ANTIBODY IMMUNOTHERAPY OF GRAM-NEGATIVE BACTERIAL SEPSIS IN AN IMMUNOSUPPRESSED ANIMAL MODEL

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Abstract
Leukopenia, immunosuppressed recipients of solid organ allografts are at high risk for gram-negative bacteria sepsis, and mortality remains unacceptably high (> 30%). The purpose of this study was to determine whether murine monoclonal antibody (MAb) directed against lipopolysaccharide (LPS, endotoxin) would reduce lethality caused by a septic insult in immunosuppressed mice, and to determine if a specific antibody class would prove more efficacious in this setting. Two MAbs (3-H9 IgG3; 7-B5, IgM) were selected that reacted by ELISA, immunodot blot, and Western blot analysis against the O antigen polysaccharide portion of Escherichia coli 0111:B4 LPS. The 3-H9 MAb, 7B-5 MAb, or sterile saline was administered i.v. to normal or neutropenic Swiss-Webster mice immediately prior to an E. coli 0111-B4 bacterial (i.v. or i.p. plus hemoglobin) or LPS (i.v.) challenge. In normal mice, administration of 3-H9 MAb or 7-B5 MAb i.v. immediately prior to a bacterial or endotoxin challenge resulted in a significant increase in the LD50. Neutropenia lowered the LD50 by nearly one log10 in both the bacteremia and peritonitis models. Both MAbs provided similar protection, raising the LD50 one log10 in neutropenic mice. Thus neutropenic animals receiving either MAb had a mortality nearly identical to that of normal animals receiving saline. No significant difference between the protective capacity of these MAbs was noted in any of the three models. These studies demonstrate that MAbs directed against LPS exert protection during gram-negative bacterial sepsis in either normal or neutropenic animals. In addition, the particular IgG and IgM MAbs examined provided similar protective capacity. Antibody directed against LPS may provide an additive form of therapy that may serve to decrease lethality during clinical gram-negative sepsis in immunosuppressed patients.