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".

Low monocyte HLA-DR expression as an indicator of immunodepression in very low birth weight infants

“…CARS was evident within 24 h after birth, with its nadir reached in 72 h. This behavior and associations of CARS postnatally are in accordance with adult and pediatric studies (6)(7)(8)(9)(10)(11)(12). Therefore, in adults and VLBW infants, the molecular mechanisms might also have similarities.…”

“…Persistent low (<60%) HLA-DR expression on monocytes is termed immunodepression or, if monocyte HLA-DR expression is <30%, immunoparalysis (4,5). In adults, immunoparalysis and immunodepression are associated with the risk of infections and death (6)(7)(8). In critically ill surgical patients, low HLA-DR is considered causative in the development of surgical infections (9).…”

Immunoparalysis and Adverse Outcomes from Critical Illness

“…In the mid-1990s Volk et al studied monocyte HLA-DR expression in 247 adult surgical patients with septic disease [61]. In their cohort, an HLA-DR expression level < 30% for five days or more was associated with a 12% survival rate.…”

Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M

“…One of the manifestations of sepsis-induced immunosuppression is macrophage dysfunction (1)(2)(3)(4)(5). Clearance of bacterial pathogens from the lung is largely dependent upon effective innate immune responses.…”