Immunomodulatory asthma therapy in the equine animal model: A dose-response study and evaluation of a long-term effect

John Klier; Carolin Bartl; Sabine Geuder; Katharina J. Geh; Sven Reese; Lutz S. Goehring; Gerhard Winter; Heidrun Gehlen

doi:10.1002/iid3.252

Immunomodulatory asthma therapy in the equine animal model: A dose-response study and evaluation of a long-term effect

John Klier, Carolin Bartl, Sabine Geuder, Katharina J. Geh, Sven Reese, Lutz S. Goehring, Gerhard Winter, Heidrun Gehlen

Veterinary Science

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Introduction: Equine asthma represents a naturally occurring animal model for human allergic neutrophilic asthma. Inhalative nanoparticle-bound cytosine-phosphate-guanosine (CpG-GNP) immunotherapy, independent of specific allergens, has already shown promising clinical and immunological results in previous studies and offers the possibility to treat the underlying cause of the disease. This study analyses the relationship between dose and response, and evaluates a possible long-term effect. Methods: In the prospective, randomised, double-blind clinical field study, 29 horses suffering from equine asthma received 10 inhalation treatments with either 187.5 µg CpG-GNP (CpG single dose [CpGsd]; n = 11), 375 µg CpG-GNP double dose (CpG double dose [CpGdd]; n = 9) (q48h for 20 days) or 1600 µg beclomethasone (n = 9) (q24h for 10 days). Each horse was examined three times: before the treatment (I), immediately after the 10 inhalations (II), and 8 weeks after the final inhalation (III). The three groups were compared according to clinical and laboratory parameters. The study examined the sustainability of the long-term effect of the treatment after 8 weeks, as well as the tolerability of the formula as a double dose. Results: The CpGsd resulted in a significant improvement in 82% of the parameters, the CpGdd in 72%. In the long-term evaluation, the CpGsd showed a significant improvement in 100% of the parameters in comparison to the initial values, the CpGdd in 67%. On the immunological level, the bronchoalveolar lavage revealed a significant reduction of IL-4, IL-8, and interferon-γ. Conclusion: Both CpG groups displayed significant improvements in clinical and laboratory parameters, especially regarding the long-term effect of CpGsd. Doubling the CpG dose did not result in any improvement in comparison to the original single dose. On the immunological level, an anti-inflammatory, as well as an immunomodulatory effect, apart from a Th2-dominated immune response, could be observed. This immunomodulatory inhalation treatment could indicate a new possibility for human allergic asthma therapy.

Original language	English
Pages (from-to)	130-149
Number of pages	20
Journal	Immunity, inflammation and disease
Volume	7
Issue number	3
DOIs	https://doi.org/10.1002/iid3.252
State	Published - Sep 2019

Bibliographical note

Funding Information:
Parts of the research were supported by the Deutsche Forschungsgemeinschaft (DFG) (Germany) (GE 2044/4-1). The Aeroneb® Go micropump nebulizer (Aerogen, Galway, Ireland) was kindly sponsored by Inspiration Medical (Bochum, Germany). The Equine Haler™® was sponsored by Equine HealthCare Aps (Hoersholm, Denmark). The authors thank Prof. Ralf S. Mueller and Ms. Elena Serkin for critical revision of the paper, and Prof. Michael Erhard for kindly providing lab facilities for conducting lab work at the Institute for Animal Welfare, Ethology, Animal Hygiene and Animal Husbandry, Faculty of Veterinary Medicine, Department of Veterinary Science, Ludwig-Maximilians-University and Christina Hoeborn for her assistance in the lab. The authors would also like to thank Dr. Michael Lehmann (Institut für Infektionsmedizin und Zoonosen, LMU München) and Dr. Madlen Hubert (Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, LMU Munich) for their support in the preliminary studies. The authors furthermore thank Dr. Conrad Coester for his support, Inspiration Medical for kindly providing the Aeroneb Go micropump nebulizer and Equine HealthCare Aps (Hoersholm, Denmark) for providing the Equine Haler. All horse owners signed an informed consent. Authors declare no off-label use of antimicrobials. The data that support the findings of this study are available from the corresponding author upon reasonable request. Parts of the research were supported by the Deutsche Forschungsgemeinschaft (DFG) (Germany) (GE 2044/4-1). The Aeroneb® Go micropump nebulizer (Aerogen, Galway, Ireland) was kindly sponsored by Inspiration Medical (Bochum, Germany). The Equine Haler™® was sponsored by Equine HealthCare Aps (Hoersholm, Denmark).

Funding Information:
Parts of the research were supported by the Deutsche Forschungsgemeinschaft (DFG) (Germany) (GE 2044/4‐1). The Aeroneb® Go micropump nebulizer (Aerogen, Galway, Ireland) was kindly sponsored by Inspiration Medical (Bochum, Germany). The Equine Haler™ was sponsored by Equine HealthCare Aps (Hoersholm, Denmark). ®

Publisher Copyright:
© 2019 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.

Keywords

allergic asthma
extrinsic asthma
heaves
inhalation
neutrophilic asthma

ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/iid3.252

Cite this

@article{34f6369286ab4175af1a42a57cf52e16,

title = "Immunomodulatory asthma therapy in the equine animal model: A dose-response study and evaluation of a long-term effect",

abstract = "Introduction: Equine asthma represents a naturally occurring animal model for human allergic neutrophilic asthma. Inhalative nanoparticle-bound cytosine-phosphate-guanosine (CpG-GNP) immunotherapy, independent of specific allergens, has already shown promising clinical and immunological results in previous studies and offers the possibility to treat the underlying cause of the disease. This study analyses the relationship between dose and response, and evaluates a possible long-term effect. Methods: In the prospective, randomised, double-blind clinical field study, 29 horses suffering from equine asthma received 10 inhalation treatments with either 187.5 µg CpG-GNP (CpG single dose [CpGsd]; n = 11), 375 µg CpG-GNP double dose (CpG double dose [CpGdd]; n = 9) (q48h for 20 days) or 1600 µg beclomethasone (n = 9) (q24h for 10 days). Each horse was examined three times: before the treatment (I), immediately after the 10 inhalations (II), and 8 weeks after the final inhalation (III). The three groups were compared according to clinical and laboratory parameters. The study examined the sustainability of the long-term effect of the treatment after 8 weeks, as well as the tolerability of the formula as a double dose. Results: The CpGsd resulted in a significant improvement in 82% of the parameters, the CpGdd in 72%. In the long-term evaluation, the CpGsd showed a significant improvement in 100% of the parameters in comparison to the initial values, the CpGdd in 67%. On the immunological level, the bronchoalveolar lavage revealed a significant reduction of IL-4, IL-8, and interferon-γ. Conclusion: Both CpG groups displayed significant improvements in clinical and laboratory parameters, especially regarding the long-term effect of CpGsd. Doubling the CpG dose did not result in any improvement in comparison to the original single dose. On the immunological level, an anti-inflammatory, as well as an immunomodulatory effect, apart from a Th2-dominated immune response, could be observed. This immunomodulatory inhalation treatment could indicate a new possibility for human allergic asthma therapy.",

keywords = "allergic asthma, extrinsic asthma, heaves, inhalation, neutrophilic asthma",

author = "John Klier and Carolin Bartl and Sabine Geuder and Geh, {Katharina J.} and Sven Reese and Goehring, {Lutz S.} and Gerhard Winter and Heidrun Gehlen",

note = "Funding Information: Parts of the research were supported by the Deutsche Forschungsgemeinschaft (DFG) (Germany) (GE 2044/4-1). The Aeroneb{\textregistered} Go micropump nebulizer (Aerogen, Galway, Ireland) was kindly sponsored by Inspiration Medical (Bochum, Germany). The Equine Haler{\texttrademark}{\textregistered} was sponsored by Equine HealthCare Aps (Hoersholm, Denmark). The authors thank Prof. Ralf S. Mueller and Ms. Elena Serkin for critical revision of the paper, and Prof. Michael Erhard for kindly providing lab facilities for conducting lab work at the Institute for Animal Welfare, Ethology, Animal Hygiene and Animal Husbandry, Faculty of Veterinary Medicine, Department of Veterinary Science, Ludwig-Maximilians-University and Christina Hoeborn for her assistance in the lab. The authors would also like to thank Dr. Michael Lehmann (Institut f{\"u}r Infektionsmedizin und Zoonosen, LMU M{\"u}nchen) and Dr. Madlen Hubert (Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, LMU Munich) for their support in the preliminary studies. The authors furthermore thank Dr. Conrad Coester for his support, Inspiration Medical for kindly providing the Aeroneb Go micropump nebulizer and Equine HealthCare Aps (Hoersholm, Denmark) for providing the Equine Haler. All horse owners signed an informed consent. Authors declare no off-label use of antimicrobials. The data that support the findings of this study are available from the corresponding author upon reasonable request. Parts of the research were supported by the Deutsche Forschungsgemeinschaft (DFG) (Germany) (GE 2044/4-1). The Aeroneb{\textregistered} Go micropump nebulizer (Aerogen, Galway, Ireland) was kindly sponsored by Inspiration Medical (Bochum, Germany). The Equine Haler{\texttrademark}{\textregistered} was sponsored by Equine HealthCare Aps (Hoersholm, Denmark). Funding Information: Parts of the research were supported by the Deutsche Forschungsgemeinschaft (DFG) (Germany) (GE 2044/4‐1). The Aeroneb{\textregistered} Go micropump nebulizer (Aerogen, Galway, Ireland) was kindly sponsored by Inspiration Medical (Bochum, Germany). The Equine Haler{\texttrademark} was sponsored by Equine HealthCare Aps (Hoersholm, Denmark). {\textregistered} Publisher Copyright: {\textcopyright} 2019 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.",

year = "2019",

month = sep,

doi = "10.1002/iid3.252",

language = "English",

volume = "7",

pages = "130--149",

journal = "Immunity, inflammation and disease",

issn = "2050-4527",

publisher = "John Wiley and Sons Ltd",

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TY - JOUR

T1 - Immunomodulatory asthma therapy in the equine animal model

T2 - A dose-response study and evaluation of a long-term effect

AU - Klier, John

AU - Bartl, Carolin

AU - Geuder, Sabine

AU - Geh, Katharina J.

AU - Reese, Sven

AU - Goehring, Lutz S.

AU - Winter, Gerhard

AU - Gehlen, Heidrun

N1 - Funding Information: Parts of the research were supported by the Deutsche Forschungsgemeinschaft (DFG) (Germany) (GE 2044/4-1). The Aeroneb® Go micropump nebulizer (Aerogen, Galway, Ireland) was kindly sponsored by Inspiration Medical (Bochum, Germany). The Equine Haler™® was sponsored by Equine HealthCare Aps (Hoersholm, Denmark). The authors thank Prof. Ralf S. Mueller and Ms. Elena Serkin for critical revision of the paper, and Prof. Michael Erhard for kindly providing lab facilities for conducting lab work at the Institute for Animal Welfare, Ethology, Animal Hygiene and Animal Husbandry, Faculty of Veterinary Medicine, Department of Veterinary Science, Ludwig-Maximilians-University and Christina Hoeborn for her assistance in the lab. The authors would also like to thank Dr. Michael Lehmann (Institut für Infektionsmedizin und Zoonosen, LMU München) and Dr. Madlen Hubert (Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, LMU Munich) for their support in the preliminary studies. The authors furthermore thank Dr. Conrad Coester for his support, Inspiration Medical for kindly providing the Aeroneb Go micropump nebulizer and Equine HealthCare Aps (Hoersholm, Denmark) for providing the Equine Haler. All horse owners signed an informed consent. Authors declare no off-label use of antimicrobials. The data that support the findings of this study are available from the corresponding author upon reasonable request. Parts of the research were supported by the Deutsche Forschungsgemeinschaft (DFG) (Germany) (GE 2044/4-1). The Aeroneb® Go micropump nebulizer (Aerogen, Galway, Ireland) was kindly sponsored by Inspiration Medical (Bochum, Germany). The Equine Haler™® was sponsored by Equine HealthCare Aps (Hoersholm, Denmark). Funding Information: Parts of the research were supported by the Deutsche Forschungsgemeinschaft (DFG) (Germany) (GE 2044/4‐1). The Aeroneb® Go micropump nebulizer (Aerogen, Galway, Ireland) was kindly sponsored by Inspiration Medical (Bochum, Germany). The Equine Haler™ was sponsored by Equine HealthCare Aps (Hoersholm, Denmark). ® Publisher Copyright: © 2019 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.

PY - 2019/9

Y1 - 2019/9

N2 - Introduction: Equine asthma represents a naturally occurring animal model for human allergic neutrophilic asthma. Inhalative nanoparticle-bound cytosine-phosphate-guanosine (CpG-GNP) immunotherapy, independent of specific allergens, has already shown promising clinical and immunological results in previous studies and offers the possibility to treat the underlying cause of the disease. This study analyses the relationship between dose and response, and evaluates a possible long-term effect. Methods: In the prospective, randomised, double-blind clinical field study, 29 horses suffering from equine asthma received 10 inhalation treatments with either 187.5 µg CpG-GNP (CpG single dose [CpGsd]; n = 11), 375 µg CpG-GNP double dose (CpG double dose [CpGdd]; n = 9) (q48h for 20 days) or 1600 µg beclomethasone (n = 9) (q24h for 10 days). Each horse was examined three times: before the treatment (I), immediately after the 10 inhalations (II), and 8 weeks after the final inhalation (III). The three groups were compared according to clinical and laboratory parameters. The study examined the sustainability of the long-term effect of the treatment after 8 weeks, as well as the tolerability of the formula as a double dose. Results: The CpGsd resulted in a significant improvement in 82% of the parameters, the CpGdd in 72%. In the long-term evaluation, the CpGsd showed a significant improvement in 100% of the parameters in comparison to the initial values, the CpGdd in 67%. On the immunological level, the bronchoalveolar lavage revealed a significant reduction of IL-4, IL-8, and interferon-γ. Conclusion: Both CpG groups displayed significant improvements in clinical and laboratory parameters, especially regarding the long-term effect of CpGsd. Doubling the CpG dose did not result in any improvement in comparison to the original single dose. On the immunological level, an anti-inflammatory, as well as an immunomodulatory effect, apart from a Th2-dominated immune response, could be observed. This immunomodulatory inhalation treatment could indicate a new possibility for human allergic asthma therapy.

AB - Introduction: Equine asthma represents a naturally occurring animal model for human allergic neutrophilic asthma. Inhalative nanoparticle-bound cytosine-phosphate-guanosine (CpG-GNP) immunotherapy, independent of specific allergens, has already shown promising clinical and immunological results in previous studies and offers the possibility to treat the underlying cause of the disease. This study analyses the relationship between dose and response, and evaluates a possible long-term effect. Methods: In the prospective, randomised, double-blind clinical field study, 29 horses suffering from equine asthma received 10 inhalation treatments with either 187.5 µg CpG-GNP (CpG single dose [CpGsd]; n = 11), 375 µg CpG-GNP double dose (CpG double dose [CpGdd]; n = 9) (q48h for 20 days) or 1600 µg beclomethasone (n = 9) (q24h for 10 days). Each horse was examined three times: before the treatment (I), immediately after the 10 inhalations (II), and 8 weeks after the final inhalation (III). The three groups were compared according to clinical and laboratory parameters. The study examined the sustainability of the long-term effect of the treatment after 8 weeks, as well as the tolerability of the formula as a double dose. Results: The CpGsd resulted in a significant improvement in 82% of the parameters, the CpGdd in 72%. In the long-term evaluation, the CpGsd showed a significant improvement in 100% of the parameters in comparison to the initial values, the CpGdd in 67%. On the immunological level, the bronchoalveolar lavage revealed a significant reduction of IL-4, IL-8, and interferon-γ. Conclusion: Both CpG groups displayed significant improvements in clinical and laboratory parameters, especially regarding the long-term effect of CpGsd. Doubling the CpG dose did not result in any improvement in comparison to the original single dose. On the immunological level, an anti-inflammatory, as well as an immunomodulatory effect, apart from a Th2-dominated immune response, could be observed. This immunomodulatory inhalation treatment could indicate a new possibility for human allergic asthma therapy.

KW - allergic asthma

KW - extrinsic asthma

KW - heaves

KW - inhalation

KW - neutrophilic asthma

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Immunomodulatory asthma therapy in the equine animal model: A dose-response study and evaluation of a long-term effect

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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