Assessment of ability of murine and human anti-lipid A monoclonal antibodies to bind and neutralize lipopolysaccharide.

Warren, H. Shaw; Amato, Stephen; Fitting, Catherine; Black, Kerry M.; Loiselle, Paul M.; Pasternack, Mark S.; Cavaillon, Jean Marc

doi:10.1084/jem.177.1.89

Cited by 121 publications

(49 citation statements)

References 48 publications

(48 reference statements)

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“…Previously developed antibodies against LPS have stressed the need to neutralize LPS to provide the greatest likelihood for clinical success (33). Therefore, we utilized a pair of mAbs targeting the O-antigen of K. pneumoniae LPS to better understand the contribution of LPS neutralization to antibody defense in a pneumonia model.…”

Section: Discussionmentioning

confidence: 99%

Anti-LPS antibodies protect against Klebsiella pneumoniae by empowering neutrophil-mediated clearance without neutralizing TLR4

Cohen¹,

Pelletier²,

Cheng³

et al. 2017

JCI Insight

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Section: Discussionmentioning

confidence: 99%

Anti-LPS antibodies protect against Klebsiella pneumoniae by empowering neutrophil-mediated clearance without neutralizing TLR4

Cohen¹,

Pelletier²,

Cheng³

et al. 2017

JCI Insight

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“…The evaluation of TNF-α production in malnourished children is important because a deficiency in TNF-α production may contribute to the immune deficits occurring in malnutrition; or, alternatively, excess production of TNF-α, by inducing anorexia and cachexia, may aggravate the nutritional status. This type of analysis must be carried out by studying cumulative production in whole blood cultures (27)(28)(29)35,36). This procedure avoids the complexities intrinsic to measurement of circulating TNF-α, which arise from its short plasma half-life, its intermittent release from several tissues, and its in vivo binding to soluble TNF-α receptors, as well as from the need for extensive local production to reach important plasma concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…For whole blood cultures, heparinized blood (diluted 1:5 in endotoxin-tested medium) was cultured in 24-well polystyrene plates (Corning Corporation, Corning, NY, USA), as described by Warren et al (27), 0.5 ml per well in triplicate. Cultures were stimulated or not with LPS, 20 pg/ml-2000 ng/ml, for 24 h at 37ºC, in the presence of 5% CO 2 .…”

Section: Laboratory Testsmentioning

confidence: 99%

Increased production of tumor necrosis factor-alpha in whole blood cultures from children with primary malnutrition

Azevedo

Luz

Victal

et al. 2005

Braz J Med Biol Res

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Because low tumor necrosis factor-alpha (TNF-alpha) production has been reported in malnourished children, in contrast with high production of TNF-alpha in experimental protein-energy malnutrition, we reevaluated the production of TNF-alpha in whole blood cultures from children with primary malnutrition free from infection, and in healthy sex- and age-matched controls. Mononuclear cells in blood diluted 1:5 in endotoxin-free medium released TNF-alpha for 24 h. Spontaneously released TNF-alpha levels (mean ± SEM), as measured by enzyme immunoassay in the supernatants of unstimulated 24-h cultures, were 10,941 ± 2,591 pg/ml in children with malnutrition (N = 11) and 533 ± 267 pg/ml in controls (N = 18) (P < 0.0001). TNF-alpha production was increased by stimulation with lipopolysaccharide (LPS), with maximal production of 67,341 ± 16,580 pg/ml TNF-alpha in malnourished children and 25,198 ± 2,493 pg/ml in controls (P = 0.002). In control subjects, LPS dose-dependently induced TNF-alpha production, with maximal responses obtained at 2000 ng/ml. In contrast, malnourished patients produced significantly more TNF-alpha with 0.02-200 ng/ml LPS, responded maximally at a 10-fold lower LPS concentration (200 ng/ml), and presented high-dose inhibition at 2000 ng/ml. TNF-alpha production a) was significantly influenced by LPS concentration in control subjects, but not in malnourished children, who responded strongly to very low LPS concentrations, and b) presented a significant, negative correlation (r = -0.703, P = 0.023) between spontaneous release and the LPS concentration that elicited maximal responses in malnourished patients. These findings indicate that malnourished children are not deficient in TNF-alpha production, and suggest that their cells are primed for increased TNF-alpha production

