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.

Abstract

The core region of LPS has a relatively similar structure in various Gram-negative bacteria, whereas the outermost O side chains are responsible for the marked antigenic diversity among Gram-negative bacteria. O side chain-specific antibodies protect against homologous strains but not against heterologous strains in animal models . The core region of LPS is exposed at the surface of the O side chain-lacking rough mutants, among which Escherichia coli J5 and Salmonella minnesota R595 have been the most studied. After immunization with such mutants, antisera ofrabbits or humans contain antibodies directed against core LPS. These antisera have been reported to protect against challenge with heterologous Gram-negative bacteria or smooth LPS (1-5). Recent publications of crossprotection afforded by core US mAbs seemed to support the concept that core LPS antibodies might have a role in the management of Gram-negative infections . The crossprotection reported against cutaneous Shwartzman reactions in rabbits or against Gram-negative bacterial peritonitis in mice with an anti-lipid A human IgM mAb HA-1A (6) was so impressive that a major multicenter clinical study has been undertaken in patients with severe Gramnegative bacteremia . The mechanisms ofthe postulated protection afforded by core LPS antibodies remain, however, largely unknown. Whereas O side chain-specific antibodies have been shown to increase the serum bactericidal activity against homologous Gram-negative bacteria and to increase the intravascular clearance of homologous bacteria or LPS (7, 8), core LPS antibodies did not increase significantly This study was supported by grants 3.825-0 .86 and 35-25550 .88 from the Fonds National Suisse de la Recherche Scientifique .

Competition between Bactericidal/Permeability-Increasing Protein and Lipopolysaccharide-Binding Protein for Lipopolysaccharide Binding to Monocytes

“…Under the conditions used in this study, TNFa release by lymphocytes present in the PBMC fraction was negligible [19]. The cytotoxic activity of TNFa was measured on WEHI clone 13 cells as described [20,21].…”

Use of Immunoglobulins in Prevention and Treatment of Infection in Critically III Patients: Review and Critique

“…Indeed, using purified MoAb instead of crude hybridomal fluid, we could not demonstrate that HA-IA could be protective [26] in models very similar to those used by Teng et al [30]. In addition, in contrast to type-specific LPS antibodies, HA-IA did not suppress LPS-induced secretion of tumor necrosis factor in mice, a circumstance suggesting that HA-IA was not able to prevent LPS from reaching its target on macrophages [26].…”

“…Some investigators, however, were unable to obtain similar results [19][20][21][22][23][24][25][26][27][28]. For instance, Greisman and Johnston [27] found that mice inoculated with LPS from S. minnesota, Salmonella typhimurium, E. coli 0127, or E. coli 0111 were not protected by either of the two antisera to the J5 and Re mutants; the mortality among these mice was even greater than the mortality for mice that received only saline.…”

“…Moreover, the animal models studied, the mode of challenge, and the nature of LPS or of bacteria used for challenge are parameters that all could have an impact on the protective efficacy of these preparations [29]. However, these considerations cannot explain all the discrepancies in data; varying results were sometimes obtained despite the use of similar antibodies, similar animal models, and similar bacterial or LPS challenges [8,9,26,27,30]. Therefore, it can bepostulated that additional, unknown negative or positive factors sometimes operate.…”

“…Indeed, when the HA-IA MoAb was tested experimentally by two independent groups, it showed divergent efficacy that was possibly related to its degree of purification [26,30]. The other antibody, the E5 MoAb, only once has been reported to be moderately efficacious in animals when tested as ascitic fluid.…”