Skip to main content
NCBI home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1993 Feb;37(2):164–170. doi: 10.1128/aac.37.2.164

Therapeutic effects of a human antiflagella monoclonal antibody in a neutropenic murine model of Pseudomonas aeruginosa pneumonia.

K Oishi 1, F Sonoda 1, A Iwagaki 1, P Ponglertnapagorn 1, K Watanabe 1, T Nagatake 1, A Siadak 1, M Pollack 1, K Matsumoto 1
PMCID: PMC187632  PMID: 8383936

Abstract

Human immunoglobulin G1 (IgG1) monoclonal antibodies (MAbs) reactive with type-specific Pseudomonas aeruginosa lipopolysaccharide (LPS) and flagella were compared for their protective activities against Fisher immunotype 2 P. aeruginosa pneumonia in neutropenic mice. The activity of the antiflagella MAb at a dose of 500 micrograms per mouse was comparable to that of the anti-LPS MAb at the same dose. In vivo protection was correlated with bacterial density in the lung tissue and blood of infected mice. In vitro data suggested that the protective activity of the antiflagella MAb was due more to inhibition of bacterial motility than to opsonophagocytosis of bacteria by alveolar macrophages. In contrast, the protective activity of the anti-LPS MAb was primarily related to alveolar macrophage-mediated opsonophagocytosis. Antiflagella MAb at a dose of 500 micrograms combined with oral sparfloxacin at a subtherapeutic dose of 62.5 micrograms produced a significant increase in survival (P < 0.05) compared with that produced by either agent alone or no treatment. The additive effects between the antiflagella MAb and sparfloxacin at sub-MICs on the inhibitory effects of bacterial motility supported the in vivo effect of the combination. These data suggest that human isotype-matched antiflagella and anti-LPS MAbs have similar protective activities against Pseudomonas pneumonia in neutropenic mice, despite discrete mechanisms of antibody-matched protection. In addition, in vivo synergy was demonstrated between antiflagella MAb and sparfloxacin in this model.

