Pharmacological regulation of the immune response

 Responsible person: Ondřej Vašíček

Immunomodulatory effects and biochemical mechanisms of immunomodulation with herbal and mushroom heteropolysaccharides

The investigation of the immunomodulatory activity of herbal and mushroom polysaccharides (PS) has enormous potential for the accumulation of essential knowledge with a real application in the development of products for medicine and dietetics. It is necessary to know the structure-activity relationship, in order to study the immunomodulatory effects and biochemical mechanisms of immunomodulation with PS. From a structural point of view, the immunologically active herbal PS are predominantly presented by glucans (cellulose, other β-glucans, and starch), pectins, inulin and hemicelluloses (xylans, xyloglucans, arabinoxylans, galactoglucomanans etc.). Extremely popular sources of immunomodulatory and antitumor mushroom PS are Lentinus edodes (lentinan), Schizophyllum commune (schizophyllan), Trametes versicolor (PSK), Ganoderma lucidum and Grifola frondosa (D-fraction). It is important to be mentioned that mushroom research has been concentrated on Asian species, suggesting the prospect of screening studies on other widely consumed, but poorly-studied mushroom species.
The immunomodulatory activity of herbal and mushroom PS is expressed by complement-fixation, immunostimulating, anti-inflammatory, antiviral, anti-cancer activities etc. These activities are related to regulation of the metabolic activity of T- and B-lymphocytes, NK cells, neutrophils, macrophages, dendritic cells, platelets, as well as in suppression of inflammatory and tumor cells. The presented activities combined with the regulatory properties of PS on immune signaling proteins, complement system, antioxidant enzymes and probiotic bacteria may be useful for prevention and support therapy in infectious, tumor, gastrointestinal and autoimmune diseases.
Macrophages and neutrophils have a central role not only in our own immune defense, but also in the development of the response to immunomodulatory PS. Furthermore, PS regulate the production of inflammatory and anti-inflammatory cytokines by macrophages, depending on the situation, exhibiting immunostimulatory or anti-inflammatory effects. Although the PS effects on neutrophils are not as clear as in macrophages, it can be said that they increase neutrophil phagocytosis, bactericidal capacity, adhesion, superoxide dismutase activity etc.
It was found that herbal PS alone stimulated NO and ROS production by phagocytes but exhibited the opposite effect in a simulated microbial infection in our collaborative studies. It is hypothesized that in vitro, ex vivo or in vivo immunomodulatory effects of PS on macrophages and neutrophils via receptors may be useful against inflammation, viral infections, allergies, tumor, autoimmune and gastrointestinal diseases. This determines the interest in studying the biochemical bases of signal transduction in phagocyte immunomodulation with PS under normal and inflammatory conditions.

Immunomodulation with herbal and mushroom heteropolysaccharides
Immunomodulation with herbal and mushroom heteropolysaccharides


Selectively modified beta-glucans: dual drug/antisense RNA carriers with immunomodulory effect for treatment of ulcerative colitis

Ulcerative colitis (UC) is an inflammatory bowel disease, which significantly increases the risk of colitis-associated cancer. Here, dual-action drug carriers for the treatment of UC are proposed, combining the immunomodulatory effects of betaglucans (BG), custom sidechain modifications improving their recognition by macrophages and stimuli-responsive binding of anti-inflammatory drugs, with the complexation of antisense RNA. The resulting system primarily uses macrophages to transport the carriers and trigger an anti-inflammatory action both at the local and at the systemic level. Proposed dual-action drug carriers will be evaluated by the state-ofthe-art in vitro models, covering various aspects, from transport across the complex epithelial barrier, detection of binding to specific receptors, to actual functional response in target immune cells. These will be followed by in vivo models describing the overall impact on UC, modulation of immune cells in the organism, the state of the intestinal epithelium, impact on the gut microbiota and pharmacokinetics and biodistribution.

Polysacahridy
Schematics of the proposed SCAL (I.) and SCOX (II.) modifications.