: Pneumocystis carinii is the prototypical opportunistic pathogen in the lung. P. carinii pneumonia only occurs with profound immunosuppression that is often characterized by functional or absolute deficiencies in T and B lymphocytes. Alveolar macrophages (AMs) are the resident immunoregulatory cells of the alveolar spaces and are responsible for clearance of P. carinii organisms from the lung. The same factors that induce immunosuppression such as infections (HIV) or drugs (cytotoxic therapy or corticosteroids) directly and indirectly impair AM function and their ability to clear opportunistic infection such as P. carinii. Important immunomodulators that activate AM function include cytokines e.g. interferon-gamma (IFN-g) or tumor necrosis actor-a (TNF-a) are often deficient during immunodeficiency. Multiple studies have demonstrated the importance of T and B lymphocytes in the host response to P. carinii, often by reconstituting these cells into immunodeficient animals and restoring host defense. The critical role of the AM in the response is often assumed or ignored. We have developed new experimental approaches to assess the critical role of the AMs in vivo in alveolar host defense. This proposal will test the following hypothesis: Host susceptibility to infections such as P. carinii is due in part to deficiencies in AM function and factors that regulate AM function; conversely, correction of these defects will restore normal alveolar host response and control infection.
The Specific Aims will include: I .To demonstrate that reconstitution of normal or activated AMs will restore local alveolar host defense in recipient SCID or immunodeficient mice; 2. To determine if reconstituted AM significantly enhance attachment/phagocytosis/killing of P. carinii and control of alveolar infection/pneumonia; 3. To determine the role of proinflammatory cytokines on the ability of reconstituted AMs to attach/phagocytose/kill P. carinii and to control alveolar infection/pneumonia; 4. To determine if ex vivo gene therapy to AMs corrects immune deficiencies in alveolar host defense and controls P. carinii alveolar infection/pneumonia. If successful, these studies may suggest it is possible to restore local alveolar host defense in an immunodeficient host despite ongoing systemic immunosuppression.
| Hussain, Shabbir; Wright, Jo Rae; Martin 2nd, William J (2003) Surfactant protein A decreases nitric oxide production by macrophages in a tumor necrosis factor-alpha-dependent mechanism. Am J Respir Cell Mol Biol 28:520-7 |
| Wu, M; Pasula, R; Smith, P A et al. (2003) Mapping alveolar binding sites in vivo using phage peptide libraries. Gene Ther 10:1429-36 |
| Zhang, D; Wu, M; Nelson, D E et al. (2003) Alpha-1-antitrypsin expression in the lung is increased by airway delivery of gene-transfected macrophages. Gene Ther 10:2148-52 |
| Pasula, Rajamouli; Weaver, Todd; Martinez, Manuel A et al. (2002) Morphologic detection and functional assessment of reconstituted normal alveolar macrophages in the lungs of SCID mice. J Immunol 169:4504-10 |
