The immune system is not well understood by the medical profession, most of whom are far more familiar with adaptive immunity. Many doctors still do not recognise, for example, that it is the innate rather than the acquired immune system that is more important in keeping us free from infection. They may know that the innate immune system is damaged by excessive hygiene (the ‘hygiene hypothesis’), which has removed important immune-priming compounds from the food chain. However, there is relatively little awareness, that innate immune function can be enhanced by the use of immuno-primers; among which the lead candidate is undoubtedly yeast-derived 1-3, 1-6 beta glucans. Thankfully this is changing.
These important new therapeutic tools are now the subject of intense research programmes; a simple search of the medical and scientific databases reveals a rapid proliferation of publications citing the 1-3, 1-6 beta glucans in a wide variety of applications. The FDA is currently supporting their development as pharmaceutical agents in cancer therapy, and as tools to reduce the incidence of post-surgical infection; the University of Berlin is using them to replace antibiotics in animal feed, as has already occurred in agriculture world-wide; the university of Oslo is working on their ability to reduce the severity of allergic disease, in parallel with medical institutions in Brazil (20) and Japan (21); the American Armed Forces Radiobiology Research Institute has demonstrated the ability of beta glucans to protect against bone marrow suppression (19); and the Canadian Department of Defence has also established that beta glucans offer comprehensive protection against even weaponised anthrax (18). These are important and pluri-potent compounds.
BETA GLUCANS – THE RISING STARS
Innate immune cells do not have the ability to recognise a wide range of antigens, but they do carry on their surface an extremely important group of 9 or 10 receptors called Toll-Like Receptors (TLR’s). TLR’s respond to only a limited number of compounds; but as these compounds are very basic elements in micro-organisms, and one or more of them occurs in every bacterium, virus and parasite, the TLR’s are able to recognise almost any infection and initiate an appropriate immune response. When they recognise a bacterial cell wall compound such as lipotechoic acid, lipopolysaccharide or flagellin, or fungal wall compound such as 1-3, 1-6 beta glucan (13,14), they initiate an antimicrobial response involving, inter alia, heightened macrophage activity. When they recognise viral DNA, they initiate an antiviral response involving interferon and enhanced NK cell activity.
Beta glucan NO40, a preparation of purified cell ghosts derived from baker’s yeast, contains two related and complementary innate immune primers. One of these, Zymosan, triggers Dectin-1 and TLR’s 2 and 6 (12); leading indirectly to increased numbers of activity of macrophages. The second primer, 1-3, 1-6 beta glucans, occupies and activates the critically important CR3 receptor (11), which occurs in the cell walls of all innate immune cells and has the special function of recognising yeast infection.
After ingestion, the yeast ghosts in beta Glucan NO40 are taken up by M-cells in Peyers Patches in the small intestine, and phagocytosed by macrophages. Macrophages digest the beta glucans into smaller fragments, and release these over a 24-36 hour period into the blood stream. The fragments bind to CR3 receptors on neutrophil granulocytes and Natural Killer (NK) cells, priming them and making them more active. The neutrophils are involved in killing bacteria, and the NK cells kill both virally infected cells and cancer cells; leading to increased resistance to infection and enhanced cancer cell killing. Activation of CR3 receptor also supports white blood cell proliferation, thereby enhancing bone marrow recovery.
There is a further integrated effect on the acquired immune system. When innate dendritic cells are activated via their CR3 receptors they ‘tell’ the acquired immune system that an infection is on hand and instruct naïve T-helper cells to develop into TH 1 cells, which have anti-microbial properties, rather than TH2 cells which are involved in allergic reactions.
BETA GLUCANS – ANTI-CANCER
Anti-cancer drugs are extremely toxic, and the latest generation of these (the mono-clonal antibodies or mAb’s) are relatively ineffective. When combined with beta glucans, however, their effectiveness is greatly enhanced; without additional toxicity (26-34). Extensive pre-clinical animal studies have demonstrated the efficacy of combined beta glucan with anti-tumor mAb therapy in terms of tumor regression and long-term survival (35, 36), and it has been proposed that the addition of beta-glucan will further improve the clinical therapeutic efficacy of antitumor mAb’s in cancer patients (34). A series of preliminary Japanese clinical trials have drawn similar conclusions (1-10). Clinical trials are underway using anti-epidermal growth factor receptor mAb (cetuximab) in combination with beta-glucan for metastatic colorectal cancer.
The 1-3, 1-6 beta glucans have intrinsic anti-cancer activity. They are capable, for example, of inducing apoptosis in a range of human cancer cell lines (15,16,17). They have anti-angiogenic and anti-metastatic effects (25). Equally critically, they have the ability to switch off tumour-induced TH2 shift, an important mechanism whereby cancers evade immuno-surveillance (24). Due to these actions it is very probable that long-term high (historically normal) intakes of 1-3, 1-6 beta glucans, whether in the diet or in supplemental form, will exert a chemoprotective effect. There is at this time no available data which would enable such an effect to be quantified; a lifetime rodent study has been discussed and might provide some insight.
Beta 1-3, 1-6 glucans are characterized by chains of glucose molecules with a beta 1,3 linked backbone and 1,6 linked branches. Glucans from different sources vary in terms of backbone structure, branching linkages, frequency and length, molecular weight, and higher order aggregates. Research presented at the national Cancer Institutes’ frontiers in Basic Immunology 2009 demonstrated that even slight variations in these characteristics affect the beta glucan’s capacity to bind to immune cells, and their subsequent bioactivity (22,23). Three beta glucans with similar but non-identical primary structures were screened: scleroglucan (fungal), Imprime PGG® (yeast-derived) and laminarin (algal).
An in vitro study analyzed the ability of these polysaccharides to bind to human immune cells. Imprime PGG had the highest level of binding, followed by the algal derivate, while the fungal beta glucan had minimal binding ability. This was unsurprising as the CR3 receptor was ‘designed’ to respond to yeast infection, rather than mushroom invasion, and yeast beta glucans are accordingly the most effective agonists (a chemical that binds to a receptor of a cell and triggers a response by that cell). The fungal and algal beta glucans are partial agonists, and less effective immune-modulators.
This was substantiated by a follow-up in vivo anti tumour study, in which the beta 1-3, 1-6 glucans were combined with a monoclonal antibody in a lymphoma model. The survival rate of animals treated with Imprime PGG was more than double of those receiving fungal and algal glucans.
These findings demonstrate that when evaluating the safety and efficacy of beta glucans, even when using different yeast beta glucans, careful attention should be given to the compound studied in the research. Research supporting one beta glucan does not necessarily support another because of differences in molecular characteristics.
1-3, 1-6 beta glucans are substantiated and important therapeutic agents, and are currently one of the hottest research topics in immunology. In our over-sanitised condition they hold the key to normalising and thus improving innate and adaptive immune function. Injectable forms such as Imprime PGG are being developed as pharmaceuticals, and are extremely promising adjuncts to mAb anti-cancer drugs. Without the co-administration of a drug such as Imprime PGG the use of anti-cancer drugs on their own will soon be regarded as unethical.
As a food extract, however, the yeast-derived 1-3, 1-6 beta glucans are available to anyone concerned with improving their immune health. Safe and extremely well tolerated, these valuable compounds restore the ‘normal’ level of background challenge that the immune system was designed to cope with; and depends on.
1. Hamuro J. Anticancer immunotherapy with perorally effective lentinan Gan To Kagaku Ryoho. 2005 Aug;32(8):1209-15. Review. Japanese.
