title: Monocyte deactivation--rationale for a new therapeutic strategy in sepsis.
abstract: Inflammatory cells, in particular monocytes/macrophages, release pro-inflammatory mediators in response to several infectious and non-infectious stimuli. The excessive release of these mediators, resulting in the development of whole body inflammation, may play an important role in the pathogenesis of sepsis and septic shock. TNF-alpha, acting synergistically 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 several 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 immunologic response in sepsis: an initial hyperinflammatory phase is followed by a hypo-inflammatory one. The latter is associated with immunodeficiency which is characterized by monocytic deactivation, which we have called "immunoparalysis". While anti-inflammatory therapy (e.g. anti-TNF antibodies, IL-1 receptor antagonist, IL-10) makes sense during the initial hyperinflammatory phase, immune stimulation by removing inhibitory factors (plasmapheresis) or the administration of monocyte activating cytokines (IFN-gamma, GM-CSF) may be more useful during "immunoparalysis".
authors.affiliation: Institut für Medizinische Immunologie, Universitätsklinikum Charité, Humboldt-Universität zu Berlin, Germany.
authors.forename: H D
authors.initials: HD
authors.lastname: Volk
authors.forename: P
authors.initials: P
authors.lastname: Reinke
authors.forename: D
authors.initials: D
authors.lastname: Krausch
authors.forename: H
authors.initials: H
authors.lastname: Zuckermann
authors.forename: K
authors.initials: K
authors.lastname: Asadullah
authors.forename: J M
authors.initials: JM
authors.lastname: Müller
authors.forename: W D
authors.initials: WD
authors.lastname: Döcke
authors.forename: W J
authors.initials: WJ
authors.lastname: Kox
mesh_terms: D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D016867:Immunocompromised Host; D007249:Inflammation; D007371:Interferon-gamma / Q000276:immunology / Q000627:therapeutic use; D007375:Interleukin-1 / Q000276:immunology / Q000627:therapeutic use*; D009000:Monocytes / Q000276:immunology*; D018579:Patient Selection; D011379:Prognosis; D018805:Sepsis / Q000276:immunology / Q000628:therapy*; D017211:Treatment Failure; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000627:therapeutic use*
chemical_list: D006684:HLA-DR Antigens; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma