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Sepsis represents a complex clinical syndrome of significant morbidity and mortality. This continues to be the case in intensive care units around the world, despite extensive use of antibiotics, aggressive surgical intervention and optimization of nutritional support. Furthermore, the failure of > 30 anti-inflammatory mediator therapeutic trials implies, beyond the issue of trial design, there remains the necessity to develop a better understanding of the evolving pathophysiology of this syndrome. Studies indicate that the development of marked immune suppression in sepsis is more often associated with morbid outcome. Dendritic cells, a critical immune cell type bridging the innate and adaptive immune response, not only are affected (killed) by the systemic inflammatory response but also contribute to (by impaired function) the development of immune suppression during sepsis. Here the authors attempt to review emerging data indicating the key role dendritic cells may play in sepsis-induced immune suppression. Undoubtedly, a better understanding of the dendritic cell's response during sepsis will be critical to developing novel strategies for fighting this deadly disease.

Although it is known that septic shock induces immunosuppression, the mechanism for this phenomenon is not well understood. Monocytes play a central role in septic shock pathophysiology, which is also characterized by an increased proportion of natural regulatory T (Treg) cells. We therefore investigated whether Treg could be involved in the decreased monocyte expression of CD14 and HLA-DR observed during septic shock. We demonstrated that human Treg inhibit LPS-induced retention of monocyte CD14. Because loss of CD14 is a hallmark of monocyte apoptosis, this suggests that Treg inhibit monocyte survival. This effect was largely mediated through the release of a soluble mediator that was not identical with either IL-10 or IL-4. The Fas/FasL pathway participated in the effect as it was blocked by anti-FasL Abs and reproduced by Fas agonist and recombinant soluble FasL. Furthermore, expression of FasL was much higher on Treg than on their CD25(-) counterparts. Collectively, these results indicate that Treg act on monocytes by inhibiting their LPS-induced survival through a proapoptotic mechanism involving the Fas/FasL pathway. This may be an important mechanism for septic shock-induced immunosuppression and may offer new perspectives for the treatment of this deadly disease.

Objective: The immediate overwhelming release of inflammatory mediators in septic shock is rapidly followed by strong anti-inflammatory responses inducing a state of immunosuppression. The patients who survive the initial hyper-inflammatory step of septic shock but subsequently die may be those who do not recover from immunosuppression. We assessed whether a low monocyte human leukocyte antigen-DR (mHLA-DR) expression, proposed as a marker of immunosuppression, is an independent predictor of mortality in patients who survived the initial 48 h of septic shock., Design and Setting: Prospective observational study performed in two adult intensive care units at a university hospital., Patients: 93 consecutive patients with septic shock., Measurements and Results: At days 1-2, mHLA-DR values (determined by flow cytometry) were not significantly different between survivors and non-survivors. A sharp difference became highly significant at days 3-4 when survivors had increased their values, while non-survivors had not (43% vs. 18%, percentage of HLA-DR positive monocyte, p < 0.001). Multivariate logistic regression analysis revealed that low mHLA-DR (< 30%) at days 3-4 remained independently associated with mortality after adjustment for usual clinical confounders, adjusted odds ratio (CI): 6.48 (95% CI: 1.62-25.93)., Conclusion: The present preliminary results show that mHLA-DR is an independent predictor of mortality in septic shock patients. Being a marker of immune failure, low mHLA-DR may provide a rationale for initiating therapy to reverse immunosuppression. After validation of the current results in multicenter studies, mHLA-DR may help to stratify patients when designing a mediator-directed therapy in a time-dependent manner.

Objective: The mechanisms involved during sepsis-induced immunosuppression are far from being extensively established. The objective of the present study was to investigate whether two characteristics of T cells were altered in this situation: the percentage of circulating gammadelta T lymphocytes and the level of CD3 expression on T lymphocytes., Design: Observational study., Setting: Adult intensive care units in a university hospital., Patients: Patients with septic shock (n = 21) and healthy individuals (n = 21)., Interventions: None., Measurements and Main Results: In patients, we first observed the decreased percentage of gammadelta T lymphocytes in peripheral blood (1% [0.7-3.1], median [interquartile range]) in comparison with healthy individuals (3.5% [2.1-4.8]). Regarding CD3, we measured a highly significant decrease of its expression on both alphabeta and gammadelta T lymphocytes from patients (p < .005), whereas the CD3 mean fluorescence intensities ratio (gammadelta/alphabeta) was not affected: 2.2 [2.1-2.4] and 2.1 [1.9-2.3] in healthy individuals and septic patients, respectively. The magnitude in the decrease of CD3 expression was thus similar in alphabeta and gammadelta cells, suggesting a common down-regulation mechanism for both T-cell lineages., Conclusions: Combined with a reduced percentage of monocytes expressing human leukocyte antigen-DR, a reduced CD3 expression may be involved in the failure of antigen presentation depicted after septic shock, whereas the diminished percentage of circulating gammadelta T cells could be partly responsible for the elevated incidence of secondary infections. These two observations constitute additional pieces of the complex puzzle of sepsis-induced immunosuppression.

Success in treating severe sepsis will require relevant tools to monitor the patient immunoinflammatory status. This study aimed to investigate the feasibility of measuring a panel of immunological mediator mRNAs in whole blood and to study their prognostic values in septic shock patients. At the onset of shock, compared to healthy volunteers, mRNA levels in septic shock patients were increased for IL-10, IL-1beta, and high mobility group B1 (HMGB1) and decreased for transforming growth factor beta 1, the Th1, and Th2 transcription factors, T-bet and GATA-3, respectively. Single parameter analysis highlighted an increased expression of IL-10 and HMGB1 mRNA in nonsurvivors and a significant rise over time of GATA3 in survivors. Combining the expression levels of four genes, hierarchical cluster analysis showed that up to 95% of the patients with a similar outcome displayed transcriptional similarities. These results illustrate both the potential of whole blood mRNA quantification assays and the interest of a multiparametric strategy to better stratify septic patients.

The shift of T lymphocytes toward a Th2 profile during septic shock has been established on the basis of in vitro cytokine production. In the present study, the Th2 response was investigated at the level of cell surface marker expression (whole blood flow cytometry). In 58 patients with septic shock, we observed a reduced CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) expression on Th2 lymphocytes and regulatory T cells in comparison with 39 healthy volunteers. Eosinophils, which constitutively express CRTH2 in healthy individuals, also exhibited low levels of CRTH2 in patients. In addition, eosinophil CCR3 expression (eotaxin receptor, type 2 chemokine) was strongly correlated with CRTH2, suggesting thus an extended modulation of Th2 related molecules. Importantly, the persistence over time of low levels of CRTH2 or CCR3 expression was found in nonsurvivors. We hypothesize that the restoration of CRTH2/CCR3 expression may be an indicator for optimal recovery after septic shock.

The diminished expression of HLA-DR on monocytes has been proposed as a reliable marker of immunosuppression occuring during septic shock. The objective of the present observational study was to establish the time-dependent relation between plasma cytokines interleukin (IL)-10, transforming growth factor (TGF)-beta1, tumor necrosis factor (TNF)-alpha and monocyte HLA-DR expression in 38 adult patients with septic shock. All patients (mortality at 28 days: 42%, mean admission SAPS II score: 54) had decreased HLA-DR expression. This expression was significantly lower in non-survivors at all time points. All patients had elevated IL-10 concentrations, the highest values were found in non-survivors. IL-10 was the sole cytokine to significantly correlate with HLA-DR expression (r: -0.6, p<0.001). TNF and TGF values did not provide any prognostic information. TGF levels from septic patients were even found to be decreased in comparison with normal values which suggested that IL-10 is likely more important than TGF regarding the immunosuppressive properties of septic patients' plasma. This preliminary work showed that, at the systemic level, the anti-inflammatory response dominated after septic shock. Monocyte HLA-DR expression and IL-10 measurement deserve to be determined in parallel in a larger longitudinal study. They might constitute helpful indicators for staging patients and making a decision about whether to institute a therapy with molecules able of reversing sepsis-induced immunosuppression.

Objective: Immunoparalysis has recently emerged as a possible cause explaining the failure of clinical trials in septic shock. Because human peripheral blood CD4+CD25+ T cells have been characterized as suppressor T cells, we hypothesized they might be increased in sepsis-induced immunoparalysis., Design: Prospective, observational, clinical study., Setting: Adult intensive care units in a university hospital., Subjects: Patients with septic shock (n = 16) and healthy individuals (n = 36)., Interventions: None., Measurements and Main Results: In patients with septic shock (mortality rate at 28 days, 56%; mean admission Simplified Acute Physiology Score II, 47), we first illustrated immunoparalysis by showing a severe diminished monocytic human leukocyte antigen (HLA)-DR expression. Afterward, compared with control values, we found in these patients a marked elevation of circulating CD4+CD25+ T cells that were also CD45RO+ and CD69- and overexpressed CTLA-4. Importantly, nonsurvivors (n = 9) presented prolonged lower monocytic HLA-DR expression and higher percentage of CD4+CD25+ T-suppressor T cells., Conclusions: These data support the concept that the persistence of a pronounced immunoparalysis after septic shock is associated with a poor outcome. Whether CD4+CD25+ T cells directly participate in sepsis-induced immunoparalysis remains to be investigated.

Objective: Circulating levels of calcitonin gene related peptide (CGRP) and calcitonin precursors, including procalcitonin (PCT) and its free aminopeptide N-procalcitonin (N-PCT), have been found dramatically increased in septic patients. PCT is known to attenuate the chemotaxis of monocytes in response to chemoattractants. This study examined whether CGRP and N-PCT modulate the LPS-induced expression of CD11b, which is one of the major integrins involved in monocyte and neutrophil chemotaxis during a response to microbial infections., Design and Setting: In vitro cell culture study in the immunology laboratory of a university hospital., Participants: Healthy volunteers., Measurements and Results: We assessed the effects of N-PCT and CGRP on CD11b expression on monocytes and neutrophils after LPS (2 ng/ml) or fMLP (10(-8) M) challenges. We used a human whole blood model, and measurements were made by flow cytometry. Both peptides in a dose-dependent manner decreased the LPS- and fMLP-induced rise in CD11b in monocytes and neutrophils. As these peptides are thought to act by raising cAMP, we also mimicked their effects with the use of rolipram and forskolin and found similar results., Conclusions: These findings are in line with recent studies demonstrating anti-inflammatory properties for this family of peptides. CGRP and calcitonin precursors may function as factors suppressing the propagation of inflammation through the inhibition of several processes involved during a response to a bacterial stimulus.