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Biomedical subjects

J D Baumgartner

Publications and source records attributed to J D Baumgartner.

At least 19 recordsLinked to original sources
PubMed1992

Control of lipopolysaccharide (LPS) binding and LPS-induced tumor necrosis factor secretion in human peripheral blood monocytes.

We used flow cytometry to determine how LPS-binding protein (LBP) effects the binding of fluorescein-labeled LPS to human monocytes via receptor-dependent mechanisms. The addition of human, rabbit, mouse, or FCS strikingly increased the binding of LPS to monocytes compared with controls incubated in serum-free medium. This binding was totally prevented by preincubation of monocytes with MY4, an anti-CD14 mAb, or by enzymatic removal of CD14 from monocytes. Depletion of LBP from rabbit serum with anti-LBP antibodies also produced a similar suppression. Solutions of albumin did not support the enhanced binding observed in serum but the addition of purified rabbit LBP to albumin solutions resulted in binding similar to that observed in serum-containing medium. When type-specific anti-LPS mAb was added to human serum, LPS binding to monocytes occurred but was only partly inhibited by anti-CD14 mAb, suggesting that receptors other than CD14 (presumably Fc or complement receptors) were involved. Serum increased by 100- to 1000-fold the sensitivity of monocytes to the triggering by LPS resulting in TNF secretion. TNF secretion was inhibited by anti-CD14 mAb up to 100 ng/ml of LPS and by anti-LPS mAb up to 1 to 10 ng/ml. The inhibition of TNF secretion by anti-LPS mAb appeared to be the result of directing LPS to monocyte receptors other than CD14. In contrast, in medium containing normal as well as acute serum and in the absence of anti-LPS antibodies, the binding of LPS to monocytes and the triggering of TNF secretion appeared to be mediated mainly by interactions between CD14 and LBP-LPS complexes.

Acute-Phase Proteins↗
PubMed1992

Cytokine production after intravenous or peritoneal gram-negative bacterial challenge in mice. Comparative protective efficacy of antibodies to tumor necrosis factor-alpha and to lipopolysaccharide.

The production of TNF-alpha, IL-1, and IL-6 was measured in mice after bolus i.v. Escherichia coli O111 LPS injections and during bacteremia induced either by bolus i.v. or by i.p. challenges of live E. coli O111. High but transient TNF-alpha peaks were observed after bolus i.v. LPS or bacterial challenges. In contrast, the levels during lethal peritonitis increased progressively to values 50- to 100-fold lower than the peak values observed after i.v. injections, and remained sustained until death. Whereas after i.v. challenge with 1000 LD50 of LPS, anti-TNF-alpha antibody fully protected mice from death and reduced serum IL-1 and IL-6 levels, anti-TNF-alpha antibody did not improve the survival of mice nor reduced serum IL-1 and IL-6 levels after i.p. bacterial challenge. In contrast to anti-TNF-alpha antibodies, anti-LPS antibodies were protective in the peritonitis model. Protection was accompanied by a striking reduction of bacterial numbers and of TNF-alpha, IL-1, and IL-6 levels in the serum, but the levels of these cytokines were only marginally affected in the peritoneal lavage fluid. This latter observation demonstrates that the local peritoneal cytokines did not diffuse readily into the circulation, thus suggesting that at least part of the circulating cytokines are produced systemically. In conclusion, the striking differences between cytokine profiles as well as the divergent efficacy of anti-TNF-alpha antibody after i.v. bolus and after i.p. challenges suggest that TNF-alpha may not be as important in the pathogenesis of lethal peritonitis than after lethal acute bacteremia.

Animals↗
PubMed1992

A novel score for predicting the mortality of septic shock patients.

OBJECTIVE: To establish a prognostic scoring system for septic shock patients. DESIGN: The clinical, biological, and hemodynamic data of these patients were retrospectively explored to select variables independently associated with outcome. According to the risk of death, ratings from 0 to 2 points were attributed to each value. SETTING: Medical intensive care service of a 1,000-bed tertiary care university medical center. PATIENTS: Eighty-eight patients in septic shock in whom hemodynamic measurements were performed using pulmonary artery flotation catheters. RESULTS: Fourteen clinical, biological, and hemodynamic variables were selected and rated for each patient. A Simplified Septic Shock Score, available immediately after admission and catheterization, was established by adding the rates of these variables. The mean Simplified Septic Shock Score was 2.5 +/- 1.7 (SD) in 43 survivors and 6.5 +/- 2.3 in 45 nonsurvivors (p less than .0001). Some underlying diseases and characteristics of infections also correlated with the outcome. Further ratings from 0 to 2 points were attributed to these conditions. A Complete Septic Shock Score was calculated by adding these rates to the Simplified Septic Shock Score. The Complete Septic Shock Score had a slightly better prognostic value than the Simplified Septic Shock Score, but it could be determined only after the availability of the microbiological data. The mean Complete Septic Shock Score was 3.1 +/- 1.9 in survivors and 8.4 +/- 2.6 in nonsurvivors (p less than .0001). Both Simplified and Complete Septic Shock Scores showed better association with patient outcome than the Simplified Acute Physiology Score or the Acute Physiology and Chronic Health Evaluation (APACHE II) score. CONCLUSIONS: The Simplified and the Complete Septic Shock Scores are simple scoring systems that appear to predict the outcome of septic shock patients more accurately than general scoring systems, such as the Simplified Acute Physiology Score and APACHE II score. These septic shock scores might be useful in assessing the severity of septic shock patients.

