Relationship of anti-GM-CSF antibody concentration, surfactant protein A and B levels, and serum LDH to pulmonary parameters and response to GM-CSF therapy in patients with idiopathic alveolar proteinosis

Seymour, JF; Doyle, Ian; Nakata, Koh; Presneill, Jeffrey; Schoch, Otto D.; Hamano, Emi; Uchida, Kanji; Fisher, R. Darryl; Dunn, AR

doi:10.1136/thorax.58.3.252

Cited by 101 publications

(69 citation statements)

References 40 publications

(45 reference statements)

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“…Ex vivo, purified GMAb reproduced the impairment of GM-CSF-stimulated leukocyte CD11b levels (i.e., the CD11b stimulation index) and other neutrophil abnormalities observed in patients with PAP (25). Notwithstanding, serum GMAb levels in patients with PAP do not correlate with disease severity (5,7). Further, GMAb are present in most or all healthy individuals (15), albeit at lower levels than in patients with PAP, and GMAb are routinely present and comprise the dominate anticytokine activity in pharmaceutical immunoglobulin prepared from healthy human individuals (26).…”

Section: What This Study Adds To the Fieldmentioning

confidence: 90%

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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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Section: What This Study Adds To the Fieldmentioning

confidence: 90%

“…Pulmonary leukocytosis also occurs (4). Serum levels of surfactant protein (SP)-A, SP-B, and SP-D are increased in patients with PAP and serve as useful biomarkers of disease activity (5)(6)(7).…”

mentioning

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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“…The correlation between the initial protein concentration and the time from diagnosis to first WLL (p50.015) seems to indicate that the abnormal lipoprotein burden of the lungs increases over time. Furthermore, the observed correlation between the initial protein concentration, duration of disease and well established biomarkers for PAP (serum LDH and BAL KL-6 levels) [31,32] suggests that also the initial protein concentration could have a role as biomarker.…”

Section: Discussionmentioning

confidence: 99%

Wash-out kinetics and efficacy of a modified lavage technique for alveolar proteinosis

Bonella

Bauer

Griese³

et al. 2012

Eur Respir J

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Whole lung lavage (WLL) is the standard treatment for pulmonary alveolar proteinosis (PAP). This study aimed to provide data about the kinetics of the protein wash-out, to identify factors influencing the protein concentration in the recovered fluid and to assess the efficacy of a modified lavage technique.Samples of 180 WLLs from 42 adult PAP patients were collected. 110 WLLs were performed according to the classical technique. In 70 WLLs, repeated manual ventilation was applied during the procedure. Spectrophotometry was used to measure the protein concentration in the recovered fluid.The initial protein concentration in the recovered fluid was 460 mg?dL -1 , the final concentration was 26 mg?dL -1 and the total amount of removed proteins during a lavage was 17.5 g. A history of dust exposure was associated with a higher residual protein concentration in the recovered fluid (p50.000013). The amount of removed proteins correlated inversely with the diffusing capacity of the lung for carbon monoxide (p50.001) and oxygen tension (p50.004). The modified technique removed a greater amount of proteins than the classical technique and prolonged the time to relapse (p50.011). Exposure to dust seems to influence the kinetics of the protein wash-out. Applying manual ventilation during the procedure can enhance the efficacy of WLL.

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“…Similarly, Seymour et al found no relationship between the serum anti-GM-CSF antibody concentration and disease severity or predicting the response to GM-CSF therapy. 135 The neutralizing capacity of the antibody has been stated to be a more accurate marker of disease severity. 136 …”

Section: Granulocyte Macrophage Colony Stimulating Factor Autoantibodmentioning

confidence: 99%

Pulmonary Alveolar Proteinosis

Khan

Agarwal

2011

Respir Care

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Relationship of anti-GM-CSF antibody concentration, surfactant protein A and B levels, and serum LDH to pulmonary parameters and response to GM-CSF therapy in patients with idiopathic alveolar proteinosis

Cited by 101 publications

References 40 publications

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

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

Wash-out kinetics and efficacy of a modified lavage technique for alveolar proteinosis

Pulmonary Alveolar Proteinosis

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