistence of these elevations is the main indicator of severe infection. Experimentally, injections of TNFalpha and IL-1 reproduce the manifestations of severe sepsis. Mice that are genetical ly unable to produce TNFalpha are resistant to the injection of endoto xin. Severe sepsis can be prevented by pretreatment of animals with an ticytokine agents (polyclonal and monoclonal antibodies and anti-recep tor agents...). Many issues remain unresolved : for instance, the expe rimental results obtained with an intravenous bolus of endotoxin or ba cteria have not been confirmed in some animal models of subacute infec tion. These models may more closely resemble human infections. The int errelations between these cytokines are extremely complex. Synergistic effects do occur, but the effects of combinations of cytokines can be different from those Of each cytokine given alone... It follows that therapeutic use in humans of anti-cytokine molecules is still an appro ach of uncertain outcome that will perhaps be clarified by ongoing mul ticenter clinical trials.