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Delivery of GM-CSF to Protect against Influenza Pneumonia.

Subramaniam R, Hillberry Z, Chen H, Feng Y, Fletcher K, Neuenschwander P, Shams H - PLoS ONE (2015)

Bottom Line: Granulocyte-macrophage colony stimulating factor (GM-CSF) contributes to maturation of mononuclear phagocytes, enhancing their capacity for phagocytosis and cytokine production.Overexpression of granulocyte macrophage-colony stimulating factor (GM-CSF) in the lung of transgenic mice provides remarkable protection against IAV, which depends on alveolar macrophages (AM).We also show that IAV-induced lung injury is the culprit for side-effects of GM-CSF in treating mice after IAV infection, and introduce a novel strategy to deliver the GM-CSF to and retain it in the alveolar space even after IAV infection.

View Article: PubMed Central - PubMed

Affiliation: Center for Pulmonary and Infectious Diseases Control (CPIDC), The University of Texas Health Science Center at Tyler, 11937 U.S. Highway 271, Tyler, TX, United States of America.

ABSTRACT

Background: Since adaptive immunity is thought to be central to immunity against influenza A virus (IAV) pneumonias, preventive strategies have focused primarily on vaccines. However, vaccine efficacy has been variable, in part because of antigenic shift and drift in circulating influenza viruses. Recent studies have highlighted the importance of innate immunity in protecting against influenza.

Methods: Granulocyte-macrophage colony stimulating factor (GM-CSF) contributes to maturation of mononuclear phagocytes, enhancing their capacity for phagocytosis and cytokine production.

Results: Overexpression of granulocyte macrophage-colony stimulating factor (GM-CSF) in the lung of transgenic mice provides remarkable protection against IAV, which depends on alveolar macrophages (AM). In this study, we report that pulmonary delivery of GM-CSF to wild type young and aged mice abrogated mortality from IAV.

Conclusion: We also demonstrate that protection is species specific and human GM-CSF do not protect the mice nor stimulates mouse immunity. We also show that IAV-induced lung injury is the culprit for side-effects of GM-CSF in treating mice after IAV infection, and introduce a novel strategy to deliver the GM-CSF to and retain it in the alveolar space even after IAV infection.

No MeSH data available.


Related in: MedlinePlus

Effect of treating IAV-infected aged mice with GM-CSF.(A&C) Aged (20-months old) C57Bl/6 WT mice (5/group) were treated with PBS or two mGM-CSF regimens, and then infected with a sublethal dose (0.1 LD50) of IAV PR8, 24 hrs after the last treatment. (B&D) Aged C57Bl/6 mice were treated with 1.3 μg mGM-CSF/g body weight (~26μg/mouse) or PBS daily for 1 week, and infected 24 hrs later with a lethal dose of PR8 (0.5 LD50). Weight loss and mortality were recorded daily. (E) Anatomical changes in the lungs of mGM-CSF-treated (E, left panel) and PBS-treated (E, right panel) aged mice after infection with IAV. Mice were treated and infected, as in panel B. Ten days post-infection, CT scanning was carried out, using a GE eXplore Locus micro CT scan. Transverse sections of the thorax are depicted.
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pone.0124593.g003: Effect of treating IAV-infected aged mice with GM-CSF.(A&C) Aged (20-months old) C57Bl/6 WT mice (5/group) were treated with PBS or two mGM-CSF regimens, and then infected with a sublethal dose (0.1 LD50) of IAV PR8, 24 hrs after the last treatment. (B&D) Aged C57Bl/6 mice were treated with 1.3 μg mGM-CSF/g body weight (~26μg/mouse) or PBS daily for 1 week, and infected 24 hrs later with a lethal dose of PR8 (0.5 LD50). Weight loss and mortality were recorded daily. (E) Anatomical changes in the lungs of mGM-CSF-treated (E, left panel) and PBS-treated (E, right panel) aged mice after infection with IAV. Mice were treated and infected, as in panel B. Ten days post-infection, CT scanning was carried out, using a GE eXplore Locus micro CT scan. Transverse sections of the thorax are depicted.

Mentions: It is known that elderly individuals are at higher risk for complications from influenza, and vaccination is less effective in this population [19]. Thus, in order to test the efficacy of GM-CSF-based therapy and to establish a protective regimen in aged mice, we delivered different doses of GM-CSF intranasally to the lungs of 20-months old WT mice. All PBS-treated aged mice infected with a sub-lethal dose (0.1 LD50) of PR8 lost weight, which they did not regain, and 1 of the 5 mice died (Fig 3A and 3C). In contrast, animals pretreated with two different regimens of GM-CSF (either 5 μg/day for 4 days or 10 μg/day for 3 days) regained weight by 14 days post-infection (Fig 3A). The protective effect of intranasal mGM-CSF was even more dramatic when the aged mice treated with high dose of mGM-CSF (1.3 μg mGM-CSF/g body weight (~26μg/mouse) for 1 week) and the infectious dose of PR8 was increased to 0.5 LD50. Animals pretreated with high dose mGM-CSF showed nominal weight loss and 87.5% survival compared to 29% for PBS-pretreated mice (Fig 3B and 3D). Micro-CT scanning provides great technology to evaluate disease severity in live animals. We used Micro-CT scanning (GE eXplore Locus) to evaluate anatomic changes and disease severity in live animals. On day 10 after IAV infection, micro-CT scanning was performed on the mGM-CSF- and PBS-treated control mice. PBS-treated IAV-infected aged mice showed extensive consolidation, reduced aerated lung volumes and pulmonary ground-glass opacities, indicative of severe pneumonia and/or pulmonary edema whereas mGM-CSF-treated mice infected with IAV had clear and normal lungs, as shown in transverse sections (Fig 3E).


