Monocyte deactivation-rationale for a new therapeutic strategy in sepsis |
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Authors: | H -D Volk P Reinke D Krausch H Zuckermann K Asadullah J M Müller W -D Döcke W J Kox |
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Institution: | 1.Institut für Medizinische Immunologie, Universit?tsklinikum Charité,Humboldt-Universit?t zu Berlin,Berlin,Germany;2.Medizinische Klinik V-Nephrologie/Transplantation, Universit?tsklinikum Charité,Humboldt-Universit?t zu Berlin,Berlin,Germany;3.Klinik für Anaethesiologie und Intensivmedizin, Universit?tsklinikum Charité,Humboldt-Universit?t zu Berlin,Berlin,Germany;4.Klinik für Abdominal- und Allgemeinchirurgie, Universit?tsklinikum Charité,Humboldt-Universit?t zu Berlin,Berlin,Germany |
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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-inflammmatory 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”. |
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