Study authors: Vaclav Vetvicka, PhD,(1) Kiyomi Terayama, MD,(2) Rosemonde Mandeville, MD, PhD,(3), Pauline Brousseau, PhD,(3), Bill Kournikakis, PhD,(4) Gary Ostroff, PhD(5)* (1) Department of Pathology, School of Medicine, University of Louisville, Louisville, Kentucky; (2) Department of Pathology, Tokyo Dental College, Ichikawa General Sugano Ichikawa City, Chiba Prefecture, Japan; (3) Biophage Pharma Inc., Montreal, Quebec Canada; (4) Defence Research Establishment Suffield, Ralston, Alberta Canada; (5) Biopolymer Engineering, Inc., Eagan, Minnesota
JANA: A Peer-Reviewed Journal on Nutraceuticals and Nutrition
In this edition of JANA, the paper by Vetvicka et al., makes an important contribution to our scientific understanding of the nutraceutical stimulation of the immune system in the treatment of both infectious disease and cancer.
While abundant evidence demonstrates the ability of Beta 1,3- glucans to activate macrophages and neutrophils when given intravenously or intraperitoneally, there has been little information concerning its efficiency when given orally.
In their study, Vetvicka et al. used oral Beta 1,3-glucan (ImucellTM WGP Beta Glucan) from a yeast source in mice infected with Bacillus anthracis. With the high incidence of complications associated with anthrax vaccines, an alternative approach is badly needed in this era of bioterrorism threat. Dr. Ken Alibek, a top-ranking scientist at the Russian bioweapons labs, stated that because of the number of possible bioweapon agents available, something other than mass inoculations would be needed. He suggested non-specific immune stimulation. The most effective form of nonspecific immune stimulation is macrophage activation.
The anthrax bacillus secretes two toxins, edema toxin and lethal toxin. Edema toxin stimulates an outpouring of fluid, especially into the lungs. Lethal toxin, inhibits neutrophil phagocytosis and triggers destructive intracellular reactions that destroy macrophage cells. Of primary interest is the fact that anthrax lethal toxin inhibits the macrophages from releasing their immune messengers, primarily IL-1, IL-2, IFN-gamma, and TNF-alpha.
Of particular importance in combating infection is the cytokine TNF-alpha. Vetvicka et al. demonstrated that yeast derived Beta 1,3 D-glucan given orally stimulates TNF-alpha release from the macrophage, apparently overcoming inhibition by anthrax lethal toxin. This would account for the high survival figures in the Beta 1,3-glucan-treated animals. Some previous studies found no increase in TNF-alpha but a significant increase in IL-1 Beta.(1) Other researchers have demonstrated increased TNF-alpha in response to Beta-glucan stimulation.(2)
My own review of the literature confirms their statement that the most effective source of Beta 1,3-glucan is from Saccharomyces cerevisiae, the one chosen by most researchers. Purity of the product is vital, since protein contaminants, as seen in the earlier-used source Zymosan, can cause untoward immune reactions.
Beta 1,3-glucan also stimulates phagocytosis of neutrophils. In one study, the killing efficiency of neutrophils was increased 20- to 50-fold.(3) This is important since the capsular antigen poly-D-glutamic acid from the anthrax organism inhibits neutrophil phagocytosis. It is the two lethal toxins and the capsular antigen that makes the anthrax organism especially deadly. In addition, Beta 1,3-glucan has been shown to increase clearance of bacteria by the reticuloendothelial system. Thus far, no other solutions have solved this problem.
As for Beta 1,3-glucan's effects on tumor growth, several studies have shown a significant effect on tumor growth in animal models.(4,5) Early studies using immune stimulation found occasional tumor growth enhancement. This was later found to be secondary to stimulation of blocking antibody production. A safer and more effective method of immune stimulation is directed at cellular immunity, in particular the stimulation of T-helper cells and NK cells.
Beta 1,3-glucan has been shown to increase lymphocyte production, NK cell activation, and activation of macrophages. Several studies have also demonstrated the role played by cytokines in inhibiting tumor growth; again, particular interest is in TNF-alpha release.(6) Of interest also is the role played by IL-1 Beta, which is increased by Beta 1,3-glucan as well. Interleukin 1 Beta has been shown to enhance mobilization of PMLs in the bone marrow and enhance their chemotactic ability. In addition, IL-1 Beta increases the lymphocyte count and increases their activity.(7)
The use of Beta 1,3-glucan is of special interest in the cancer patient undergoing chemotherapy and/or radiation treatment, since Beta-glucans have shown a remarkable ability to accelerate hematopoetic recovery in both sublethally and lethally irradiated mice, even when given after the radiation dose. It can also stimulate recovery of the bone marrow following chemotherapy, something vital to restricting tumor growth and preventing infectious complications during treatment.
While data provided in the research by Vetvicka and co-workers is preliminary and needs to be confirmed by a larger controlled trial, this is an important pilot study, in that it demonstrates the effectiveness of oral Beta 1,3-glucan in treating both infectious agents and tumors.
1. Rasmussen L-T, Seljelid R. Novel immunomodulators with pronounced in vivo effects caused by stimulation of cytokine release. J Cellular Biochem. 1991;46:60-68.
2. Sherwood ER, Williams DL, Di Luzio NR. Glucan stimulates production of antitumor cytolytic/cytostatic factors(s) by macrophages. J Biol Response Modifiers.1986;5:504-526.
3. Onderdonk AB, Cisneros RL. et al. Anti-infective effect of poly-Beta-1,6-glucotriosyl-Beta 1,3-glucopyranose glucan in vivo. Infection and Immunity. 1992;60:1642-1647.
4. Mansell PWA, Ichinose H, et al. Macrophage-mediated destruction of human malignant cells in vivo. J Nat Cancer Inst. 1975;54:571-576.
5. Sherwood ER, Williams DL, Di Luzio NR. Glucan stimulates production of antitumor cytolytic/cytostatic factors(s) by macrophages. J Biol Response Modifiers. 1986;5:504-526.
6. Carswell EA, Old LJ, et al. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sc. 1975;72:3666-3670.
7. Browder W, Williams D, et al. Beneficial effect of enhanced macrophage function in the trauma patient. Ann Surg. 1990;211:605-613.
Source: Journal of the American Nutraceutical Association. Vol. 5, No. 2, Winter 2002.