Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: A randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients

Abraham, Edward; Laterre, Pierre‐François; Garbino, Jorge; Pingleton, Susan K.; Butler, Thomas; Dugernier, Thierry; Margolis, Benjamin D.; Kudsk, Kenneth A.; Zimmerli, Werner; Anderson, Paula; Reynaert, Marc; Lew, Daniel Pablo; Lesslauer, Werner; Cooper, Sharon Passe; Philip; Burdeska, Alex; Modi, Marlene; Leighton, Anton; Salgo, Miklos; Auwera, P Van der

doi:10.1097/00003246-200103000-00006

Cited by 277 publications

(154 citation statements)

References 10 publications

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“…We show that lps high and lps low individuals can be identified within this cohort, that these intermediate phenotypes are stable, and that significant gene expression differences exist between the two groups. We also show that the expression of one of these genes, adipophilin (ADFP), 3 is expressed at higher levels in the lps high subphenotype and may regulate LPS-induced responses.…”

Section: Identification Of High and Low Responders To Lipopolysaccharmentioning

confidence: 76%

Identification of High and Low Responders to Lipopolysaccharide in Normal Subjects: An Unbiased Approach to Identify Modulators of Innate Immunity

Wurfel

Park

Radella

et al. 2005

The Journal of Immunology

110

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LPS stimulates a vigorous inflammatory response from circulating leukocytes that varies greatly from individual to individual. The goal of this study was to use an unbiased approach to identify differences in gene expression that may account for the high degree of interindividual variability in inflammatory responses to LPS in the normal human population. We measured LPS-induced cytokine production ex vivo in whole blood from 102 healthy human subjects and identified individuals who consistently showed either very high or very low responses to LPS (denoted lpshigh and lpslow, respectively). Comparison of gene expression profiles between the lpshigh and lpslow individuals revealed 80 genes that were differentially expressed in the presence of LPS and 21 genes that were differentially expressed in the absence of LPS (p < 0.005, ANOVA). Expression of a subset of these genes was confirmed using real-time RT-PCR. Functional relevance for one gene confirmed to be expressed at a higher level in lpshigh, adipophilin, was inferred when reduction in adipophilin mRNA by small interfering RNA in the human monocyte-like cell line THP-1 resulted in a modest but significant reduction in LPS-induced MCP-1 mRNA expression. These data illustrate a novel approach to the identification of factors that determine interindividual variability in innate immune inflammatory responses and identify adipophilin as a novel potential regulator of LPS-induced MCP-1 production in human monocytes.

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Section: Identification Of High and Low Responders To Lipopolysaccharmentioning

confidence: 76%

Identification of High and Low Responders to Lipopolysaccharide in Normal Subjects: An Unbiased Approach to Identify Modulators of Innate Immunity

Wurfel

Park

Radella

et al. 2005

The Journal of Immunology

110

View full text Add to dashboard Cite

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“…Furthermore, elevated levels of specific cytokines, e.g., type I IFN, have been linked to neutropenia (18), which by itself is an important predictor of poor outcomes of systemic bacterial infections (25). Nonetheless, specific underlying mechanisms of lethal outcomes of bacterial infections remain poorly understood (8), as perhaps best illustrated by the fact that therapies seeking to down-modulate key inflammatory mediators (26) or to boost granulopoiesis (27) during sepsis have generally not proved as successful as hoped. Our data illustrate that the proliferative potential of the bacterial inoculum (i.e., the infectious dose) is merely one factor in lethal sepsis.…”

Section: Discussionmentioning

confidence: 99%

Innate immune-induced depletion of bone marrow neutrophils aggravates systemic bacterial infections