2. Kawaoko T, Yoshino S Kondo H, Yamamoto K, hazama S, Oka M. Clinical evaluation of intrapleural or peritoneal repetitive administration of Lentinan and OK-432 for malignant effusion Gan To Kagaku Ryoho. 2005 Oct;32(11):1565-7. Japanese
3. Kimura Y, Iijima S, Kato T, Tsujie M, Naoi Y, Hayashi T, Tanigawa T, Yamamoto H, Kurokawa E, Matsuura N, Kikkawa N. TS-1 and lentinan combination immunochemotherapy for advanced or recurrent gastric cancer: a preliminary report Gan To Kagaku Ryoho. 2003 Oct;30(11):1791-3. Japanese
4. Nagahashi S, Suzuki H, Nishiwaki M, Okuda K, Kurosawa Y, Terada S, Sugihara T, Andou K, Hibi T. Ts-1/CDDP/Lentinan combination chemotherapy for inoperable advanced gastric cancer Gan To Kagku Ryoho. 2004 Nov;31(12):1999-2003. Japanese
5. Nakono H, Namatame K, Nemoto H, Motohashi H, Nishiyama K, Kumada K. A multi-institutional prospective study of lentinan in advanced gastric cancer patients with unresectable and recurrent diseases: effect on prolongation of survival and improvement of quality of life. Kanagawa Lentinan Research Group. Hepatogastroenterology. 1999 Jul-Aug;46(28):2662-8.
6. Namatame K, Nemoto H, Motohashi H, Nishiyma K, Kumada K. A multi-institutional prospective study of lentinan in advanced gastric cancer patients with unresectable and recurrent diseases: effect on prolongation of survival and improvement of quality of life; Kanagawa Lentinan Research Group. Hepatogastroenterology. 1999 Jul-Aug;46(28):2662-8
7. Nakayama H, Aoki N, Hayashi S, Wakabayashi K, Karube H, Ogame H, Aoki H, Sakamoto N, Masuda H, Hemmi A. A case of long survival with UFT and lentinan treatment in a patient with peritoneal metastasis of gastric carcinoma Gat To Kagaku Ryoho. 2004 Fet;31(2):241-3. Jabanese.
8. Nimura H, Mitsumori N, Tsukagoshi S, Nakajima M, Atomi Y, Suzuki S, Kusano M, Yoshiyuki T, Tokunaga A. Pilot study of TS-1 combined with lentinan in patients with unresectable or recurrent advanced gastric cancer Gan to Kagoku Ryoho. 2003 Sep;30(9):1289-96. Japanese.
9. Tari K, Satake I, Nakagomi K, Ozawa K, Oowada F, Higashi Y, Negishi T, Yamada T, Saito H, Yoshida K. Effect of lentinan for advanced prostate carcinoma Hinyokika Kiyo. 1994 Fet;40(2):119-3. Japanese
10. Ueda Y, Naito K, Iwamoto A, Tagi T, Shimizu K, Shiozaki A, Tamai H, Ochiai T, Sonoyama T, Yamagishi H. Two case reports of complete regression of liver metastases from colorectal cancer after locoregional immunochemotherapy Gan To Kagaku Ryoho. 2004 Oct;31(11):1671-3. Japanese.
