Immune enhancement by increased number of B-cells

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1 Page 1 of 6 Immune enhancement by increased number of B-cells - A summary report of scientific studies with GlycaNova s beta-glucan, Lentinex Background Human immunity can be divided in two main parts, innate and acquired. The innate system is not specific and has no memory, but is the first line of defence, activating NK-cells and macrophages. The acquired immunity is again separated into two systems, the cellular immunity and the humoral system. Even though there are some clear differences, the two systems are overlapping and the two acquired systems work in close cooperation with the innate system. Cellular immunity protects the body by activating antigen-specific cytotoxic T- lymphocytes that are able to induce cell death in body cells displaying foreign antigen on their surface, such as virus-infected cells and some cancer cells displaying tumor antigens. The system may activate macrophages and natural killer cells, enabling them to destroy intracellular pathogens, and stimulating cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive immune responses and innate immune responses. The humoral immune system is the aspect of immunity that is mediated by secreted antibodies, produced by the cells of the B lymphocyte lineage (B cells). Secreted antibodies bind to antigens on the surfaces of invading microbes (such as viruses or bacteria), which flags them for destruction. Dectin-1, is the major receptor for fungal beta-glucans on macrophages and has demonstrated that it plays a significant role in the cellular response to these carbohydrates. The human Dectin-1, the beta-glucan receptor, is widely expressed and present on all monocyte populations as well as macrophages, dendritic cells, neutrophils and eosinophils. This receptor is also expressed on B cells. 1 Not surprisingly, beta-glucans may increase the number of B-cells to enhance the immune system. 2, 3

2 Page 2 of 6 Results in GlycaNova studies. Animals. In early safety and efficacy studies in mice and rats conducted by GlycaNova, an increase in B-cells was observed. In a study performed in the USA 4, an almost doubling of B-cells, from 16% in controls to 25% after oral intake of Lentinex 1, was observed in mice. The effect of Lentinex on B-cells could also be observed in a rat safety study, performed in Bergen, Norway. 5 (Fig 1). B lymphocytes as % of lymphocytes and Monocytes Igκ as% of Lymphocytes and Monocytes Wk 9 Wk 11 Wk 13 Sample points *** Fig. 1. A considerable increase in B-cells (p<0.0001) was observed after increasing the dose from 7.8mg/kg to 9.2 mg/kg in rats. The author of the study suggested that the increase in B-cell and monocytic population could be partly related to the decrease in the immunosuppressive Interleukin-10 (IL-10). Increases observed in B-cell and monocyte populations in addition to increased interferon-gamma (INF-γ) levels may suggest an immunostimulatory response by Lentinex. The humoral immune system, as previously mentioned, is mediated by secreted antibodies, produced by the B-cells. So an increase in antibodies is an expression of increased matured B-cells, which in the presence of antigens produce specific antibodies directed against the antigens. In a study 6 performed at the School of Veterinary Medicine Louisiana State University, USA, the aim was to determine the effect of oral Lentinex treatment on the colonization load of H. pylori in a mouse model. Some inconsistent and minor effects on colonization were observed, but quite unexpectedly, Lentinex treatment resulted in a statistically significant increase in 1 Lentinex is a product trademark of GlycaNova Norge AS primarily used in Europe. Immuna is the trademark primarily used in the United States

3 Page 3 of 6 antibody responses when compared to the non-treated mice (p=0.033). Using one serum sample as a reference, an estimated titer was calculated and the differences were more striking (Fig 2). Fig 2. Difference in antibody titer after Lentinex compared to controls. Lentinex treatment resulted in an average increase in antibody of 256-fold compared to non-treated animals. As the author states: The surprising result from this study was that oral Lentinex significantly increased antibody responses to H.pylori. The adjuvant effect was unexpected, particularly following oral administration. A recent publication strongly supports these observations 7.

4 Page 4 of 6 Results in GlycaNova studies (continued). Humans. In a double-blind, cross-over study in healthy elderly subjects, no changes in cytokines were observed and the Lentinex group did not differ from placebo. However, Lentinex supplementation did prevent a fall in the number of B-cells observed in the control group, and a significant difference between Lentinex and control was observed. (Fig 2) Change from untreated PP-population, B-cells (CD19+) Placebo Lentinex 0,6 0,4 Diff in % B-cells 0,2 0-0,2-0,4-0,6-0,8 Fig 2 Lentinex was able to prevent the fall in B-cells observed in an elderly population. The difference between the treatments were significant, p=0.038 When a subgroup with pre-treatment values below the group median at entry was analyzed, a highly statistically difference in response in B-cells was observed 8 (Fig 3). Change from untreated subgruppe (< median), B-cells (CD19+) Placebo Lentinex 2 1,5 Diff in % B-cells 1 0, ,5 Fig 3. Change from untreated in a subgroup of subjects Fig 3 shows the increase in B-cells from zero-time (pre-treated) to after 6 weeks of treatment with Lentinex. The differences between the B-cells in the Lentinex

5 Page 5 of 6 group compared to those number of B-cells in the control (placebo) group was statistically significant, p= Apart from showing this one critical immune marker responding to Lentinex supplementation, the results from the study indicated that beta-glucans are most effective when the immune system is not optimal. Therefore, the intake of supplements like Lentinex will probably work like prophylactics, keeping the immune system alert (i.e. immune surveillance ). This would be in accordance with the observations that lentinan reduces infections when pre-fed to mice before they are exposed to an antigenic insult (murine Listeria monocytogenes) 9, but do not express antibacterial effects in vitro. Conclusion: Results from the referenced studies, strongly suggest that when Lentinex from GlycaNova is administered to animals and humans with less than optimal immune systems, the Lentinex will enhance the immune system by normalizing (i.e. increasing) lowered level of B-cells. Thus, when antigens are present (as in disease), an increased number of antibodies are able to be produced (adjuvant effect). T.Albrektsen Medical Director GlycaNova Report

6 Page 6 of 6 References: 1 The human beta-glucan receptor is widely expressed and functionally equivalent to murine Dectin-1 on primary cells. Willment JA et al. Eur J Immunol May;35(5): Synergistic action of lentinan (LNT) with endocrine therapy of breast cancer in rats and humans. Kosaka A et al. Gan To Kagaku Ryoho Feb;14(2): Immune receptors for polysaccharides from Ganoderma lucidum. Shao BM Biochem Biophys Res Commun Oct 8;323(1): Data on file: Kathy L O Reilly, Study report 5 Data on file: Evaluation of Lentinex Toxicity in Healthy BN Rats. Study report. 6 Data on file. Kathy L. O Reilly. Characterization of the effect of lentinan on Helicobacter pylori colonization in the mouse model. Final report, 7 Specific immune response to HBsAg is enhanced by beta-glucan oligosaccharide containing an alpha-(1-->3)-linked bond and biased towards M2/Th2. Dong SF et al. Int Immunopharmacol Jun;7(6): Data on file: Efficacy and safety of Lentinex as an immune stimulant in healthy elderly humans. A crossover, placebo, controlled study. Clinical report. 9 Lentinan has a stimulatory effect on innate and adaptive immunity against murine Listeria monocytogenes infection. Kupfahl C et al. Int Immunopharmacol Apr;6(4):