Immunomodulatory therapies in sepsis

Despite advances in critical care medicine, mortality from sepsis in ICU pa tients remains high. In response to several infectious and non-infectious s timuli, monocytes/ macrophages release a number of mediators, including cyt okines, involved in the proinflammatory response that underlies sepsis. The excessive release of these mediators results in the development of whole b ody inflammation, and plays an important role in the pathogenesis of sepsis and septic shock. In addition, patients with sepsis also under-go an anti- inflammatory phase (the compensatory anti-inflammatory response syndrome) a nd at times, a mixed response with both pro-and anti-inflammatory component s (the mixed antagonistic response syndrome). The initial systemic hyper-in flammation is caused by production of inflammatory cytokines, especially tu mour necrosis factor-alpha (TNF-alpha), and also interleukin-1 (IL-1), IL-6 , and interferon gamma, which act synergistically with TNF-alpha in inducin g shock in animal models. However, clinical trials aimed at downregulating these mediators using antibodies against endotoxin, TNF-alpha, antagonists of IL-1 or platelet activating factor have proved to be uniformly disappoin ting. Not only have these agents been found to have no effect, but they may also increase mortality. One of the reasons for such failure may be the la ck of precise immunological monitoring during the course of sepsis. We have recently demonstrated that sepsis shows a biphasic immunological pattern d uring the initial and later phase: the early hyperinflammatory phase is cou nterbalanced by an anti-inflammatory response which may lead to a hypoinfla mmatory state. The latter is associated with immunodeficiency that is chara cterised by monocytic deactivation, so-called immunoparalysis. Interferon g amma-1 b has an immunoregulatory effect in patients with immunoparalysis du ring the compensatory anti-inflammatory response syndrome, not only restori ng levels of HLA-DR expression but also re-establishing the ability of mono cytes to secrete cytokines such as TNF-alpha. By monitoring immune status i n septic patients, targeted intervention may lead to more success in immuno modulation of sepsis.