Acetylated Trivalent Mannobioses: Chemical Modification, Structural Elucidation, and Biological Evaluation

Abstract

People suffering from allergies can be treated with repeated injections of increasing amounts of a specific allergen. This type of specific immunotherapy is currently the only way to treat the underlying pathological immune response associated with an allergy. The approach can afford long-lasting protection, but the process takes 3-5 years, can produce allergic reactions, and in severe cases treatment is often aborted due to anaphylaxis. However, treatment can be optimized with the use of specific adjuvants that modify the immune response, its duration, and that increase the production of the correct type of antibodies. In the pursuit of such adjuvants, two new trivalent acetylated β-(1→2)-linked mannobioses based on a previously discovered lead molecule were prepared. The new molecules, along with the previously developed lead, were investigated by rigorous NMR and molecular modeling experiments in order to elucidate their behavior and preferred conformations in solution. Furthermore, the molecules were subjected to a biological investigation in which their immunostimulatory properties were evaluated by assessing their effect on the production of TH 2-type cytokine interleukin-4 (IL-4) and Treg pro-inflammatory cytokine tumor necrosis factor (TNF). Treatment of peripheral mononuclear blood cell cultures from patients suffering from birch allergy with birch allergen Bet v induced a strong IL-4 response, whereas the same treatment together with the trivalent acetylated mannobioses caused significant suppression of the induced IL-4.

A novel glycocluster molecule prevents timothy‐induced allergic airway inflammation in mice

“…We have earlier shown in vitro that TADM beneficially affects cytokine production of peripheral blood cells among allergic subjects and favours T helper 1 and T regulatory cell type responses . Previously, we have also shown that, in contrast to CpG and MPLA, TADM does not appear to function as TLR agonist . In addition, our studies in an acute murine asthma model proved that TADM significantly suppresses allergen‐specific IgE production and increases mRNA expression of IFN‐γ in lung tissues …”

“…Triacedimannose is a trivalent glycocluster, consisting of fully acetylated β‐(1→2)‐linked mannobiose units, designed to mimic C. albicans cell wall mannan oligosaccharides, which are known to possess immunostimulatory properties . We have earlier shown in vitro that TADM beneficially affects cytokine production of peripheral blood cells among allergic subjects and favours T helper 1 and T regulatory cell type responses . Previously, we have also shown that, in contrast to CpG and MPLA, TADM does not appear to function as TLR agonist .…”

“…Adjuvants are used in allergen preparations in SIT to enhance the effect and modulate the immune response towards Treg and Th1‐type responses. Our recent studies have shown that a synthetic trivalent glycocluster (generated from fully acetylated β‐(1→2)‐linked mannobioses), triacedimannose (TADM) (Figure ), suppresses the Th2‐type allergic inflammatory response . The aim of this study was to compare TADM with two well‐known adjuvants, unmethylated cytosine‐phosphate‐guanine oligodeoxynucleotide (CpG) and monophosphoryl lipid A (MPLA) in a grass allergen‐induced chronic allergic inflammation model in mice.…”