title: Suppression of Canine Dendritic Cell Activation/Maturation and Inflammatory Cytokine Release by Mesenchymal Stem Cells Occurs Through Multiple Distinct Biochemical Pathways.
abstract: Mesenchymal stem cells (MSC) represent a readily accessible source of cells with potent immune modulatory activity. MSC can suppress ongoing inflammatory responses by suppressing T cell function, while fewer studies have examined the impact of MSC on dendritic cell (DC) function. The dog spontaneous disease model represents an important animal model with which to evaluate the safety and effectiveness of cellular therapy with MSC. This study evaluated the effects of canine MSC on the activation and maturation of canine monocyte-derived DC, as well as mechanisms underlying these effects. Adipose-derived canine MSC were cocultured with canine DC, and the MSC effects on DC maturation and activation were assessed by flow cytometry, cytokine ELISA, and confocal microscopy. We found that canine MSC significantly suppressed lipopolysaccharide (LPS)-stimulated upregulation of DC activation markers such as major histocompatibility class II (MHCII), CD86, and CD40. Furthermore, pretreatment of MSC with interferon gamma (IFNγ) augmented this suppressive activity. IFNγ-activated MSC also significantly reduced LPS-elicited DC secretion of tumor necrosis factor alpha without reducing secretion of interleukin-10. The suppressive effect of IFNγ-treated MSC on LPS-induced DC activation was mediated by soluble factors secreted by both MSC and DC. Pathways of DC functional suppression included programmed death ligand-1 expression and secretion of nitrous oxide, prostaglandin E2, and adenosine by activated MSC. Coculture of DC with IFNγ-treated MSC maintained DC in an immature state and prolonged DC antigen uptake during LPS maturation stimulus. Taken together, canine MSC are capable of potently suppressing DC function in a potentially inflammatory microenvironment through several separate immunological pathways and confirm the potential for immune therapy with MSC in canine immune-mediated disease models.
authors.affiliation: Department of Clinical Sciences, Center for Immune and Regenerative Medicine, College of Veterinary Medicine and Biomedical Sciences, Colorado State University , Fort Collins, Colorado.
authors.forename: William H
authors.initials: WH
authors.lastname: Wheat
authors.affiliation: Department of Clinical Sciences, Center for Immune and Regenerative Medicine, College of Veterinary Medicine and Biomedical Sciences, Colorado State University , Fort Collins, Colorado.
authors.forename: Lyndah
authors.initials: L
authors.lastname: Chow
authors.affiliation: Department of Clinical Sciences, Center for Immune and Regenerative Medicine, College of Veterinary Medicine and Biomedical Sciences, Colorado State University , Fort Collins, Colorado.
authors.forename: Jade N
authors.initials: JN
authors.lastname: Kurihara
authors.affiliation: Department of Clinical Sciences, Center for Immune and Regenerative Medicine, College of Veterinary Medicine and Biomedical Sciences, Colorado State University , Fort Collins, Colorado.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Regan
authors.affiliation: Department of Clinical Sciences, Center for Immune and Regenerative Medicine, College of Veterinary Medicine and Biomedical Sciences, Colorado State University , Fort Collins, Colorado.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Coy
authors.affiliation: Department of Clinical Sciences, Center for Immune and Regenerative Medicine, College of Veterinary Medicine and Biomedical Sciences, Colorado State University , Fort Collins, Colorado.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Webb
authors.affiliation: Department of Clinical Sciences, Center for Immune and Regenerative Medicine, College of Veterinary Medicine and Biomedical Sciences, Colorado State University , Fort Collins, Colorado.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Dow
mesh_terms: D000818:Animals; D000941:Antigens / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D018920:Coculture Techniques; D016207:Cytokines / Q000494:pharmacology*; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D004285:Dogs; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D056747:Immunomodulation / Q000187:drug effects; D007165:Immunosuppression Therapy; D018836:Inflammation Mediators / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects*; D012867:Skin / Q000166:cytology; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000941:Antigens; D015703:Antigens, CD; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: activation; canine; cytokine; dendritic cell; mesenchymal stem cell