Delivery of GM-CSF to Protect against Influenza Pneumonia.

Subramaniam R, Hillberry Z, Chen H, Feng Y, Fletcher K, Neuenschwander P, Shams H - PLoS ONE (2015)

Effect of treating IAV-infected aged mice with GM-CSF.(A&C) Aged (20-months old) C57Bl/6 WT mice (5/group) were treated with PBS or two mGM-CSF regimens, and then infected with a sublethal dose (0.1 LD50) of IAV PR8, 24 hrs after the last treatment. (B&D) Aged C57Bl/6 mice were treated with 1.3 μg mGM-CSF/g body weight (~26μg/mouse) or PBS daily for 1 week, and infected 24 hrs later with a lethal dose of PR8 (0.5 LD50). Weight loss and mortality were recorded daily. (E) Anatomical changes in the lungs of mGM-CSF-treated (E, left panel) and PBS-treated (E, right panel) aged mice after infection with IAV. Mice were treated and infected, as in panel B. Ten days post-infection, CT scanning was carried out, using a GE eXplore Locus micro CT scan. Transverse sections of the thorax are depicted.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4414562&req=5

pone.0124593.g003: Effect of treating IAV-infected aged mice with GM-CSF.(A&C) Aged (20-months old) C57Bl/6 WT mice (5/group) were treated with PBS or two mGM-CSF regimens, and then infected with a sublethal dose (0.1 LD50) of IAV PR8, 24 hrs after the last treatment. (B&D) Aged C57Bl/6 mice were treated with 1.3 μg mGM-CSF/g body weight (~26μg/mouse) or PBS daily for 1 week, and infected 24 hrs later with a lethal dose of PR8 (0.5 LD50). Weight loss and mortality were recorded daily. (E) Anatomical changes in the lungs of mGM-CSF-treated (E, left panel) and PBS-treated (E, right panel) aged mice after infection with IAV. Mice were treated and infected, as in panel B. Ten days post-infection, CT scanning was carried out, using a GE eXplore Locus micro CT scan. Transverse sections of the thorax are depicted.
Mentions: It is known that elderly individuals are at higher risk for complications from influenza, and vaccination is less effective in this population [19]. Thus, in order to test the efficacy of GM-CSF-based therapy and to establish a protective regimen in aged mice, we delivered different doses of GM-CSF intranasally to the lungs of 20-months old WT mice. All PBS-treated aged mice infected with a sub-lethal dose (0.1 LD50) of PR8 lost weight, which they did not regain, and 1 of the 5 mice died (Fig 3A and 3C). In contrast, animals pretreated with two different regimens of GM-CSF (either 5 μg/day for 4 days or 10 μg/day for 3 days) regained weight by 14 days post-infection (Fig 3A). The protective effect of intranasal mGM-CSF was even more dramatic when the aged mice treated with high dose of mGM-CSF (1.3 μg mGM-CSF/g body weight (~26μg/mouse) for 1 week) and the infectious dose of PR8 was increased to 0.5 LD50. Animals pretreated with high dose mGM-CSF showed nominal weight loss and 87.5% survival compared to 29% for PBS-pretreated mice (Fig 3B and 3D). Micro-CT scanning provides great technology to evaluate disease severity in live animals. We used Micro-CT scanning (GE eXplore Locus) to evaluate anatomic changes and disease severity in live animals. On day 10 after IAV infection, micro-CT scanning was performed on the mGM-CSF- and PBS-treated control mice. PBS-treated IAV-infected aged mice showed extensive consolidation, reduced aerated lung volumes and pulmonary ground-glass opacities, indicative of severe pneumonia and/or pulmonary edema whereas mGM-CSF-treated mice infected with IAV had clear and normal lungs, as shown in transverse sections (Fig 3E).

Bottom Line: Granulocyte-macrophage colony stimulating factor (GM-CSF) contributes to maturation of mononuclear phagocytes, enhancing their capacity for phagocytosis and cytokine production.Overexpression of granulocyte macrophage-colony stimulating factor (GM-CSF) in the lung of transgenic mice provides remarkable protection against IAV, which depends on alveolar macrophages (AM).We also show that IAV-induced lung injury is the culprit for side-effects of GM-CSF in treating mice after IAV infection, and introduce a novel strategy to deliver the GM-CSF to and retain it in the alveolar space even after IAV infection.

View Article: PubMed Central - PubMed

Affiliation: Center for Pulmonary and Infectious Diseases Control (CPIDC), The University of Texas Health Science Center at Tyler, 11937 U.S. Highway 271, Tyler, TX, United States of America.

ABSTRACT

Background: Since adaptive immunity is thought to be central to immunity against influenza A virus (IAV) pneumonias, preventive strategies have focused primarily on vaccines. However, vaccine efficacy has been variable, in part because of antigenic shift and drift in circulating influenza viruses. Recent studies have highlighted the importance of innate immunity in protecting against influenza.

Methods: Granulocyte-macrophage colony stimulating factor (GM-CSF) contributes to maturation of mononuclear phagocytes, enhancing their capacity for phagocytosis and cytokine production.

Results: Overexpression of granulocyte macrophage-colony stimulating factor (GM-CSF) in the lung of transgenic mice provides remarkable protection against IAV, which depends on alveolar macrophages (AM). In this study, we report that pulmonary delivery of GM-CSF to wild type young and aged mice abrogated mortality from IAV.

Conclusion: We also demonstrate that protection is species specific and human GM-CSF do not protect the mice nor stimulates mouse immunity. We also show that IAV-induced lung injury is the culprit for side-effects of GM-CSF in treating mice after IAV infection, and introduce a novel strategy to deliver the GM-CSF to and retain it in the alveolar space even after IAV infection.

No MeSH data available.


Related in: MedlinePlus