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

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

doi:10.1172/jci115390

Cited by 62 publications

(21 citation statements)

References 29 publications

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“…These results are consistent with the idea that even when cytokines are detected in the blood, their timing does not always correlate with acute-phase activation after administration of immune stimuli (19). Concerning the role of administration of cyclophosphamide, it has previously been shown that this immunosuppressive drug induces a nonspecific leukopenia (fewer than 100 cells/ml for 6 to 7 days) (24,26) and a selective depletion of the lymphoid tissue (2,42). When such treated patients become afflicted with a bacterial infection, they develop high fevers.…”

Section: Discussionsupporting

confidence: 85%

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Circulating Inflammatory Mediators during Start of Fever in Differential Diagnosis of Gram-Negative and Gram-Positive Infections in Leukopenic Rats

Tavares

Maldonado

Ojeda

et al. 2005

Clin Vaccine Immunol

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Gram-negative and gram-positive infections have been considered the most important causes of morbidity and mortality in patients with leukopenia following chemotherapy. However, discrimination between bacterial infections and harmless fever episodes is difficult. Because classical inflammatory signs of infection are often absent and fever is frequently the only sign of infection, the aim of this study was to assess the significance of serum interleukin-6 (IL-6), IL-10, macrophage inflammatory protein-2 (MIP-2), procalcitonin (PCT), and C-reactive protein (CRP) patterns in identifying bacterial infections during start of fever in normal and cyclophosphamide-treated (leukopenic) rats following an injection of lipopolysaccharide (LPS) or muramyl dipeptide (MDP) as a model for gram-negative and gram-positive bacterial infections. We found that, compared to normal rats, immunosuppressed animals exhibited significantly higher fevers and lesser production of all mediators, except IL-6, after toxin challenge. Moreover, compared to rats that received MDP, both groups of animals that received an equivalent dose of LPS showed significantly higher fevers and greater increase in serum cytokine levels. Furthermore, in contrast to those in immunocompetent rats, serum levels of IL-6 and MIP-2 were not significantly changed in leukopenic animals after MDP injection. Other serum markers such as PCT and CRP failed to discriminate between bacterial stimuli in both groups of animals. These results suggest that the use of the analyzed serum markers at an early stage of fever could give useful information for the clinician for excluding gram-negative from gram-positive infections.

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Section: Discussionsupporting

confidence: 85%

“…Chemotherapy-induced profound leukopenia in rats was achieved as described previously (24,26). In brief, rats were rendered leukopenic by i.p.…”

Section: Methodsmentioning

confidence: 99%

Circulating Inflammatory Mediators during Start of Fever in Differential Diagnosis of Gram-Negative and Gram-Positive Infections in Leukopenic Rats

Tavares

Maldonado

Ojeda

et al. 2005

Clin Vaccine Immunol

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“…Further studies investigating endotoxin and the endotoxin-induced cascade of cytokines are needed to understand the mechanisms by which endotoxin exerts its toxic effects in patients with neutropenia and to identify relevant mediators whose neutralization, in addition to endotoxin elimination, may improve the prognosis of patients with gram-negative sepsis. In a neutropenic rat model, for example, a combined therapeutic administration of monoclonal antibodies to serotype-specific P. aeruginosa endotoxin and tumor necrosis factor provided greater protection against experimental P. aeruginosa sepsis than did either monoclonal antibody alone (28).…”

Section: Discussion Irrelation Was Tounamentioning

confidence: 99%

“…Investigations in neutropenic animals indicated that both the therapeutic administration of a hyperimmune IgG antibody to P. aensginosa (29) and the therapeutic (28,42) or prophylactic (8) application of monoclonal IgG and IgM antibodies to species-specific endotoxin side chains protected against the corresponding homologous bacteria. A monoclonal IgM antibody (HA-1A) against lipid A of the E. coli J5 mutant, consisting of lipid A and some core sugars, also showed therapeutic efficacy and reduced mortality from heterologous Pseudomonas bacteremia (41).…”

Section: Discussion Irrelation Was Tounamentioning

confidence: 99%

Endotoxin concentration in neutropenic patients with suspected gram-negative sepsis: correlation with clinical outcome and determination of anti-endotoxin core antibodies during therapy with polyclonal immunoglobulin M-enriched immunoglobulins