Full text

PDF
164

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson T. R., Montie T. C. Flagellar antibody stimulated opsonophagocytosis of Pseudomonas aeruginosa associated with response to either a- or b-type flagellar antigen. Can J Microbiol. 1989 Sep;35(9):890–894. doi: 10.1139/m89-148. [DOI] [PubMed] [Google Scholar]
  2. Anderson T. R., Montie T. C. Opsonophagocytosis of Pseudomonas aeruginosa treated with antiflagellar serum. Infect Immun. 1987 Dec;55(12):3204–3206. doi: 10.1128/iai.55.12.3204-3206.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ansorg R. A., Knoche M. E., Spies A. F., Kraus C. J. Differentiation of the major flagellar antigens of Pseudomonas aeruginosa by the slide coagglutination technique. J Clin Microbiol. 1984 Jul;20(1):84–88. doi: 10.1128/jcm.20.1.84-88.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bryan C. S., Reynolds K. L. Bacteremic nosocomial pneumonia. Analysis of 172 episodes from a single metropolitan area. Am Rev Respir Dis. 1984 May;129(5):668–671. doi: 10.1164/arrd.1984.129.5.668. [DOI] [PubMed] [Google Scholar]
  5. Collins H. H., Cross A. S., Dobek A., Opal S. M., McClain J. B., Sadoff J. C. Oral ciprofloxacin and a monoclonal antibody to lipopolysaccharide protect leukopenic rats from lethal infection with Pseudomonas aeruginosa. J Infect Dis. 1989 Jun;159(6):1073–1082. doi: 10.1093/infdis/159.6.1073. [DOI] [PubMed] [Google Scholar]
  6. Collins M. S., Ladehoff D., Mehton N. S. Therapy of established experimental Pseudomonas aeruginosa infections with oral ciprofloxacin and five human monoclonal antibodies against lipopolysaccharide antigens. Antibiot Chemother (1971) 1991;44:185–195. doi: 10.1159/000420313. [DOI] [PubMed] [Google Scholar]
  7. Drake D., Montie T. C. Flagella, motility and invasive virulence of Pseudomonas aeruginosa. J Gen Microbiol. 1988 Jan;134(1):43–52. doi: 10.1099/00221287-134-1-43. [DOI] [PubMed] [Google Scholar]
  8. Drake D., Montie T. C. Protection against Pseudomonas aeruginosa infection by passive transfer of anti-flagellar serum. Can J Microbiol. 1987 Sep;33(9):755–763. doi: 10.1139/m87-130. [DOI] [PubMed] [Google Scholar]
  9. Holder I. A., Naglich J. G. Experimental studies of the pathogenesis of infections due to Pseudomonas aeruginosa: immunization using divalent flagella preparations. J Trauma. 1986 Feb;26(2):118–122. doi: 10.1097/00005373-198602000-00003. [DOI] [PubMed] [Google Scholar]
  10. Kojima T., Inoue M., Mitsuhashi S. In vitro activity of AT-4140 against clinical bacterial isolates. Antimicrob Agents Chemother. 1989 Nov;33(11):1980–1988. doi: 10.1128/aac.33.11.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. LaForce F. M. Hospital-acquired gram-negative rod pneumonias: an overview. Am J Med. 1981 Mar;70(3):664–669. doi: 10.1016/0002-9343(81)90593-3. [DOI] [PubMed] [Google Scholar]
  12. Luzar M. A., Thomassen M. J., Montie T. C. Flagella and motility alterations in Pseudomonas aeruginosa strains from patients with cystic fibrosis: relationship to patient clinical condition. Infect Immun. 1985 Nov;50(2):577–582. doi: 10.1128/iai.50.2.577-582.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Nakamura S., Kurobe N., Ohue T., Hashimoto M., Shimizu M. Pharmacokinetics of a novel quinolone, AT-4140, in animals. Antimicrob Agents Chemother. 1990 Jan;34(1):89–93. doi: 10.1128/aac.34.1.89. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Nakamura S., Minami A., Nakata K., Kurobe N., Kouno K., Sakaguchi Y., Kashimoto S., Yoshida H., Kojima T., Ohue T. In vitro and in vivo antibacterial activities of AT-4140, a new broad-spectrum quinolone. Antimicrob Agents Chemother. 1989 Aug;33(8):1167–1173. doi: 10.1128/aac.33.8.1167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ochi H., Ohtsuka H., Yokota S., Uezumi I., Terashima M., Irie K., Noguchi H. Inhibitory activity on bacterial motility and in vivo protective activity of human monoclonal antibodies against flagella of Pseudomonas aeruginosa. Infect Immun. 1991 Feb;59(2):550–554. doi: 10.1128/iai.59.2.550-554.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Oishi K., Koles N. L., Guelde G., Pollack M. Antibacterial and protective properties of monoclonal antibodies reactive with Escherichia coli O111:B4 lipopolysaccharide: relation to antibody isotype and complement-fixing activity. J Infect Dis. 1992 Jan;165(1):34–45. doi: 10.1093/infdis/165.1.34. [DOI] [PubMed] [Google Scholar]
  17. Oishi K., Sonoda F., Iwagaki A., Kobayashi S., Nagatake T., Matsumoto K. Effects of the combination of lipopolysaccharide-specific monoclonal antibodies and sparfloxacin against Pseudomonas aeruginosa pneumonia in neutropenic mice. Antimicrob Agents Chemother. 1992 Jul;36(7):1352–1357. doi: 10.1128/aac.36.7.1352. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Oishi K., Sonoda F., Miwa H., Tanaka H., Watanabe K., Matsumoto K., Pollack M. Pharmacodynamic and protective properties of a murine lipopolysaccharide-specific monoclonal antibody in experimental Pseudomonas aeruginosa pneumonia in mice. Microbiol Immunol. 1991;35(12):1131–1141. doi: 10.1111/j.1348-0421.1991.tb01634.x. [DOI] [PubMed] [Google Scholar]
  19. Pennington J. E., Reynolds H. Y., Carbone P. P. Pseudomonas pneumonia. A retrospective study of 36 cases. Am J Med. 1973 Aug;55(2):155–160. doi: 10.1016/0002-9343(73)90163-0. [DOI] [PubMed] [Google Scholar]
  20. Pennington J. E., Small G. J., Lostrom M. E., Pier G. B. Polyclonal and monoclonal antibody therapy for experimental Pseudomonas aeruginosa pneumonia. Infect Immun. 1986 Oct;54(1):239–244. doi: 10.1128/iai.54.1.239-244.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pier G. B., Small G. J., Warren H. B. Protection against mucoid Pseudomonas aeruginosa in rodent models of endobronchial infections. Science. 1990 Aug 3;249(4968):537–540. doi: 10.1126/science.2116663. [DOI] [PubMed] [Google Scholar]
  22. Pollack M. The virulence of Pseudomonas aeruginosa. Rev Infect Dis. 1984 Sep-Oct;6 (Suppl 3):S617–S626. doi: 10.1093/clinids/6.supplement_3.s617. [DOI] [PubMed] [Google Scholar]
  23. Reynolds H. Y., Kazmierowski J. A., Newball H. H. Specificity of opsonic antibodies to enhance phagocytosis of Pseudomonas aeruginosa by human alveolar macrophages. J Clin Invest. 1975 Aug;56(2):376–385. doi: 10.1172/JCI108102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Reynolds H. Y., Thompson R. E. Pulmonary host defenses. I. Analysis of protein and lipids in bronchial secretions and antibody responses after vaccination with pseudomonas aeruginosa. J Immunol. 1973 Aug;111(2):358–368. [PubMed] [Google Scholar]
  25. Rosok M. J., Stebbins M. R., Connelly K., Lostrom M. E., Siadak A. W. Generation and characterization of murine antiflagellum monoclonal antibodies that are protective against lethal challenge with Pseudomonas aeruginosa. Infect Immun. 1990 Dec;58(12):3819–3828. doi: 10.1128/iai.58.12.3819-3828.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Terashima M., Uezumi I., Tomio T., Kato M., Irie K., Okuda T., Yokota S., Noguchi H. A protective human monoclonal antibody directed to the outer core region of Pseudomonas aeruginosa lipopolysaccharide. Infect Immun. 1991 Jan;59(1):1–6. doi: 10.1128/iai.59.1.1-6.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Thompson K. M., Hough D. W., Maddison P. J., Melamed M. D., Hughes-Jones N. The efficient production of stable, human monoclonal antibody-secreting hybridomas from EBV-transformed lymphocytes using the mouse myeloma X63-Ag8.653 as a fusion partner. J Immunol Methods. 1986 Nov 20;94(1-2):7–12. doi: 10.1016/0022-1759(86)90208-5. [DOI] [PubMed] [Google Scholar]
  28. Uezumi I., Terashima M., Kohzuki T., Kato M., Irie K., Ochi H., Noguchi H. Effects of a human antiflagellar monoclonal antibody in combination with antibiotics on Pseudomonas aeruginosa infection. Antimicrob Agents Chemother. 1992 Jun;36(6):1290–1295. doi: 10.1128/aac.36.6.1290. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES