scholarly journals Inhaled granulocyte-macrophage colony stimulating factor for mild-to-moderate autoimmune pulmonary alveolar proteinosis - a six month phase II randomized study with 24 months of follow-up

2020 ◽  
Author(s):  
Xinlun Tian ◽  
Yanli Yang ◽  
Lulu Chen ◽  
Xin Sui ◽  
Wenshuai Xu ◽  
...  
Keyword(s):  
Treatment Group ◽  
Pulmonary Alveolar Proteinosis ◽  
Arterial Oxygen ◽  
Control Group ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Alveolar Proteinosis ◽  
Macrophage Colony ◽  
Observation Period

Abstract Background: Treatment of autoimmune pulmonary alveolar proteinosis (aPAP) by inhaled granulocyte-macrophage colony stimulating factor (GM-CSF) is considered safe and effective. Evidence of benefit from GM-CSG inhalation for mild to moderate aPAP patients is limited.Methods: In this multicenter, randomized, open-labeled clinical trial, 36 aPAP patients with mild to moderate disease severity were randomized into either the GM-CSF treatment group or control group. Inhaled GM-CSF was prescribed for 6 months, and patients received follow-up for another 18 months without treatment. Physiological features of the patients were analyzed.Results: There were 36 patients (19 in the treatment group, 17 in the control group) included. There were no significant differences in the primary endpoints as measured by the change of alveolar arterial oxygen gradient (A-aDO2) from the baseline values to the values obtained during treatment or during the following 18-month non-treatment observation period [control group vs. treatment group: 0.51±12.09 mmHg vs. -0.35±13.76 mmHg, p=0.848 (3 month); 1.85±11.21 mmHg vs. 7.31±8.81 mmHg, p=0.146 (6 months); 6.05±11.14 mmHg vs. 6.61±10.64mmHg, p=0.899 (24 months)]). Percentage of diffusion capacity predicted (DLCO%) and percentage of total lung capacity predicted (TLC%), however, were significantly improved in the treatment group by the end of the study (P=0.010 and 0.027). St. George Respiratory questionnaire (SGRQ) scores were better after 6 months treatment with GM-CSF compared to the control group, and the benefits of treatment were maintained throughout the observation period. No severe side effects were observed during the study.Conclusion: Six months of inhaled GM-CSF treatment had no effect on the alveolar–arterial oxygen gradient in patients with mild to moderate pulmonary alveolar proteinosis. There were changes in some clinical or laboratory measures, but no clinically important changes were noted at the end of study. (Clinical Trial Registry: NCT02243228, Registered on September 17, 2014, https://www.clinicaltrials.gov/ct2/show/NCT02243228?term=NCT02243228&draw=2&rank=1)

scholarly journals Inhaled granulocyte-macrophage colony stimulating factor for mild-to-moderate autoimmune pulmonary alveolar proteinosis - a phase II randomized study for 6 months and follow-up to 24 months

2020 ◽  
Author(s):  
Xinlun Tian ◽  
Yanli Yang ◽  
Lulu Chen ◽  
Xin Sui ◽  
Wenshuai Xu ◽  
...  
Keyword(s):  
Treatment Group ◽  
Pulmonary Alveolar Proteinosis ◽  
Arterial Oxygen ◽  
Control Group ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Alveolar Proteinosis ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Observation Period

Abstract Background: Treatment of autoimmune pulmonary alveolar proteinosis (aPAP) by inhaled granulocyte-macrophage colony stimulating factor (GM-CSF) is considered safe and effective. Evidences of benefit from GM-CSG inhalation for mild to moderate aPAP patients are limited. Methods: In this multicenter, randomized, open-labeled clinical trial, 36 aPAP patients with mild to moderate disease severity were randomized into either GM-CSF treatment group or control group. Inhaled GM-CSF was prescribed for 6 months, and patients were followed-up for another 18 months without treatment. Physiological features of the patients were analyzed.Results: There were 36 patients (19 in treatment group, 17 in control group) included. No significant difference in primary endpoints measured by the change of alveolar arterial oxygen gradient (A-aDO2) from the baseline value to the values obtained during treatment or during the following 18-month non-treatment observation period [control group vs. treatment group: 0.51±12.09 mmHg vs. -0.35±13.76 mmHg, p=0.848 (3 month); 1.85±11.21 mmHg vs. 7.31±8.81 mmHg, p=0.146 (6 months); 6.05±11.14 mmHg vs. 6.61±10.64mmHg, p=0.899 (24 months)]). Percentage of diffusion capacity predicted (DLCO%) and percentage of total lung capacity predicted (TLC%), however, were significantly improved in the treatment group at the end of the study (P=0.010 and 0.027). St. George Respiratory questionnaire (SGRQ) scores were better after 6 months treatment with GM-CSF than control group, and the benefits of treatment were maintained throughout the observation period. No severe side effects were observed during the study. Conclusion: Six months of inhaled GM-CSF treatment had no effect on the alveolar–arterial oxygen gradient in patients with mild to moderate pulmonary alveolar proteinosis. There were changes in some clinical or laboratory measures, but no clinically important changes were noted at the end of study.

scholarly journals Therapeutic effect of subcutaneous injection of low dose recombinant human granulocyte-macrophage colony-stimulating factor on pulmonary alveolar proteinosis

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Fen Zhang ◽  
Dong Weng ◽  
Yiliang Su ◽  
Chengsheng Yin ◽  
Li Shen ◽  
...  
Keyword(s):  
Subcutaneous Injection ◽  
Low Dose ◽  
Pulmonary Alveolar Proteinosis ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Alveolar Proteinosis ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Objective To observe the efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) for pulmonary alveolar proteinosis (PAP). Materials and methods A total of 55 patients with PAP were screened at Shanghai Pulmonary Hospital between May 2014 and May 2018. Among these, 42 were diagnosed with idiopathic PAP, 24 were included in this study, 20 were treated for 6 months, and 17 were followed up for additional 6 months. All patients received a subcutaneous injection of 75μg/d GM-CSF qd for 1 month. The therapeutic dose was adjusted according to the changes in the lesions of chest CT. If the lesions were absorbed, subcutaneous injections of 75μg/d GM- CSF qd and 75μg/d GM-CSF qod were given for 2 and 3 months, otherwise, the dose was increased to 150μg/d GM-CSF qd and 150μg/d qod for 2 and 3 months, respectively. All cases were treated once a day in the first 3 months and once every other day in the last 3 months. The total course of treatment was 6 months. After withdrawal, the patients were followed up for another 6 months. The deadline of follow up was September 30, 2019. Results Twenty patients completed the treatment and efficacy evaluation. One patient was completely cured, 16 cases improved, three cases were noneffective. After 1-month evaluation, 12 patients received an increased dose (150μg) from the second month of treatment. Seventeen patients completed the 12-month follow-up, among which fourteen improved. CT showed the lesions were slightly increased in three cases. Economic burden was the following: RMB 7324–15,190 Yuan were required for the 6-month treatment course, which is significantly lower compared to other treatment methods. Conclusion Subcutaneous injection of rhGM-CSF at low dose (75μg-150μg /d) is effective treatment for patients with idiopathic PAP. Trial registration NCT01983657. Registered 16 April 2013.

scholarly journals The pulmonary alveolar proteinosis in granulocyte macrophage colony-stimulating factor/interleukins 3/5 beta c receptor-deficient mice is reversed by bone marrow transplantation.

1996 ◽  
Vol 183 (6) ◽  
pp. 2657-2662 ◽  
Author(s):  
R Nishinakamura ◽  
R Wiler ◽  
U Dirksen ◽  
Y Morikawa ◽  
K Arai ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Pulmonary Alveolar Proteinosis ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Alveolar Proteinosis ◽  
Macrophage Colony ◽  
Stimulating Factor

Mice mutant for granulocyte macrophage colony-stimulating factor (GM-CSF) or the common receptor component (beta c) for GM-CSF, interleukin (IL)-3, and IL-5 exhibit a lung disorder similar to human pulmonary alveolar proteinosis, a rare disease with congenital, infantile, and adult forms. Bone marrow transplantation and hematopoietic reconstitution of beta c mutant mice with wild-type bone marrow reversed the established disease state in the lungs, defining this disease as hematopoietic in nature. It is likely that the disease involves alveolar macrophages, as donor myeloid cell engraftment into the lungs of mutant recipient mice correlated with reverting both the disease and an abnormal macrophage morphology seen in the lungs of affected animals. Recombination Activating Gene-2 mutant donor bone marrow, which lacks the potential to develop lymphocytes, reversed the pathology in the lungs to the same extent as whole bone marrow. These data establish that certain lung disorders, if of cell-autonomous hematopoietic origin, can be manipulated by bone marrow transplantation.

Molecular structure of human GM-CSF in complex with a disease-associated anti-human GM-CSF autoantibody and its potential biological implications

2012 ◽  
Vol 447 (2) ◽  
pp. 205-215 ◽  
Author(s):  
Michaela Blech ◽  
Daniel Seeliger ◽  
Barbara Kistler ◽  
Margit M. T. Bauer ◽  
Mathias Hafner ◽  
...  
Keyword(s):  
Pulmonary Alveolar Proteinosis ◽  
Complex Structure ◽  
Structural Basis ◽  
Gm Csf ◽  
Reliable Model ◽  
Perturbation Data ◽  
Macrophage Colony Stimulating Factor ◽  
Alveolar Proteinosis ◽  
Macrophage Colony ◽  
Stimulating Factor

Polyclonal autoantibodies against human GM-CSF (granulocyte/macrophage colony-stimulating factor) are a hallmark of PAP (pulmonary alveolar proteinosis) and several other reported autoimmune diseases. MB007 is a high-affinity anti-(human GM-CSF) autoantibody isolated from a patient suffering from PAP which shows only modest neutralization of GM-CSF bioactivity. We describe the first crystal structure of a cytokine-directed human IgG1λ autoantibody-binding fragment (Fab) at 1.9 Å (1 Å=0.1 nm) resolution. Its CDR3-H substantially differs from all VH7 germline IgG1 structures reported previously. We derive a reliable model of the antigen–autoantibody complex by using NMR chemical shift perturbation data in combination with computational methods. Superposition of the modelled complex structure with the human GM-CSF–GM-CSF ternary receptor complex reveals only little overlap between receptor and Fab when bound to GM-CSF. Our model provides a structural basis for understanding the mode of action of the MB007 autoantibody.

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