MONOCYTE DEACTIVATION - RATIONALE FOR A NEW THERAPEUTIC STRATEGY IN SEPSIS

Inflammatory cells, in particular monocytes/macrophages, release pro-i nflammatory mediators in response to several infectious and non-infect ious stimuli. The excessive release of these mediators, resulting in t he development of whole body inflammation, may play an important role in the pathogenesis of sepsis and septic shock. TNF-alpha, acting syne rgistically with cytokines such as IL-1, GM-CSF and IFN-gamma, is the key mediator in the induction process of septic shock, as shown in sev eral experimental models. Based on this concept and on the encouraging results obtained in several experimental models, a number of clinical sepsis trials targeting the production or action of TNF-alpha or IL-1 have been performed in recent years. Unfortunately, these trials have failed to demonstrate a therapeutic benefit. One reason for this may be the lack of exact immunologic analyses during the course of septic disease. Recently, we demonstrated that there is a biphasic immunologi c response in sepsis: an initial hyperinflammatory phase is followed b y a hypo-inflammmatory one. The latter is associated with immunodefici ency which is characterized by monocytic deactivation, which we have c alled ''immunoparalysis''. While anti-inflammatory therapy (e.g. anti- TNF antibodies, IL-1 receptor antagonist, IL-10) makes sense during th e initial hyperinflammatory phase, immune stimulation by removing inhi bitory factors (plasmapheresis) or the administration of monocyte acti vating cytokines (IFN-gamma, GM-CSF) may be more useful during ''immun oparalysis''