title: Chemistry and biology of oligovalent β-(1→2)-linked oligomannosides: new insights into carbohydrate-based adjuvants in immunotherapy.
abstract: A series of oligovalent carbohydrate assemblies (ranging from mono- to pentavalent), derived from three structurally different β-linked or β-(1→2)-linked mannosides, has been chemically synthesized, and the respective compounds have been biologically evaluated in order to investigate their immunostimulatory properties. The Crich methodology for β-mannosylation was successfully utilized to introduce the β-linkages, and a click chemistry protocol was utilized to generate the oligovalent derivatives. A convenient protecting group strategy involving the simultaneous use of both p-methoxybenzyl and benzylidene groups was employed, which allowed a simple and cost-effective global deprotection step. The immunomodulatory properties of the synthesized multivalent mannosides were evaluated by assessing cytokine production in human white blood cell cultures. The Th2-type cytokines interleukin-4 and interleukin-5 (IL-4 and IL-5), the Th1 cytokine interferon-γ (IFN-γ), the Treg cytokine IL-10, and the pro-inflammatory cytokine tumor necrosis factor (TNF) were included in the screening. A single trivalent acetylated mannobiose derivative was identified as a potent inducer of Treg and Th1 immune response, resulting in strong IL-10 and moderate IFN-γ productions dose-dependently, while inducing no Th2 cytokine response. The immunomodulatory properties of this trivalent mannoside were further studied in vitro in allergen (Bet v)-stimulated human peripheral blood mononuclear cell cultures of birch pollen allergic subjects. Stimulation with birch pollen induced strong IL-4 and IL-5 responses, which could be suppressed by the trivalent acetylated mannobiose derivative. The IL-10 response was also suppressed, whereas the production of IFN-γ was strongly enhanced. The results suggest that the identified lead compound has suppressive effects on the Th2-type allergic inflammatory response and shows potential as a possible lead adjuvant for the specific immunotherapy of allergies.
authors.affiliation: Laboratory of Organic Chemistry, Åbo Akademi University, 20500 Åbo, Finland.
authors.forename: Chinmoy
authors.initials: C
authors.lastname: Mukherjee
authors.forename: Kaarina
authors.initials: K
authors.lastname: Mäkinen
authors.forename: Johannes
authors.initials: J
authors.lastname: Savolainen
authors.forename: Reko
authors.initials: R
authors.lastname: Leino
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000737:chemistry; D000485:Allergens / Q000097:blood / Q000737:chemistry / Q000276:immunology*; D029662:Betula / Q000737:chemistry / Q000276:immunology; D057930:Click Chemistry; D016207:Cytokines / Q000097:blood / Q000276:immunology; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000097:blood / Q000276:immunology; D015847:Interleukin-4 / Q000097:blood / Q000276:immunology; D015848:Interleukin-5 / Q000097:blood / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008297:Male; D008362:Mannosides / Q000097:blood / Q000138:chemical synthesis* / Q000276:immunology; D015394:Molecular Structure; D009844:Oligosaccharides / Q000097:blood / Q000138:chemical synthesis* / Q000276:immunology; D011058:Pollen / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000276:immunology
chemical_list: C585400:1,2,3-tris(1-((2,3,4,6-tetra-O-acetyl-beta-D-mannopyranosyl)-(1-2)-(3,4,6-tri-O-acetyl-alpha-D-mannopyranosyloxyethyl))-4-(methyl-1-oxy)-1,2,3-triazolyl)propane; D000276:Adjuvants, Immunologic; D000485:Allergens; D016207:Cytokines; D015848:Interleukin-5; D008362:Mannosides; D009844:Oligosaccharides; D014409:Tumor Necrosis Factor-alpha; C028569:oligomannoside; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma