Serial increase of IL-12 response and human leukocyte antigen-DR expression in severe sepsis survivors

Abstract

IntroductionSepsis-induced immunosuppression may result in death. The mechanisms of immune suppression include loss of macrophage and monocyte expression of the major histocompatibility complex, increased anti-inflammatory cytokine expression and decreased expression of proinflammatory cytokines. In this study, we sought to determine the mechanisms of immune suppression in severe sepsis by repeated detection.MethodsWe designed this prospective observational study to measure monocyte human leukocyte antigen (HLA)-DR expression, plasma cytokine levels and cytokine responses on days 1 and 7 in stimulated peripheral blood mononuclear cells (PBMCs) of healthy controls and patients with severe sepsis.ResultsOf the 35 enrolled patients, 23 survived for 28 days and 12 died, 6 of whom died within 7 days. Plasma levels of IL-1β, IL-6, IL-10, IL-17, transforming growth factor (TGF)-β1 and TNF-α were higher, but plasma IL-12 level was lower in septic patients than those in controls. Day 1 plasma levels of IL-1β, IL-6, IL-10 and TGF-β1 in nonsurvivors were higher than those in survivors. Day 7 plasma IL-10 levels in nonsurvivors were higher than in survivors. IL-1β response was higher, but IL-12 and TNF-α responses were lower in septic patients than in controls. Day 1 IL-6 response was lower, but day 1 TGF-β1 response was higher in nonsurvivors than in survivors. Plasma IL-6 and IL-10 levels were decreased in survivors after 6 days. IL-6 response was decreased in survivors after 6 days, but IL-12 response was increased. Monocyte percentage was higher, but positive HLA-DR percentage in monocytes and mean fluorescence intensity (MFI) of HLA-DR were lower in septic patients than in controls. MFI of HLA-DR was increased in survivors after 6 days.ConclusionsMonocyte HLA-DR expression and IL-12 response from PBMCs are restored in patients who survive severe sepsis.

Associations of T helper 1, 2, 17 and regulatory T lymphocytes with mortality in severe sepsis

“…Perhaps Nascimento et al’s research investigated the role of T reg cells in the immune response to secondary infection and our study analyzed a primary infection. Plasma IL-6 level in survivors with severe sepsis was lower than that in non-survivors [19, 20]. In this work, total T reg cells in survivors were higher.…”

Sepsis: Multiple Abnormalities, Heterogeneous Responses, and Evolving Understanding

“…It has also been found that peripheral monocytes isolated from septic humans and mice produce less IL-12 in response to stimulation ex vivo with TLR ligands than those from healthy controls, yet cells from patients that survive sepsis produce greater amounts of IL-12 than those from nonsurvivors. In contrast, levels of IL-10 are elevated in nonsurvivors relative to survivors (113,359,439). In both experimental models and patients with sepsis, APCs demonstrate decreased capacity to stimulate the T-cell proliferative response compared with healthy controls (113,227,246).…”

“…Monocytes isolated from animal models and patients with sepsis release lower amounts of proinflammatory cytokines when stimulated with Toll-like receptor ligands, suggesting that their capacity to sense and respond to new infections is impaired (6,112,220,257). In septic humans, the expression of HLA-DR is markedly decreased (174,257); however, sur- vivors demonstrate a significant recovery of HLA-DR expression compared with nonsurvivors (247,248,439). It has also been found that peripheral monocytes isolated from septic humans and mice produce less IL-12 in response to stimulation ex vivo with TLR ligands than those from healthy controls, yet cells from patients that survive sepsis produce greater amounts of IL-12 than those from nonsurvivors.…”

Cytokines in Sepsis: Potent Immunoregulators and Potential Therapeutic Targets—An Updated View

“…Clinically, a prospective study in patients undergoing major visceral surgery suggested that a selective defect in preoperative monocyte IL-12 production impairs the host defense against postoperative infections and, thus, increases the risk of lethal sepsis [148]. Likewise, it was reported that survivors from severe sepsis produce more IL-12 from LPS-stimulated peripheral blood mononuclear cells (PBMCs) than nonsurvivors [149], and that they show serial increases in their IL-12 response from PBMCs [150]. …”