Efficacy of a Monoclonal Antibody Directed against Tumor Necrosis Factor in Protecting Neutropenic Rats from Lethal Infection with Pseudomonas aeruginosa

Opal, Steven M.; Cross, Alan S.; Kelly, N. M.; Sadoff, Jerald C.; Bodmer, Mark; Palardy, John E.; Victor, Gary H.

doi:10.1093/infdis/161.6.1148

Cited by 114 publications

(20 citation statements)

References 30 publications

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“…The results of the current study indicate that anti-TNF MAb alone, even in the absence of antimicrobial agents, will partially protect animals from otherwise lethal P. aeruginosa infection during a period ofchemotherapy-induced neutropenia. These findings demonstrate that an anti-TNF MAb not only protects animals in toxicity models (11)(12)(13)(14) but also in an actual infection model (15,18). The neutropenic rat model more closely mimics a clinical infection in that endogenously mediated bacteremia occurs after alimentary tract colonization with an opportunistic gram-negative bacillus such as Pseudomonas aeruginosa (17).…”

Section: Discussionmentioning

confidence: 95%

“…The protective efficacy of polyclonal and monoclonal antibody directed against TNF has been amply demonstrated in a variety ofendotoxic models in experimental animals (1 1-14). The neutropenic rat model offers an opportunity to study the value of this immunotherapeutic approach against a virulent, replicating bacterial infection in an immunocompromised animal (17,18).…”

Section: Discussionmentioning

confidence: 99%

“…Utilizing a recently developed neutropenic rat model ofactive Pseudomonas sepsis, we have demonstrated that antimicrobial agents combined with a monoclonal antibody against the O-side chain of LPS (17) or combined with a monoclonal antibody against TNF (18) provide protection from lethal infection. Because each of these monoclonal antibodies act at a different phase in the development of the septic state, we sought to determine if a combination both monoclonal antibodies would be superior to either monoclonal antibody alone in the protection of neutropenic animals during Pseudomonas sepsis.…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of antilipopolysaccharide and anti-tumor necrosis factor monoclonal antibodies in a neutropenic rat model of Pseudomonas sepsis.

Opal

Cross²,

Sadoff³

et al. 1991

J. Clin. Invest.

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Monoclonal antibodies (MAb) directed against bacterial lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF) provide partial protection in experimental models of septic shock. To determine if additional benefit accrues from a combination of anti-TNF and anti-LPS MAb in the treatment of septic shock, a neutropenic rat model was developed to study active infection with Pseudomonas aeruginosa 12.4A. Animals were treated intravenously with an irrelevant MAb (group 1); anti-TNF MAb (group 2); MAb directed against P. aeruginosa 12.4.4 LPS (group 3); or a combination of anti-TNF and anti-LPS MAb (group 4). None of the control animals in group 1 survived the 7-d period of neutropenia (0/16). In contrast, the survival rate was 44% in group 2 (P < 0.02); 37% in group 3 (P < 0.05); and 75% in group 4 (P < 0.0002). The combination of monoclonal antibodies provided greater protection than either MAb given alone (P < 0.05). Serum TNF levels during infection were significantly greater in groups 1 and 3 (20.1±3.3 U. mean±SE) than in groups 2 and 4 (0.9±0.8 U, P < 0.0001). These results indicate that a combination of monoclonal antibodies to LPS and TNF have additive benefit in experimental Pseudomonas aeruginosa sepsis. This immunotherapeutic approach may be of potential utility in the management ofserious, gram-negative bacterial infection in neutropenic patients. (J.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Efficacy of antilipopolysaccharide and anti-tumor necrosis factor monoclonal antibodies in a neutropenic rat model of Pseudomonas sepsis.

Opal

Cross²,

Sadoff³

et al. 1991

J. Clin. Invest.

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“…Different approaches to neutralize TNF have been tested in both animal models (13)(14)(15) and clinical trials yielding variable results so far (16)(17)(18)(19)(20). Nevertheless, effective immunotherapies may prevent the development of organ dysfunctions (13,15,18,(21)(22)(23) and thereby improve outcome (13,14,(20)(21)(22).…”

mentioning

confidence: 99%

Impact of Immunomodulating Therapy on Morbidity in Patients with Severe Sepsis

Pittet¹,

Harbarth²,

Suter³

et al. 1999

Am J Respir Crit Care Med

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We assessed the impact, over a 28-d period, of therapy with the tumor necrosis factor (TNF) neutralizing receptor fusion protein (p55-IgG) on the incidence of end-organ failures in patients with severe sepsis or early septic shock in a subgroup of 165 patients recruited into a randomized, multicenter clinical trial to receive placebo (n = 78) or a single infusion of p55-IgG, 0.083 mg/kg (n = 87). At study entry, distribution of organ dysfunctions and other baseline characteristics were similar for the two study groups. Treatment with p55-IgG was associated with a trend toward reduced 28-d mortality (p = 0.07), a decreased incidence of new organ dysfunctions (relative risk [RR], 0.57; 95% confidence interval [95% CI] 0.29 to 1.10, p = 0.10), and a decreased overall incidence-density of organ failures (RR 0.65; 95% CI 0.60 to 0.71, p = 0.0001). Patients treated with p55-IgG had more organ failure-free days after study entry than those who received placebo. Average intensive care unit (ICU) stay was 2.6 d shorter (95% CI 0.2 to 5.0) for patients who received p55-IgG than for those who received placebo. For those patients who survived, this difference was 4.1 d (95% CI 1.6 to 6.6). Duration of ventilatory support was 3.2 d shorter (95% CI 0.1 to 6.3) among 28-d survivors who received p55-IgG, compared with placebo. In conclusion, in the population of septic patients studied, treatment with p55-IgG was associated with a trend toward shorter need for mechanical ventilatory support, a decreased length of stay (LOS), and a decreased incidence and duration of organ failure.

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“…The placebo and LBP-BPI fusion peptide were given daily for 3 days. The details of the neutropenic rat model have been described previously (21). The Sprague-Dawley, specific-pathogen-free, female albino rats (Charles River Laboratory, Wilmington, Mass.)…”

mentioning

confidence: 99%

Activity of lipopolysaccharide-binding protein-bactericidal/permeability-increasing protein fusion peptide in an experimental model of Pseudomonas sepsis

Opal

Palardy

Jhung

et al. 1995

Antimicrob Agents Chemother

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A chimeric protein consisting of the N-terminal domain of lipopolysaccharide-binding protein and the C-terminal domain of bactericidal/permeability-increasing protein demonstrated a dose-dependent survival benefit (P ‫؍‬ 0.001) and reduced endotoxin levels (P < 0.01) in neutropenic rats with Pseudomonas aeruginosa sepsis. This lipopolysaccharide-binding protein-bactericidal/permeability-increasing peptide has favorable pharmacokinetics and antiendotoxin properties which may be of value for human sepsis.Current therapeutic options for gram-negative bacterial sepsis are limited to antimicrobial agents, hemodynamic support, and management of sepsis-induced organ dysfunction (4). Efforts to interfere directly in the pathophysiologic mechanisms which underlie the septic process have yielded inconsistent and largely disappointing results. Antiendotoxin monoclonal antibodies (11, 18), anticytokine therapies (1,6,8), and other anti-inflammatory strategies (5, 24) have not proven to be of sufficient benefit to warrant approval as standard adjunctive therapies for human sepsis.Despite these setbacks, it is anticipated that refinements in clinical trial design and innovations in the synthesis of more potent therapeutic agents will lead to significant advances in the treatment of sepsis in the future. A naturally occurring endotoxin-binding and neutralizing protein which may prove to be particularly effective in endotoxemic states is bactericidal/ permeability-increasing protein (BPI) (17,25). This cationic human neutrophil-derived, 456-amino-acid protein is known to possess potent endotoxin neutralizing properties and intrinsic antimicrobial actions (16,20,26). It has recently been shown that BPI is protective in a variety of endotoxin challenge experiments both in vitro (3, 9, 19) and in vivo (2, 7, 16).A potential limitation to the therapeutic utility of BPI in clinical endotoxic shock is its rapid clearance from the central circulation, with a plasma half-life of only 2 to 4 min in experimental animals (7). A recombinant fusion construct of human BPI with a closely related endotoxin-binding protein, known as lipopolysaccharide (LPS)-binding protein (LBP) (23, 27), has been generated; this combines the endotoxin-neutralizing properties of BPI with the favorable clearance properties of LBP. BPI and LBP are genetically (10) and structurally (26) related proteins, yet they have opposing physiologic actions in the presence of LPS (12,22). BPI inhibits interactions between LPS and CD14-bearing effector cells such as neutrophils and monocytes. LBP, in contrast, facilitates the delivery of LPS to CD14 antigens on cell membranes and potentiates LPS activity.A chimeric protein consisting of the first 199 amino acids of the amino terminus of LBP and the C-terminal 257 amino acids of BPI was found to possess desirable attributes of both LBP and BPI in endotoxin challenge models (15). This fusion peptide was tested in a bacteremic infection model of Pseudomonas aeruginosa sepsis in neutropenic rats.(This paper was presented in part ...

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Efficacy of a Monoclonal Antibody Directed against Tumor Necrosis Factor in Protecting Neutropenic Rats from Lethal Infection with Pseudomonas aeruginosa

Cited by 114 publications

References 30 publications

Efficacy of antilipopolysaccharide and anti-tumor necrosis factor monoclonal antibodies in a neutropenic rat model of Pseudomonas sepsis.

Efficacy of antilipopolysaccharide and anti-tumor necrosis factor monoclonal antibodies in a neutropenic rat model of Pseudomonas sepsis.

Impact of Immunomodulating Therapy on Morbidity in Patients with Severe Sepsis

Activity of lipopolysaccharide-binding protein-bactericidal/permeability-increasing protein fusion peptide in an experimental model of Pseudomonas sepsis

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