Respiratory infections due to Pseudomonas aeruginosa remain a significant health problem for immunocompromised hosts and cystic fibrosis (CF) patients. Efforts to control these infections with antibiotics and better pulmonary therapy have done little to reduce the high degree of mortality related to P. aeruginosa pneumonia. Immunotherapeutic interventions with active vaccination or passive therapy may impact significantly on this condition. It is the long term goal of this proposal to understand the role of antibodies and lymphocytes in protection against P. aeruginosa lung infections. Two murine models will be employed: one is a neutropenic mouse, which dies from P. aeruginosa pneumonia following intratracheal instillation of fewer than 20 organisms; the other is a chronic lung infection following intratracheal instillation of bacteria encased in agar beads. We will treat animals prior to infection with polyclonal and monoclonal human antibodies, or monoclonal mouse antibodies, to evaluate the role of antibodies of different immunoglobulin isotypes in protection. Another parameter to evaluate in protection and enhancement of lung clearance will be the specificity of these antibodies for different P. aeruginosa surface polysaccharide antigens. Studies are planned which will evaluate the role of T cell immunity in protection of neutropenic mice from pneumonia by adoptively transferring immune splenic and lung T cells to mice prior to challenge. The investigations planned here will also evaluate the contribution of host monokines, inter- leukin-1 and tumor necrosis factor, to the lung pathology resulting from chronic P. aeruginosa colonization. These data should provide important insights into which therapies, both active and passive immunotherapies and/or other pharacologic interventions, may have the most beneficial effect on P. aeruginosa lung infections.
