Rituximab Depletes B-Lymphocytes and Improves Symptoms in Pulmonary Alveolar Proteinosis

Dalrymple, Heidi; Malur, Anagha; Gagnon, Gregory; Marshall, Irene; Kavuru, Mani S.; Barna, Barbara P.; Thomassen, Mary Jane

doi:10.1016/j.jaci.2007.12.890

Cited by 2 publications

(2 citation statements)

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“…Advances in the pathogenesis spawned several new therapeutic approaches for autoimmune PAP. These include plasmapheresis [99], GM-CSF augmentation [100; 101; 102; 103; 104], and rituximab [105; 106]. All are aimed at restoring signaling by GM-CSF, the first by removing the GM-CSF-blocking autoantibody, the second by augmenting GM-CSF beyond the neutralizing capacity of the antibody, and the third by depleting autoantibody-producing B lymphocytes.…”

Section: Therapy For Disorders Of Surfactant Homeostasismentioning

confidence: 99%

The molecular basis of pulmonary alveolar proteinosis

Carey¹,

Trapnell²

2010

Clinical Immunology

202

188

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Pulmonary alveolar proteinosis (PAP) comprises a heterogenous group of diseases characterized by abnormal surfactant accumulation resulting in respiratory insufficiency, and defects in alveolar macrophage-and neutrophil-mediated host defense. Basic, clinical and translational research over the past two decades have raised PAP from obscurity, identifying the molecular pathogenesis in over 90% of cases as a spectrum of diseases involving the disruption of GM-CSF signaling. Autoimmune PAP represents the vast majority of cases and is caused by neutralizing GM-CSF autoantibodies. Genetic mutations that disrupt GM-CSF receptor signaling comprise a rare form of hereditary PAP. In both autoimmune and hereditary PAP, loss of GM-CSF signaling blocks the terminal differentiation of alveolar macrophages in the lungs impairing the ability of alveolar macrophages to catabolize surfactant and to perform many host defense functions. Secondary PAP occurs in a variety of clinical diseases that presumedly cause the syndrome by reducing the numbers or functions of alveolar macrophages, thereby impairing alveolar macrophage-mediated pulmonary surfactant clearance. A similar phenotype occurs in mice deficient in the production of GM-CSF or GM-CSF receptors. PAP and related research has uncovered a critical and emerging role for GM-CSF in the regulation of pulmonary surfactant homeostasis, lung host defense, and systemic immunity.

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Section: Therapy For Disorders Of Surfactant Homeostasismentioning

confidence: 99%

The molecular basis of pulmonary alveolar proteinosis

Carey¹,

Trapnell²

2010

Clinical Immunology

202

188

View full text Add to dashboard Cite

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“…Thus, our data predict that a decrease in serum GMAb concentration below the critical threshold may be associated with resolution of PAP. This may be useful for predicting clinical responses to therapies that target reduction in GMAb levels (i.e., plasmapheresis [30,43] or rituximab-mediated depletion of antibodyproducing B lymphocytes [44]). Further, these results predict that spontaneous resolution of PAP may be associated with a fall in GMAb levels.…”

Section: Implications For the Biologic Role Of Gm-csf And Pathogenesimentioning

confidence: 99%

Patient-derived Granulocyte/Macrophage Colony–Stimulating Factor Autoantibodies Reproduce Pulmonary Alveolar Proteinosis in Nonhuman Primates

Sakagami

Beck

Uchida

et al. 2010

Am J Respir Crit Care Med

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Rationale: Granulocyte/macrophage colony-stimulating factor (GM-CSF) autoantibodies (GMAb) are strongly associated with idiopathic pulmonary alveolar proteinosis (PAP) and are believed to be important in its pathogenesis. However, levels of GMAb do not correlate with disease severity and GMAb are also present at low levels in healthy individuals. Objectives: Our primary objective was to determine whether human GMAb would reproduce PAP in healthy primates. A secondary objective was to determine the concentration of GMAb resulting in loss of GM-CSF signaling in vivo (i.e., critical threshold). Methods: Nonhuman primates (Macaca fascicularis) were injected with highly purified, PAP patient-derived GMAb in dose-ranging (2.2-50 mg) single and multiple administration studies, and after blocking antihuman immunoglobulin immune responses, in chronic administration studies maintaining serum levels greater than 40 mg/ml for up to 11 months. Measurements and Main Results: GMAb blocked GM-CSF signaling causing (1) a milky-appearing bronchoalveolar lavage fluid containing increased surfactant lipids and proteins; (2) enlarged, foamy, surfactant-filled alveolar macrophages with reduced PU.1 and PPARg mRNA, and reduced tumor necrosis factor-a secretion; (3) pulmonary leukocytosis; (4) increased serum surfactant protein-D; and (5) impaired neutrophil functions. GM-CSF signaling varied inversely with GMAb concentration below a critical threshold of 5 mg/ml, which was similar in lungs and blood and to the value observed in patients with PAP. Conclusions: GMAb reproduced the molecular, cellular, and histopathologic features of PAP in healthy primates, demonstrating that GMAb directly cause PAP. These results have implications for therapy of PAP and help define the therapeutic window for potential use of GMAb to treat other disorders.

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Rituximab Depletes B-Lymphocytes and Improves Symptoms in Pulmonary Alveolar Proteinosis

Cited by 2 publications

References 0 publications

The molecular basis of pulmonary alveolar proteinosis

The molecular basis of pulmonary alveolar proteinosis

Patient-derived Granulocyte/Macrophage Colony–Stimulating Factor Autoantibodies Reproduce Pulmonary Alveolar Proteinosis in Nonhuman Primates

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