Chemistry and Biology of Oligovalent beta-(1 -> 2)-Linked Oligomannosides: New Insights into Carbohydrate-Based Adjuvants in Immunotherapy

A series of oligovalent carbohydrate assemblies (ranging from mono- to pentavalent), derived from three structurally different -linked or -(12)-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 -mannosylation was successfully utilized to introduce the -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- (IFN-), 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- productions dose-dependently, while inducing no Th2 cytokine response. The immunomodulatory properties of this trivalent mannoside were further studied in vitro in allergen (Betv)-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- 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.