Immunostimulation of bronchoalveolar lavage cells from recurrent airway obstruction-affected horses by different CpG-classes bound to gelatin nanoparticles.
Abstract: Recurrent airway obstruction (RAO) in horses has become a common problem in stabled horses in industrialized countries and deserves new therapeutic strategies. CpG-oligodeoxynucleotides (CpG-ODNs) were developed as effective immunostimulating agents to induce a Th2/Th1 shift. These agents showed a beneficial therapeutic effect in allergic diseases with predominant Th2 immunoresponse. CpG-ODN delivery by gelatin nanoparticles (GNPs) resulted in enhanced cellular uptake in murine and human in vitro studies and was a starting point for the present trial. The aim of this study was to identify an optimal stimulating CpG motif in horses with regard to species specificity on equine bronchoalveolar lavage (BAL) cells, in terms of a possible specific immunomodulation effect (Th2/Th1 shift) by used CpG-ODN. Accordingly, GNPs were evaluated as a delivery system to improve CpG-ODN immunostimulation in equine BAL cells. BAL fluid (BALF) was obtained from seven horses with moderate RAO and from four healthy horses and was subsequently incubated with five different CpG-ODN sequences (from A-, B- and C-class) and one ODN without any CpG motif. Release of three key cytokines (IL-4, IL-10 and IFN-γ) was quantified by ELISA to detect an allergy mediated Th2 immunoresponse (IL-4) as well as a proinflammatory Th1 response (IFN-γ). Due to its specific anti-inflammatory and anti-allergic effects, IL-10 was considered as a beneficial agent in pathophysiology of RAO. Results showed a significant upregulation of IL-10 and IFN-γ on the one hand and a downregulation of IL-4 on the other hand in RAO affected horses. Cell cultures from healthy horses had a significantly stronger response in cytokine release to all the applied stimuli in contrast to RAO derived cells. Comparing all five CpG sequences, A-class 2216 significantly showed the highest immunomodulatory effects on equine BALF cells and, hence, was chosen for follow-up preliminary clinical studies.
Copyright © 2011 Elsevier B.V. All rights reserved.
Publication Date: 2011-07-20 PubMed ID: 21831455DOI: 10.1016/j.vetimm.2011.07.009Google Scholar: Lookup
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- Journal Article
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Summary
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The research study investigates the potential of using CpG-oligodeoxynucleotides (CpG-ODNs) bound to gelatin nanoparticles to stimulate bronchoalveolar lavage cells from horses suffering from recurrent airway obstruction. The study’s goal was to identify the most effective stimulating CpG motif and evaluate gelatin nanoparticles as a delivery system for CpG-ODN immunostimulation.
Introduction and Background
- Recurrent airway obstruction (RAO) is a frequent problem in horses in industrialized countries, necessitating the development of new therapeutic strategies.
- The research primarily focuses on CpG-oligodeoxynucleotides (CpG-ODNs), which have been found to induce an immune response shift from Th2 to Th1. The therapeutic value of these agents in allergic diseases characterized by a predominant Th2 immune response has been previously studied.
- The study also places emphasis on gelatin nanoparticles (GNPs) as a means of delivering CpG-ODNs, based on prior human and murine studies that showed enhanced cellular uptake with this method.
Methods
- Bronchoalveolar lavage (BAL) fluid was collected from seven horses with moderate RAO and four healthy ones.
- This fluid was then incubated with five CpG-ODN sequences (A-, B- and C-class) and a control ODN without any CpG motif to study the effects of the different classes of CpG-ODNs and evaluate their immunomodulatory effect.
- The release of three key cytokines (IL-4, IL-10 and IFN-γ) was measured to determine immune response. IL-4 indicates an allergy-mediated Th2 immune response and IFN-γ points to a proinflammatory Th1 response, while IL-10 has anti-inflammatory and anti-allergic effects.
Results
- The results demonstrated a significant increase in the production of IL-10 and IFN-γ in horses with RAO, along with a corresponding decrease in the levels of IL-4.
- BAL cell cultures from healthy horses showed a stronger response to the applied stimuli compared to those derived from RAO-affected horses.
- The study found that among the five CpG sequences tried, A-class 2216 had the highest immunomodulatory effects on equine BALF cells and was chosen for further testing in preliminary clinical studies.
Conclusions
- This study indicates the potential of using CpG-ODns bound to GNPs as a therapeutic strategy for horses suffering from RAO, with A-class 2216 showing the most promising results.
- The differential response of cells from healthy and RAO-affected horses to CpG-ODN stimulation suggests specific immunomodulatory effects of these agents.
Cite This Article
APA
Klier J, May A, Fuchs S, Schillinger U, Plank C, Winter G, Gehlen H, Coester C.
(2011).
Immunostimulation of bronchoalveolar lavage cells from recurrent airway obstruction-affected horses by different CpG-classes bound to gelatin nanoparticles.
Vet Immunol Immunopathol, 144(1-2), 79-87.
https://doi.org/10.1016/j.vetimm.2011.07.009 Publication
Researcher Affiliations
- Ludwig Maximilians University, Department of Veterinary Medicine, Equine Clinic, Veterinärstr. 13, 80539 Munich, Germany.
MeSH Terms
- Airway Obstruction / drug therapy
- Airway Obstruction / immunology
- Airway Obstruction / veterinary
- Animals
- Bronchoalveolar Lavage Fluid / cytology
- Bronchoalveolar Lavage Fluid / immunology
- Cell Survival
- Cells, Cultured
- CpG Islands / immunology
- Cytokines / metabolism
- Drug Delivery Systems / veterinary
- Enzyme-Linked Immunosorbent Assay / veterinary
- Gelatin / therapeutic use
- Horse Diseases / drug therapy
- Horse Diseases / immunology
- Horses
- Immunization / methods
- Immunization / veterinary
- Interferon-gamma / metabolism
- Interleukin-10 / metabolism
- Interleukin-4 / metabolism
- Nanoparticles / therapeutic use
Citations
This article has been cited 12 times.- Gu Y, Hu Y, Huang S, Ruiz S, Kawai T, Bai Y, Han X. CpG ODN/Mangiferin Dual Delivery through Calcium Alginate Hydrogels Inhibits Immune-Mediated Osteoclastogenesis and Promotes Alveolar Bone Regeneration in Mice.. Biology (Basel) 2023 Jul 10;12(7).
- Klier J, Fuchs S, Winter G, Gehlen H. Inhalative Nanoparticulate CpG Immunotherapy in Severe Equine Asthma: An Innovative Therapeutic Concept and Potential Animal Model for Human Asthma Treatment.. Animals (Basel) 2022 Aug 16;12(16).
- Pali-Schöll I, DeBoer DJ, Alessandri C, Seida AA, Mueller RS, Jensen-Jarolim E. Formulations for Allergen Immunotherapy in Human and Veterinary Patients: New Candidates on the Horizon.. Front Immunol 2020;11:1697.
- Barton AK, Shety T, Klier J, Geis S, Einspanier R, Gehlen H. Metalloproteinases and their Inhibitors under the Course of Immunostimulation by CPG-ODN and Specific Antigen Inhalation in Equine Asthma.. Mediators Inflamm 2019;2019:7845623.
- Klier J, Bartl C, Geuder S, Geh KJ, Reese S, Goehring LS, Winter G, Gehlen H. Immunomodulatory asthma therapy in the equine animal model: A dose-response study and evaluation of a long-term effect.. Immun Inflamm Dis 2019 Sep;7(3):130-149.
- Klier J, Geis S, Steuer J, Geh K, Reese S, Fuchs S, Mueller RS, Winter G, Gehlen H. A comparison of nanoparticullate CpG immunotherapy with and without allergens in spontaneously equine asthma-affected horses, an animal model.. Immun Inflamm Dis 2018 Mar;6(1):81-96.
- Pacholewska A, Jagannathan V, Drögemüller M, Klukowska-Rötzler J, Lanz S, Hamza E, Dermitzakis ET, Marti E, Leeb T, Gerber V. Impaired Cell Cycle Regulation in a Natural Equine Model of Asthma.. PLoS One 2015;10(8):e0136103.
- Schnabel CL, Steinig P, Koy M, Schuberth HJ, Juhls C, Oswald D, Wittig B, Willenbrock S, Murua Escobar H, Pfarrer C, Wagner B, Jaehnig P, Moritz A, Feige K, Cavalleri JM. Immune response of healthy horses to DNA constructs formulated with a cationic lipid transfection reagent.. BMC Vet Res 2015 Jun 23;11:140.
- Klier J, Lehmann B, Fuchs S, Reese S, Hirschmann A, Coester C, Winter G, Gehlen H. Nanoparticulate CpG immunotherapy in RAO-affected horses: phase I and IIa study.. J Vet Intern Med 2015 Jan;29(1):286-93.
- Rosenthal JA, Huang CJ, Doody AM, Leung T, Mineta K, Feng DD, Wayne EC, Nishimura N, Leifer C, DeLisa MP, Mendez S, Putnam D. Mechanistic insight into the TH1-biased immune response to recombinant subunit vaccines delivered by probiotic bacteria-derived outer membrane vesicles.. PLoS One 2014;9(11):e112802.
- Hanagata N. Structure-dependent immunostimulatory effect of CpG oligodeoxynucleotides and their delivery system.. Int J Nanomedicine 2012;7:2181-95.
- Klier J, Fuchs S, May A, Schillinger U, Plank C, Winter G, Coester C, Gehlen H. A nebulized gelatin nanoparticle-based CpG formulation is effective in immunotherapy of allergic horses.. Pharm Res 2012 Jun;29(6):1650-7.
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