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Granulocyte-Macrophage Colony–Stimulating Factor and Lung Immunity in Pulmonary Alveolar Proteinosis

Institute of Development, Aging, and Cancer, Tohoku University; Department of Hematology and Immunology, Tohoku University Hospital; Sendai Kosei Hospital, Sendai; Research Institute, International Medical Center of Japan; Department of Human Pathology, Tokyo Medical and Dental University, Tokyo; National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka; Saitama Medical School, Saitama; and Niigata University Medical and Dental Hospital, Niigata, Japan

Correspondence and requests for reprints should be addressed to Koh Nakata, M.D., Ph.D., Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, Asahimachi-dori 1, Niigata, 951-8520, Japan. E-mail: knak{at}med.niigata-u.ac.jp

The anti–granulocyte-macrophage colony–stimulating factor (GM-CSF) autoantibody is inferred to cause idiopathic pulmonary alveolar proteinosis (iPAP): the antibody neutralizes GM-CSF and thereby impairs differentiation of alveolar macrophages. Administration of GM-CSF improves respiratory function of patients with iPAP, as confirmed in this study using aerosolized GM-CSF. To elucidate its mechanism, we characterized bronchoalveolar lavage fluid and alveolar macrophages obtained from three patients with iPAP who were treated successfully with aerosolized GM-CSF. Cell number, expressions of surface mannose receptor and the transcription factor PU.1, and phagocytic ability of alveolar macrophages were all restored to control levels. With treatment, the neutralizing capacity of GM-CSF activity was reduced markedly, concomitant with the decreasing autoantibody levels. Interestingly, the amount of GM-CSF autoantibody complex also decreased. In one case in which the complex was analyzed, the majority of GM-CSF binding the complex was endogenous protein, suggesting that the complex is removed immediately from the lung after treatment. Our study shows that GM-CSF administration engenders a decrease in the neutralizing capacity against the protein in the lungs. Thereby, it facilitates restoration of the normal function of alveolar macrophages.

Key Words: anti–GM-CSF antibody • bronchoalveolar fluid • GM-CSF • pulmonary alveolar proteinosis

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