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“…One reason might be that the therapeutic tools applied are directed to only a single pathogenetic factor, such as blocking of TNF-␣ by soluble TNF-␣ receptors (Reinhart and Karzai, 2001) or monoclonal antibodies (Tracey et al, 1987), neutralization of LPS by anti-endotoxin antibodies (Warren et al, 1993) or polymyxin B (Danner et al, 1989) as well as antagonizing IL-1␤ (McNamara et al, 1993) or migration inhibitory factor (Bernhagen et al, 1994). Second, exact timing of the therapeutic intervention seems to be crucial, because levels of TNF-␣ and IL-1␤ after an initial burst decline as the process proceeds.…”

Section: Discussionmentioning

confidence: 99%

Polymyxin B-Conjugated α2-Macroglobulin as an Adjunctive Therapy to Sepsis: Modes of Action and Impact on Lethality

Birkenmeier

Nicklisch²,

Pockelt³

et al. 2006

J Pharmacol Exp Ther

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A drug targeting both the inflammatory initiators (lipopolysaccharide; LPS) and mediators [tumor necrosis factor-␣ (TNF-␣)]should have advantage over a "single-factor targeting strategy" in sepsis prevention trials. We have prepared conjugates of polymyxin B (PMB) and the cytokine binding protein ␣2-macroglobulin (A2M). The conjugate binds TNF-␣ as well as LPS as studied by electrophoresis and phase partitioning. Compared with free PMB, the conjugate is nontoxic to cells and does not affect the viability of human monocytes. The A2M-PMB conjugate binds to the A2M receptor (CD91/low-density lipoprotein receptor-related protein 1) with affinity similar to that of the nonmodified protein. Fluorescein isothiocyanate-labeled LPS in the presence of A2M-PMB is rapidly transported into fibroblasts for degradation via receptor-mediated endocytosis. In vitro, A2M-PMB demonstrated inhibition of LPS-induced secretion of TNF-␣ from isolated monocytes as well as in the whole blood assay. The efficacy of the drug was tested in mice after induction of acute inflammation (LPS model) and after induction of a polymicrobial sepsis by cecal ligation and puncture (CLP) model. Treatment of mice with A2M-PMB up to 250 g/g body weight was not toxic to the animal. When the drug was administered 30 min before or 30 min after the LPS challenge, a survival rate of 90 and 70%, respectively, was obtained compared with the placebo control group (5%). A2M-PMB also protected mice after induction of polymicrobial sepsis when administered 30 min before CLP. These results support our hypothesis that A2M-PMB acts as a polyvalent drug to target different host mediators as well as sepsis inducer at the same time.In the past several years, mortality in patients with sepsis syndrome has decreased somewhat, but in those patients with septic shock and multiple organ failure, mortality still exceeds 50% (Danai and Martin, 2005). This high mortality is observed despite ventilatory, hemodynamic, metabolic, and renal support. Some patients-in particular, patients with genetic polymorphisms associated with low or moderate TNF response-survive the ordeal more often, but it remains frustrating not being able to stop the downhill course leading to multiple organ failure and death in other patients that results from overwhelming inflammation. New therapies have been sought and tested, including those preventing the biological activity of pathogen-associated molecular patterns, such as endotoxin or the downhill host response, most notably TNF-␣. Based on a wealth of animal studies, anti-inflammatory strategies, such as neutralizing TNF-␣, have been advocated to provide adjunctive therapy to the patient who continues to deteriorate in the face of considerable support in the intensive care unit. Unfortunately, these anticytokine therapies have not dramatically reduced mortality in doubleblind, placebo-controlled trials involving thousands of patients, although there is a consistent but statistically non-

show abstract

Assessment of ability of murine and human anti-lipid A monoclonal antibodies to bind and neutralize lipopolysaccharide.

Cited by 121 publications

References 48 publications

Anti-LPS antibodies protect against Klebsiella pneumoniae by empowering neutrophil-mediated clearance without neutralizing TLR4

Anti-LPS antibodies protect against Klebsiella pneumoniae by empowering neutrophil-mediated clearance without neutralizing TLR4

Increased production of tumor necrosis factor-alpha in whole blood cultures from children with primary malnutrition

Polymyxin B-Conjugated α2-Macroglobulin as an Adjunctive Therapy to Sepsis: Modes of Action and Impact on Lethality

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