Cytokine Dysregulation in GM-CSF Autoimmunity

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DESCRIPTION (provided by applicant): Idiopathic pulmonary alveolar proteinosis (PAP) is a newly recognized autoimmune disorder characterized by neutralizing autoantibodies to granulocyte-macrophage colony stimulating factor (GMCSF) and severely dysregulated lung surfactant metabolism, the GM-CSh requirement in normal surfactant homeostasis is evidenced by studies of GM-CSF-deficient mice which develop a PAP-like syndrome reversible with exogenous GM-CSF. How GM-CSF maintains surfactant homeostasis is unknown. Human PAP alveolar macrophages (AM) can produce and respond to GM-CSF but have low expression of the nuclear transcription factor, peroxisome proliferator-activated receptor qamma (PPARgamma). GM-CSF upregulates PPARgamma, suggesting a GM-CSF-PPARgamma link in human PAP. Interestingly, PPARgamma deficiency is also linked to B cell hyperactivity and autoimmunity in experimental models. Other cytokine anomalies associated with B cell dysfunction occur in PAP. lnterleukm-10 (IL-10), a pleiotropic cytokine that stimulates antibody synthesis, is elevated in PAP lung and blood and blocks AM GM-CSF production. Activin A, a cytokine that may restrain B cell cycling, is upregulated by GM-CSF, and is also reduced in PAP. Thus, these data suggest that the presence of neutralizing auto-antibodies to GMCSF in PAP results in cytokine dysregulation, severely impaired surfactant catabolism and clinical disease. Depletion of B lymphocytes has shown promising clinical results in autoimmune disease. Rituximab, a chimeric murine-human monoclonal antibody directed against the B cell-specific membrane antigen CD20, selectively depletes B cells. Based upon our PAP data, it is hypothesized that reducing PAP B Cells in the context of a Rituximab clinical trial will diminish levels of anti- GM-CSF antibodies, and thus resolve pulmonary disease. Mechanism studies outlined in Aims 1-3 will be conducted on immune cells from lung and blood at baseline and post Rituximab therapy. Aim 1 will investigate: (a) effects of IL-10, activin A, and PPARgamma on untreated PAP B cell proliferation and anti- GM-CSF synthesis; and (b) B cell levels and anti-GM-CSF liters. Aim 2 will examine the role of PAP AM in localized B-cell regulation, specifically: (a) GM-CSF effect on expression of IL-10, activin A and follistatin, (activin A inhibitor); and (b) activin A effect on PPARgamma expression. Aim 3 will examine PAP T cells for: (a) regulation of PAP B cell synthesis of anti-GM-CSF; and (b) regulatory phenotype (CD4/CD25, PPARgamma expression), cytokines (activin A, IL-2, IL-10), and proliferation. The long-term objective of this application is to delineate relationships among immune cells, cytokines and anti-GM-CSF autoantibody in PAP pathophysiology. The rituximab trial offers a unique opportunity to explore effects of B cell depletion on PAP pulmonary AM function and at the same time investigate new therapy that may improve the lung disease in PAP.