The most common cause of death among patients with cystic fibrosis (CF) is prolonged purulent bronchitis caused by Pseudomonas aeruginosa, resulting in eventual respiratory failure. Antibiotic therapy has been unsuccessful in eradicating Pseudomonas lung infection among these patients. Accordingly, alternative clinical strategies for prevention or treatment of Pseudomonas respiratory infection in CF patients are essential. Recent work in our laboratory has demonstrated that active immunization of guinea pigs with lipopolysaccharide Pseudomonas vaccine produces significant protection against subsequent experimentally induced chronic Pseudomonas pneumonia. This lung protection was manifested by reduced numbers of Pseudomonas in the lungs of vaccinees and also reduced pulmonary histopathology. The present proposal is designed to expand these studies. Specifically, a variety of immunizing regimens will be evaluated to determine the most feasible yet protective method for active immunization with LPS Pseudomonas vaccine. Also, immunologic methods will be studied to evaluate prospective systems of monitoring the degree of pulmonary protection after vaccination. Further, an evaluation of the mechanisms by which LPS vaccine confers pulmonary protection will be carried out. Specifically, humoral and cellular immune responses, plus intrapulmonary immune events will be evaluated. And finally, the adverse and/or beneficial effects of glucocorticosteroid administration during chronic Pseudomonas lung infection will be assessed; and the interaction of LPS immunization and steroids in this model will be determined. It is our intent that these studies provide the requisite pre-clinical data necessary for determining the feasibility and planning the methodology for a clinical trial of prophylactic Pseudomonas immunization among cystic fibrosis patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI022534-01
Application #
3133733
Study Section
Bacteriology and Mycology Subcommittee 1 (BM)
Project Start
1984-12-01
Project End
1987-11-01
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
Stegmann, T; Schoen, P; Bron, R et al. (1993) Evaluation of viral membrane fusion assays. Comparison of the octadecylrhodamine dequenching assay with the pyrene excimer assay. Biochemistry 32:11330-7
Bron, R; Wahlberg, J M; Garoff, H et al. (1993) Membrane fusion of Semliki Forest virus in a model system: correlation between fusion kinetics and structural changes in the envelope glycoprotein. EMBO J 12:693-701
Pier, G B; Grout, M; Desjardins, D (1991) Complement deposition by antibodies to Pseudomonas aeruginosa mucoid exopolysaccharide (MEP) and by non-MEP specific opsonins. J Immunol 147:1869-76
Garner, C V; DesJardins, D; Pier, G B (1990) Immunogenic properties of Pseudomonas aeruginosa mucoid exopolysaccharide. Infect Immun 58:1835-42
Pier, G B; Small, G J; Warren, H B (1990) Protection against mucoid Pseudomonas aeruginosa in rodent models of endobronchial infections. Science 249:537-40
Pennington, J E; Small, G J (1987) Passive immune therapy for experimental Pseudomonas aeruginosa pneumonia in the neutropenic host. J Infect Dis 155:973-8
Pennington, J E (1987) Therapeutic strategies for Pseudomonas aeruginosa pneumonia in the myelosuppressed host. Antibiot Chemother 39:51-9
Pennington, J E; Small, G J; Lostrom, M E et al. (1986) Polyclonal and monoclonal antibody therapy for experimental Pseudomonas aeruginosa pneumonia. Infect Immun 54:239-44
Pennington, J E; Pier, G B; Sadoff, J C et al. (1986) Active and passive immunization strategies for Pseudomonas aeruginosa pneumonia. Rev Infect Dis 8 Suppl 4:S426-33