Behre

Schedel

Nentwig

et al. 1992

Antimicrob Agents Chemother

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We carried out a study in patients with severe neutropenia from hematologic malignancy and suspected gram-negative sepsis to evaluate the clinical significance of endotoxin concentrations in plasma before and during a therapeutic intervention with a human polyclonal immunoglobulin M (IgM)-enriched immunoglobulin preparation (Pentaglobin; Biotest, Dreieich, Germany). Twenty-one patients with acute leukemia or nonHodgkin's lymphoma entered the study upon the development of clinical signs of gram-negative sepsis and received the IgM-enriched immunoglobulin preparation every 6 h for 3 days (total dose, 1.3 liter with 7.8 g of IgM, 7.8 g of IgA, and 49.4 g of IgG), in addition to standardized antibiotic treatment. Concentrations of endotoxin and IgM and IgG antibodies against lipid A and Re lipopolysaccharide (LPS) in plasma were determined by a modified chromogenic Limulus amebocyte lysate test and semiquantitative enzyme linked immunosorbent assay, respectively, before each immunoglobulin infusion and during the following 25 days. Seventeen patients were endotoxin positive; in five of these patients, gram-negative infection was confirmed by microbiologic findings. Prior to therapy, endotoxemia correlated significantly with the occurrence of fever, and a quantitative correlation between the endotoxin concentration and body temperature was found during the individual course of infection in 8 of the 17 patients. Overall mortality from endotoxin-positive sepsis was 41% (7 of 17) and 64% (7 of 11) in patients with symptoms of septic shock. Nonsurvivors had significantly higher maximum concentrations of endotoxin in plasma compared with those of survivors at the first study day (median of 126 versus 34 pg/ml; P < 0.05) and during the whole septic episode (median of 126 versus 61 pglml; P < 0.05). In survivors, immunoglobulin therapy resulted in a significant decrease in endotoxin levels in plasma within the initial 18-h treatment period, from a pretreatment median value of 28 pg/ml to a value of 8 pg/ml (P < 0.05). In the seven patients who died from uncontrollable infection, no effect of therapy on endotoxin levels in plasma was observed. IgM and IgG antibodies against Upid A and Re LPS increased significantly under immunoglobulin treatment, with significant correlations between antibodies against lipid A and Re LPS. These data strongly suggest a prognostic significance of the endotoxin levels in plasma and a potential effect of treatment with a polyclonal IgM-enriched immunoglobulin preparation. Further studies are needed to substantiate these findings and to assess the impact on the clinical course by way of a prospective placebo-controlled clinical trial.Despite the development of new and effective antimicrobial agents and their early application in combination regimens, gram-negative sepsis is still associated with an overall mortality of 20 to 40% (22,39,40) or even 40 to 75% in patients who develop clinical signs of septic shock (3,16,39,40). This high death rate is at least partly attributed to endotoxin, the lip...

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“…Additionally, neutralizing monoclonal antibodies, or receptor antagonists, directed against the proinflammatory cytokines tumor necrosis factor alpha (TNF-␣), interleukins 1, 6, and gamma interferon can protect animals against LPS-induced lethality (2,10,16,30). Current evidence suggests that, at least in experimental animals, a combination of antiendotoxin immunotherapy and anticytokine immunotherapy may be synergistic in preventing LPS lethality (8,24). In addition, recently published studies by our laboratory have provided evidence that targeting both the cytokine (gamma interferon) and its receptor with neutralizing monoclonal antibodies can lead to synergy in their ability to protect animals from a lethal LPS challenge (4).…”

mentioning

confidence: 99%

Therapeutic efficacy of a polymyxin B-dextran 70 conjugate in experimental model of endotoxemia

Bucklin

Lake

Lögdberg

et al. 1995

Antimicrob Agents Chemother

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Numerous studies have suggested that lipopolysaccharide (LPS), a major component of the cell wall of gram-negative bacteria, is responsible for the initiation of gram-negative septic shock. Previously, others have designed therapeutic regimens to target the biologically active lipid A region of LPS by either neutralization of the biological properties of LPS or enhancement of clearance of this molecule. One such compound capable of neutralizing lipid A is the antibiotic polymyxin B. However, the clinical utility of polymyxin B is limited by its toxicity. We therefore covalently conjugated this antibiotic to the high-molecular-weight polysaccharide dextran 70, resulting in reduced toxicity of polymyxin B but retention of its endotoxin-neutralizing ability. The studies described in this report were designed to test the in vivo efficacy of this compound in an experimental animal model of gram-negative septic shock. Mice were administered graded doses of Escherichia coli or Pseudomonas aeruginosa along with D-galactosamine and the antibiotic imipenem. We had previously determined that antibiotic chemotherapy provides significant protection against E. coli-mediated lethality with smaller doses of bacteria; however, the antibiotic does not provide protection against larger doses of bacteria, but it is effective at killing the bacterial inoculum in vivo. Administration of the polymyxin B-dextran 70 conjugate provided significant protection when given with an antibiotic but was not effective by itself. A requirement for a pretreatment period prior to E. coli challenge was shown to depend upon the bacterial challenge dose. In other studies using this D-galactosamine sensitization model, we demonstrated that the lipid A-specific conjugate had no effect on lethality caused by Staphylococcus aureus or tumor necrosis factor alpha. The results of these studies indicate that this compound is effective in preventing lethal gram-negative septic shock in mice and may be useful as a potential therapeutic agent in humans as well.

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

Cited by 62 publications

References 29 publications

Circulating Inflammatory Mediators during Start of Fever in Differential Diagnosis of Gram-Negative and Gram-Positive Infections in Leukopenic Rats

Circulating Inflammatory Mediators during Start of Fever in Differential Diagnosis of Gram-Negative and Gram-Positive Infections in Leukopenic Rats

Endotoxin concentration in neutropenic patients with suspected gram-negative sepsis: correlation with clinical outcome and determination of anti-endotoxin core antibodies during therapy with polyclonal immunoglobulin M-enriched immunoglobulins

Therapeutic efficacy of a polymyxin B-dextran 70 conjugate in experimental model of endotoxemia

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