Navarini

Lang

Verschoor

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Neutrophils are the most abundant leukocytes in circulation and provide a primary innate immune defense function against bacterial pathogens before development of a specific immune response. These specialized phagocytes are short lived (12-24 hours) and continuously replenished from bone marrow. We found that if the host is overwhelmed by a high inoculum of Listeria monocytogenes, neutrophils are depleted despite high granulocyte-colony stimulating factor induction. In contrast to a low-dose innocuous L. monocytogenes infection, high-dose Listeria challenge blocks neutrophil recruitment to infectious abscesses and bacterial proliferation is not controlled, resulting in lethal outcomes. Administering synthetic TLR2-ligand or heat-killed bacteria during the innocuous L. monocytogenes infection reproduced these effects, once again leading to overwhelming bacterial propagation. The same stimuli also severely aggravated Salmonella typhimurium, Staphylococcus aureus, and Streptococcus pyogenes systemic infection. These data implicate systemic innate immune stimulation as a mechanism of bone marrow neutrophil exhaustion which negatively influences the outcome of bacterial infections.Listeria monocytogenes ͉ neutropenia ͉ TLR2 ͉ sepsis ͉ exhaustion

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“…This is followed by a secondary immune paralysis phase accompanied by uncontrolled growth of bacteria and tissue damage. Although therapy to suppress the immediate cytokine response, such as treatment with TNF and IL-1β antibodies, have failed in clinical trials (4)(5)(6), it has now come to be recognized that, at least in animal models, high-mobility group protein 1 (HMGB1), which is secreted from macrophages and dendritic cells (DCs) but not lymphocytes late in the disease, acts as a master regulator of late and sustained cytokine storm, upregulating many cytokines including TNF-α, IL-6, IL-1β, and IL-8 (reviewed in refs. [7][8][9][10][11].…”

mentioning

confidence: 99%

Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model

Choi

Abraham

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Hypersecretion of cytokines by innate immune cells is thought to initiate multiple organ failure in murine models of sepsis. Whether human cytokine storm also plays a similar role is not clear. Here, we show that human hematopoietic cells are required to induce sepsisinduced mortality following cecal ligation and puncture (CLP) in the severely immunodeficient nonobese diabetic (NOD)/SCID/IL2Rγ −/− mice, and siRNA treatment to inhibit HMGB1 release by human macrophages and dendritic cells dramatically reduces sepsis-induced mortality. Following CLP, compared with immunocompetent WT mice, NOD/SCID/IL2Rγ −/− mice did not show high levels of serum HMGB1 or murine proinflammatory cytokines and were relatively resistant to sepsis-induced mortality. In contrast, NOD/SCID/IL2Rγ −/− mice transplanted with human hematopoietic stem cells [humanized bone marrow liver thymic mice (BLT) mice] showed high serum levels of HMGB1, as well as multiple human but not murine proinflammatory cytokines, and died uniformly, suggesting human cytokines are sufficient to induce organ failure in this model. Moreover, targeted delivery of HMGB1 siRNA to human macrophages and dendritic cells using a short acetylcholine receptor (AchR)-binding peptide [rabies virus glycoprotein (RVG)-9R] effectively suppressed secretion of HMGB1, reduced the human cytokine storm, human lymphocyte apoptosis, and rescued humanized mice from CLP-induced mortality. siRNA treatment was also effective when started after the appearance of sepsis symptoms. These results show that CLP in humanized mice provides a model to study human sepsis, HMGB1 siRNA might provide a treatment strategy for human sepsis, and RVG-9R provides a tool to deliver siRNA to human macrophages and dendritic cells that could potentially be used to suppress a variety of human inflammatory diseases.

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Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: A randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients

Cited by 277 publications

References 10 publications

Identification of High and Low Responders to Lipopolysaccharide in Normal Subjects: An Unbiased Approach to Identify Modulators of Innate Immunity

Identification of High and Low Responders to Lipopolysaccharide in Normal Subjects: An Unbiased Approach to Identify Modulators of Innate Immunity

Innate immune-induced depletion of bone marrow neutrophils aggravates systemic bacterial infections

Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model

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