Adult↗
PubMed1991

High circulating levels of interleukin-6 in patients with septic shock: evolution during sepsis, prognostic value, and interplay with other cytokines. The Swiss-Dutch J5 Immunoglobulin Study Group.

PURPOSE AND PATIENTS: We measured the serum concentrations of interleukin-6 (IL-6) in 70 patients with established septic shock caused predominantly by gram-negative bacteria. The aims of the study were to determine whether and for how long IL-6 was detectable in the circulation of these patients, to assess whether IL-6 levels were associated with patients' outcomes, and, finally, to examine the interplay between IL-6, tumor necrosis factor (TNF), interleukin-1 beta (IL-1 beta), and interferon-gamma (IFN-gamma). RESULTS: IL-6 was detected in 64% of the patients at study entry but in only 18% on Day 1 and 2% on Day 10. Serum levels of IL-6 were higher (median: 3.5 ng/mL, range: less than 0.1 to 305 ng/mL) in patients dying of fulminant septic shock than in those surviving (median: 0.5 ng/mL, range: less than 0.1 to 135 ng/mL; p = 0.003) or in those with a transient reversal of shock but who ultimately died of a relapse of shock (median: less than 0.1 ng/mL, range: less than 0.1 to 12.5 ng/mL; p = 0.005). However, no cutoff values of IL-6 confidently predicted the outcome of an individual patient. The serum concentrations of IL-6 measured at study entry correlated with the duration of survival (r = -0.51, p = 0.004) and with the levels of TNF-alpha (r = 0.53; p less than 0.0001) but not with the levels of either IL-1 beta (r = 0.01, p = 0.90) or IFN-gamma (r = 0.06, p = 0.60). CONCLUSIONS: These results indicate that circulating levels of IL-6 are detectable in a majority of patients with gram-negative septic shock. Concentrations of IL-6 peaked near the onset of shock and rapidly decreased to undetectable levels within approximately 24 hours in most patients. Levels of IL-6 measured at study entry correlated with levels of TNF and with patients' outcomes. Yet, IL-6 does not appear to be a clinically useful laboratory test for predicting the outcome of an individual patient.

Adolescent↗
PubMed1991

Antibodies to core lipopolysaccharide determinants: absence of cross-reactivity with heterologous lipopolysaccharides.

Using monoclonal antibodies directed against defined epitopes of endotoxin core, this study demonstrated that the presentation of lipopolysaccharide (LPS) to antibodies is critical for measuring the specific binding of antibodies to LPS structures. False cross-reactive reactions apparently were observed when free core LPS or lipid A were used as antigens in ELISA, whereas coating with complexes of high-density lipoproteins with core LPS increased both the sensitivity and the specificity of the test compared with coating with free core LPS, so that nonspecific binding of antibodies was largely avoided. Using this technique, it was not possible to find broadly cross-reactive core LPS antibodies after immunization of rabbits and humans with rough mutants of gram-negative bacteria. These observations underscore the need for careful evaluation of the potential for cross-reactivity of antisera and of monoclonal antibodies directed against endotoxin core.

Animals↗
PubMed1991

Antibodies to lipopolysaccharides after immunization of humans with the rough mutant Escherichia coli J5.

To investigate whether immunization with Escherichia coli J5 boiled cells induces antibodies directed at deep core structures, antibodies against J5 lipopolysaccharide (LPS), Re LPS, and lipid A were measured in the serum of 70 volunteers before and 2 weeks after immunization. To improve the sensitivity and the specificity of ELISA, complexes of core LPS with high-density lipoproteins were used instead of free core LPS as antigens. A median three-fold increase in antibodies directed against J5 LPS was observed, but no significant increase in the antibodies against Re LPS or lipid A was found. Since J5 antiserum did not react with several smooth LPS or with Re LPS and lipid A, cross-reactivity could not be demonstrated. Thus, immunization of volunteers with E. coli J5 produced a modest specific antibody response against J5 LPS. The mechanism of protection previously observed with J5 antiserum remains unclear.

Antibodies, Bacterial↗
PubMed1991

Anti-lipopolysaccharide and anti-tumor necrosis factor/cachectin antibodies for the treatment of gram-negative bacteremia and septic shock.

