Pulmonary alveolar proteinosis (PAP) is a very rare lung disease characterized by the accumulation of surfactant material within the alveoli. Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) deficient mice develop a PAP like syndrome which is corrected by exogenous GM-CSF, suggesting a pivotal role for GM-CSF in normal lung homeostasis and clearance of surfactant. Administration of exogenous GM-CSF ameliorates lung disease in a subset of PAP patients, providing support for GM-CSF role in human PAP. Monocytes and alveolar macrophages from PAP patients produce GM-CSF and respond to GM-CSF, indicating no intrinsic defects in their ability to produce GM-CSF or in the GM-CSF receptor. Further, all PA patients tested have antibodies against GM-CSF in the BAL and serum. Iinterleukin-10 (IL-10), a pleiotropic cytokine which stimulates antibody production, is also a potent inhibitor of GM-CSF production from alveolar macrophages. PAP patients have less detectable GM-CSF in bronchoalveolar lavage fluids (BAL) but higher levels of IL-10 than healthy controls. IL-10 polymorphisms have been associated with increased IL-10 in some autoimmune diseases, but not yet in PAP. A polymorphism in the GM-CSF gene of a single PAP patient has been described, although the functional significance has not been studied. Based on these data, the investigators hypothesize that in PAP, the availability of GM-CSF is decreased by anti-GM-CSF antibodies and by elevated levels of IL-10 and these events in PAP may be associated with polymorphisms in the IL-10/GM-CSF genes. In the context of an open-label Phase II clinical trail of treatment with subcutaneous GM-CSF for patients presenting with exacerbations of idiopathic or primary PAP, the applicant's propose the following aims: (1) Define the clinical significance of free GM-CSF, anti-GM-CSF antibodies and GM-CSF/antibody complexes in PAP patients with differential response to GM-CSF therapy (responders versus non-responders). (2) Determine mechanisms of decreased GM-CSF availability by investigating (1) Role of GM-CSF antibody production in PAP by mapping epitope(s) recognized by GM-CSF antibody and (b) Role of IL-10 in PAP by determining cellular source of IL-10 in PAP, the effect of IL-10 on GM-CSF production and the effect of IL-10 on B cell proliferation and antibody production of PAP patients. (3) Determine the association of PAP with polymorphisms in the IL-10/GM-CSF genes by sequence analysis. The long-term objective of this proposal is to delineate the role of anti-GM-CSF antibodies and IL-10 in decreasing the availability of GM-CSF, which is pivotal in the pathophysiology of alveolar proteinosis. The applicants feel that these studies coupled with data from the GM-CSF clinical trial will provide novel insights into the basic mechanisms underlying human PAP.
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