Neutralization of Shwartzman‐Inducing Activity by Antibodies Recognizing the Re Core or Lipid A Structures of Lipopolysaccharide from <i>Salmonella minnesota</i> R595 and <i>Pseudomonas vesicularis</i> JCM1477

Three murine hybridomas secreting IgM monoclonal antibodies (MAbs) to lipid A (LA) of Salmonella minnesota R595 were generated. These MAbs serologically cross-reacted with LA and lipopolysaccharide (LPS) of unrelated gram-negative bacterial species. All three MAbs significantly suppressed the ability of LA and LPS from various gram-negative bacteria to induce tumor necrosis factor (TNF)-alpha (36%-67%) and interleukin-1 (30%-98%) in murine peritoneal macrophages and to stimulate B lymphocytes (37%-78%). Lipid A-induced TNF alpha production was also suppressed in mice (86%-88%). All three antibodies protected adrenalectomized mice against lethal shock induced by LA of S. minnesota R595. Optimal protection was achieved with one of the antibodies (MLA-1), if it was administered 2 h before injection of lipid A, and full protection persisted < or = 24 h. Moreover, MLA-1 was able to protect adrenalized or D(+)-galactosamine-sensitized mice against lethal shock induced by LPS derived from various gram-negative bacteria. This cross-protection could be predicted on the basis of serologic cross-reactivity and cross-neutralization by MLA-1 of the bioactivity of the heterologous LA or LPS in vitro.

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Inhibition of Lipid A- and Lipopolysaccharide-Induced Cytokine Secretion, B Cell Mitogenesis, and Lethal Shock by Lipid A-Specific Murine Monoclonal Antibodies

Ramachandra

Berczi

Sehon

et al. 1993

Journal of Infectious Diseases

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Role of Bacterial Endotoxin in Chronic Heart Failure

Charalambous

Stephens²,

Feavers³

et al. 2007

Shock

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Proinflammatory cytokines are now thought to play a key role in the pathophysiology of chronic heart failure, driving both symptomatic presentation and disease progression. We propose that this proinflammatory state, in turn, may be sustained through a chronic release of enterically derived bacterial endotoxin. Human trials have indicated that bacterial decontamination of the gut with concomitant decrease in lipopolysaccharide (LPS) has a positive outcome on heart disease patients. Antiendotoxin antibodies may thus represent therapeutic agents in this setting. Previously, antiendotoxin antibodies were targeted to the inner hydrophobic lipid A moiety of endotoxin in an attempt to neutralize its toxicity. These antibodies failed because they lacked specificity and bound to LPS weakly. In contrast, our studies on antiendotoxin antibodies have revealed that antibodies targeted to the hydrophilic oligosaccharides of the endotoxin have the potential to bind specifically with high affinity. Development of immunotherapeutics that can reduce systemic LPS or other agents, such as bactericidal/permeability-increasing protein that can neutralize LPS and limit inflammation safely, will enable the role of LPS in chronic heart failure to be elucidated and may pave the way to develop a new generation of effective therapeutic agents that may be directed to the treatment of chronic heart failure.

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In Vivo Production of Various Cytokines in Splenocytes of Sheep Erythrocyte‐Immunized Mice after Intravenous Administration of Bacterial Lipid A

Mashimo

Mita

1995

Microbiology and Immunology

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The effects of an intravenous administration of lipid A from Salmonella minnesota R595 lipopolysaccharide on the in vivo production of interleukin-2 (IL-2), IL-4, IL-5 and IL-6 in the spleens of mice intravenously immunized with sheep red blood cell (SRBC) antigen were investigated. The increased number of antigen-specific IgM antibody-producing cells and the titer of the IgM serum antibody were measured using the plaque-forming cell (PFC) assay and an enzyme-linked immunosorbent assay (ELISA). Simultaneous injections of SRBC antigen and lipid A adjuvant enhanced IgM-PFC number on days 3 and 4 and the serum IgM titer on days 4 and 5 after the immunization. We found that the enhanced IL-4 and IL-5 levels correlated with the PFC number and IgM titer. When lipid A was injected intravenously 2 days after immunization with SRBC, the PFC number in lipid A-treated groups were similar to those in controls 3 and 4 days after the immunization. However, it was found that a twofold increase in the IgM titer in serum was induced by lipid A 5 days after immunization. In relation to this increase, lipid A stimulated the production of only IL-5 among the cytokines tested.

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Neutralization of Shwartzman‐Inducing Activity by Antibodies Recognizing the Re Core or Lipid A Structures of Lipopolysaccharide from Salmonella minnesota R595 and Pseudomonas vesicularis JCM1477

Cited by 3 publications

References 28 publications

Inhibition of Lipid A- and Lipopolysaccharide-Induced Cytokine Secretion, B Cell Mitogenesis, and Lethal Shock by Lipid A-Specific Murine Monoclonal Antibodies

Inhibition of Lipid A- and Lipopolysaccharide-Induced Cytokine Secretion, B Cell Mitogenesis, and Lethal Shock by Lipid A-Specific Murine Monoclonal Antibodies

Role of Bacterial Endotoxin in Chronic Heart Failure

In Vivo Production of Various Cytokines in Splenocytes of Sheep Erythrocyte‐Immunized Mice after Intravenous Administration of Bacterial Lipid A

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