Endotoxin is composed of lipid A, the toxic moiety, of the core region, a conserved structure among Gram-negative bacteria, and of the O-side chains, a highly variable part responsible for the antigenic specificity. The concept of cross-protection afforded by antiserum raised against the core region of endotoxin is supported by the following data: experimentally antiserum protected against infections caused by a wide range of Gram-negative bacteria or endotoxins; in patients with Gram-negative bacteremia, survival was associated with high levels of anti-core antibodies, and mortality was reduced by the prophylactic or therapeutic use of immune serum or plasma. However, the proof that protection is afforded by cross-protective anti-core antibodies is still lacking. Furthermore, many experimental studies and clinical studies trials have shown controversial results. Ongoing experimental studies and recently completed clinical trials, using either polyclonal or monoclonal anti-core antibodies should help clarify the issues both of the clinical efficacy and of the mechanism of protection. Tumor necrosis factor/cachectin has been unequivocally shown, both in experimental animal models and in humans to be a pivotal mediator of the clinical and humoral manifestations of shock induced by endotoxin or by whole Gram-negative bacteria. In humans, TNF was been transiently detected in the blood of volunteers challenged with endotoxin, in a small proportion of patients with Gram-negative sepsis, but in the vast majority of patients with established septic shock. However, in patients the magnitude and the evolution of the blood concentration of TNF differed from that observed in animal models or in human volunteers after an acute challenge with either Gram-negative bacteria or endotoxin, probably reflecting differences in infectious stimuli. In children with meningococemia and in adults with Gram-negative septic shock, TNF was associated with the patient's outcome. Anti-TNF monoclonal antibodies are presently undergoing clinical investigation in patients with septic shock. However, one should keep in mind that TNF serves both beneficial and detrimental functions depending upon its concentration in body fluids.

Antibodies, Monoclonal↗
PubMed1991

Anti-lipopolysaccharide antibodies in gram-negative bacteremia.

The experimental and clinical studies underlying the concept of cross-protection afforded by core lipopolysaccharides (LPS) antibodies are reviewed. These studies did not allow to clarify the epitope(s) and the effector mechanism(s) involved in the protection. Recently, two antilipid A IgM monoclonal antibodies, called E5 and HA-1A, have been investigated in patients with Gram-negative infections and a clinical picture of septicemia. E5 reduced the mortality of patients, bacteremic or not, but only as long as they were not in shock. A confirmatory study has been initiated. In contrast to E5, HA-1A protected patients in shock, but only when they were bacteremic at randomization. However, experimental studies have yielded contradictory results concerning the protective power of this antibody. Although the clinical studies suggest a beneficial effect of both antibodies in some patients, no definitive conclusions can be drawn until the extensive data will be published, and until further experimental investigations will have clarified the protective power of these antibodies.

Antibodies, Bacterial↗
PubMed1990

Association between protective efficacy of anti-lipopolysaccharide (LPS) antibodies and suppression of LPS-induced tumor necrosis factor alpha and interleukin 6. Comparison of O side chain-specific antibodies with core LPS antibodies.

Two-core LPS antibodies, the rabbit J5 polyclonal antiserum and the human anti-lipid A IgM mAb HA-1A, did not improve the survival of mice challenged with E. coli O111 or P. aeruginosa 3, or with the LPS extracted from them, and did not decrease the incidence of Shwartzman reactions in rabbits challenged with O111 LPS. In contrast, O side chain-specific rabbit antisera were protective in these models. The protection afforded by O side chain-specific antisera against endotoxin lethality was associated with decreased LPS-induced serum TNF and IL-6 levels, whereas core LPS antibodies had no effect on TNF or IL-6 levels. The absence of reduction of LPS-induced cytokines levels by core LPS antibodies suggests that these antibodies are not able to prevent the interactions between LPS and target cells.

Animals↗
PubMed1990

Monoclonal anti-endotoxin antibodies for the treatment of gram-negative bacteremia and septic shock.

The role of anti-endotoxin antibodies in the management of gram-negative bacteremia and the experimental and clinical studies on the cross-protection afforded by core LPS antibodies are reviewed. These studies did not achieve clarification of the epitope(s) and effector mechanism(s) involved in protection. Recently, two anti-lipid A IgM monoclonal antibodies, designated E5 and HA-1A, have been investigated in patients with gram-negative bacterial infections and clinical manifestations of septicemia. E5 reduced the mortality of patients if they were not in shock, whether they were bacteremic or not. A confirmatory study has been initiated. In contrast to E5, HA-1A protected patients whether they were in shock or not, but only when they were bacteremic at randomization. Although these studies suggest beneficial effects, the type of patients who may benefit from this expensive therapy should be further defined. Further investigations are needed to clarify the mechanisms of protection of these antibodies.

Antibodies, Bacterial↗