But lower levels of IL-12 and IL-18 than those with severe

But lower levels of IL-12 and IL-18 than those with severe sepsis. The possible role of increased expression of inhibitory NK receptors and/or decreased NK-cell stimulating cytokines warrants further validation. This study has some limitations. First, evaluation of direct cytotoxicity was not performed for all patients due to the incidence of lymphopenia in ICU patients. However, we observed a very good correlation with degranulation assays, which may represent a good surrogate marker for cytotoxic function of NK cells through their degranulation capacities [45]. Second, we assessed NK immuno-monitoring in patients with severe sepsis and septic shock, but not in patients with non-severe sepsis who are usually not admitted to the ICU. These patients correspond to a less severe, but also to an earlier stage of sepsis, and might have presented the expected over-activated NK functional status as those observed in our non-septic SIRS patients. Thus, similar extensive functional 17460038 studies, but done at an earlier times relative to onset of sepsis, or ideally, with Ebselen serial timepoints, still need to be done. Third, partly due to severe lymphopenia, we did not assess functions of other cells (ie, monocytes, dendritic cells or Treg) that might have significant influence on NK cells functions. Finally, NK cells are present in the lungs at homeostasis, where their frequency is greater than in liver, peripheral blood mononuclear cells, spleen, or lymph nodes [9]. NK cells can be rapidly recruited to the sites of inflammation and we must keep in mind that, with regards to the concept of compartmentalization, that the status of NK cells within tissues may differ [10]. Overall, the present study provides the first report of extensive monitoring of the phenotype and functions of NK cells in critically-ill septic patients. Importantly, our results contrast with what has been reported in murine models [11?7]. Indeed, most murine models of septic shock have demonstrated a deleterious role of NK cells, with a protective effect on survival of NK-cell depletion. However, there are obvious differences between murine sepsis model and human data generated at bedside that could prevent direct comparison and/or explain apparent discrepancies. Conversely to patients that exhibit significant heterogeneity, miceare genetically identical, have same age and gender, are challenged in the same way (pathogen type, dose and route of administration) and present no confounding factors such as other treatments or comorbidities. Also, one of the major differences between the murine sepsis model and the human data provided here is the delay between the onset of sepsis and biological investigations. In the animal model, the timing is very short and controlled, whereas in patients, only the time from admission is known precisely whereas the time from sepsis onset can vary considerably. However, the timing of sampling in our study corresponded to “real-life” situations with regards to the development of future immuno-interventions. Transposed to human septic shock, the murine experiments might have prompted us to design an immuno-therapeutic trial with early NK depletion. Instead, the results of this work show that, in critically-ill septic patients, NK cells rapidly exhibit a normal or CASIN chemical information hypo-responsiveness status that may be part of the “immunoparalysis” (or tolerance), as reported for monocytes [6?]. This hyporesponsiveness particularly involves patients with septic shock and IF.But lower levels of IL-12 and IL-18 than those with severe sepsis. The possible role of increased expression of inhibitory NK receptors and/or decreased NK-cell stimulating cytokines warrants further validation. This study has some limitations. First, evaluation of direct cytotoxicity was not performed for all patients due to the incidence of lymphopenia in ICU patients. However, we observed a very good correlation with degranulation assays, which may represent a good surrogate marker for cytotoxic function of NK cells through their degranulation capacities [45]. Second, we assessed NK immuno-monitoring in patients with severe sepsis and septic shock, but not in patients with non-severe sepsis who are usually not admitted to the ICU. These patients correspond to a less severe, but also to an earlier stage of sepsis, and might have presented the expected over-activated NK functional status as those observed in our non-septic SIRS patients. Thus, similar extensive functional 17460038 studies, but done at an earlier times relative to onset of sepsis, or ideally, with serial timepoints, still need to be done. Third, partly due to severe lymphopenia, we did not assess functions of other cells (ie, monocytes, dendritic cells or Treg) that might have significant influence on NK cells functions. Finally, NK cells are present in the lungs at homeostasis, where their frequency is greater than in liver, peripheral blood mononuclear cells, spleen, or lymph nodes [9]. NK cells can be rapidly recruited to the sites of inflammation and we must keep in mind that, with regards to the concept of compartmentalization, that the status of NK cells within tissues may differ [10]. Overall, the present study provides the first report of extensive monitoring of the phenotype and functions of NK cells in critically-ill septic patients. Importantly, our results contrast with what has been reported in murine models [11?7]. Indeed, most murine models of septic shock have demonstrated a deleterious role of NK cells, with a protective effect on survival of NK-cell depletion. However, there are obvious differences between murine sepsis model and human data generated at bedside that could prevent direct comparison and/or explain apparent discrepancies. Conversely to patients that exhibit significant heterogeneity, miceare genetically identical, have same age and gender, are challenged in the same way (pathogen type, dose and route of administration) and present no confounding factors such as other treatments or comorbidities. Also, one of the major differences between the murine sepsis model and the human data provided here is the delay between the onset of sepsis and biological investigations. In the animal model, the timing is very short and controlled, whereas in patients, only the time from admission is known precisely whereas the time from sepsis onset can vary considerably. However, the timing of sampling in our study corresponded to “real-life” situations with regards to the development of future immuno-interventions. Transposed to human septic shock, the murine experiments might have prompted us to design an immuno-therapeutic trial with early NK depletion. Instead, the results of this work show that, in critically-ill septic patients, NK cells rapidly exhibit a normal or hypo-responsiveness status that may be part of the “immunoparalysis” (or tolerance), as reported for monocytes [6?]. This hyporesponsiveness particularly involves patients with septic shock and IF.