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Am J Respir Cell Mol Biol. 2018 Jan;58(1):55-65. doi: 10.1165/rcmb.2017-0184OC.

Toll-Like Receptor 7/8 Ligand, S28463, Suppresses Ascaris suum-induced Allergic Asthma in Nonhuman Primates.

Author information

1
1 Faculty of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
2
2 The Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.
3
3 Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic.
4
4 Institut National de la Recherche Scientifique at the Armand Frappier, Laval, Quebec, Canada.
5
5 Sir Frederick G. Banting Research Centre, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada.
6
6 Comparative Medicine, McGill University, Montreal, Quebec, Canada.
7
7 Faculty of Medicine, University of Ottawa, Pediatric Critical Care, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
8
8 Respiratory Division, McGill University, Montreal, Quebec, Canada.
9
9 Department of Pediatrics, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic; and.
10
10 Department of Human Genetics, McGill University, Montreal, Quebec, Canada.

Abstract

S28463 (S28), a ligand for Toll-like receptor 7/8, has been shown to have antiinflammatory properties in rodent models of allergic asthma. The principle goal of this study was to assess whether these antiinflammatory effects can also be observed in a nonhuman primate (NHP) model of allergic asthma. NHPs were sensitized then challenged with natural allergen, Ascaris suum extract. The animals were treated with S28 orally before each allergen challenge. The protective effect of S28 in NHPs was assessed by measuring various asthma-related phenotypes. We also characterized the metabolomic and proteomic signatures of the lung environment and plasma to identify markers associated with the disease and treatment. Our data demonstrate that clinically relevant parameters, such as wheal and flare response, blood IgE levels, recruitment of white blood cells to the bronchoalveolar space, and lung responsiveness, are decreased in the S28-treated allergic NHPs compared with nontreated allergic NHPs. Furthermore, we also identified markers that can distinguish allergic from nonallergic or allergic and drug-treated NHPs, such as metabolites, phosphocreatine and glutathione, in the plasma and BAL fluid, respectively; and inflammatory cytokines, IL-5 and IL-13, in the bronchoalveolar lavage fluid. Our preclinical study demonstrates that S28 has potential as a treatment for allergic asthma in primate species closely related to humans. Combined with our previous findings, we demonstrate that S28 is effective in different models of asthma and in different species, and has the antiinflammatory properties clinically relevant for the treatment of allergic asthma.

KEYWORDS:

experimental model; inflammation; metabolomics; proteomics; treatment

PMID:
28850259
DOI:
10.1165/rcmb.2017-0184OC
[Indexed for MEDLINE]

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