11. van Bruggen R, Derwniak A, Jansen M van Houdt M, Roos D, Chapel H, Verhoeven AJ, Kuijpers TW. Complement receptor 3, not Dectin-1, is the major receptor on human neutrophils for beta-glucan-bearing particles. Mol Immunol. 2009 Dec;47(2-3):575-81
12. Gantner BN, Simmons RM, Canavera SJ, Akira S, Underhill DM. Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J Exp Med. 2003 May 5;197(9):1107-17
13. Goodridge HS, Wolf AJ, Underhill DM. Beta-glucan recognition by the innate innume system. Immunol Ref. 2009 Jul;230(1):38-50
14. Underhill DM. Macrophage recognition of zymosan particles. J Endotoxin Res 2009:9(3):176-180
15. Hida S, Miura NN, Adachi Y, Ohno N. Cell wall beta-glucan derived from Candida albicans acts as a trigger for autoimmune arthritis in SKG mice. Biol Pharm Bull. 2007 Aug;30(8):1589-92
16. Fullerton SA, Samadi AA, Tortorelis DG, Choudhury MS, Mallouh C, Tazaki H, Konno S. Induction of apoptosis in human prostatic cancer cells with beta-glucan (Maitake mushrrom polysaccharide). Mol Urol. 2000 Sprin;4(1):7-13
17. Zhang M, Chiu LC, Cheung PC, Ooi VE, Growth-inhibitory effects of beta-glucan from the mycelium of Poria cocos on human breast carcinoma MCF-7 cells: cell-cycle arrest and apoptosis induction. Oncol Rep. 2006 Mar;15(3):637-43
18. Kournikakis B, Mandeville R, Brousseau P, Ostroff G. Anthrax-protective effects of yeast beta 1,3 glucans. MedGenMed. 2003 Mar 21;5(1):1
19. Patchen ML, MacVittie TJ, Brook I. Glucan-induced hemopoietic and immune stimulation: therapeutic effects in sublethally and lethally irradicated mice. Methods Find Exp Clin Pharmacol. 1986 Mar;8(3):151-5.
20. Sarinho E, Medeiros D, Schor D, Rego Silva A, Sales V, Motto ME, Costa A, Azoubel A, Rizzo JA. Production of interleukin-10 in asthmatic children after Beta-1-3-glucan: Allergol Immunopathol (Madr). 2009Jul-Aug;37(4):188-92
21. Yamada J. Alleviation of seasonal allergic symptoms with superfine beta-1,3-glucan: a randomized study Nippon Ganka Gakkai Zasshi. 2009 Nov;113(11):1082-7. Review
23. Driscoll M, Hansen R, Ding C, Cramer DE, Yan J. Therapeutic potential of various beta-glucan sources in conjunction with anti-tumor monoclonal antibody in cancer therapy. Cancer Biol Ther. 2009 Mar 3;8(3)
24. Baran J, Allendorf DJ, Hong F, Ross GD. Oral Beta-glucan adjuvant therapy converts nonprotective Th2 response to protective Th1 cell-mediated immune response in mammary tumor-bearing mice. Folia Histochem Cytobiol. 2007;45(2):107-14
25. Yamamoto K, Kimura T, Sugitachi A, Matsuura N. Anti-angiogenic and anti-metastatic effects of beta 1,3-D-glucan purified from Hanabiratake, Sparassis crispa. Biol Pharm Bull. 2009 Feb;32(2):259-63.
26. Hong F, Yan J, Baran JT, Allendorf DJ, Hansen RD, Ostoff GR, Xing PX, Cheung N-KV, Ross GD; Mechanism by Which Orally Administered b-1,3-Glucans Enhance the Tumoricidal Activity of Antitumor Monoclonal Antibodies in Murine Tumor Models The Journal of Immunology, 2004, 173: 797-806
27. Yan J, Vetvicka V, Xia Y, Coxon A, Carroll MC, Mayadas TN, Ross GD. 1999. Beta-glucan, a “specific” biologic response modifier that uses antibodies to target tumors for recognition by complement receptor type 3 (CD11b/CD18). J. Immunol. 163:3045.
28. Vetvicka V, Thornton BP, Wieman TJ, Ross DG. 1997. Targeting of NK cells to mammary carcinoma via naturally occurring tumor cell-bound iC3b and beta-glucan-primed CR3 (CD11b/CD18). J. Immunol. 159:599.
29. Vetvicka V, Thornton BP, Ross GD. 1996. Soluble beta-glucan polysaccharide binding to the lectin site of neutrophil or NK cell complement receptor type 3 (CD11b/CD18) generates a primed state of the receptor capable of mediating cytotoxicity of iC3b-opsonized target cells. J. Clin. Invest. 98:50.
30. Allendorf DJ, Yan J, Ross GD, Hansen RD, Baran JT, Subbarao K, Want L, Haribabu B. C5e-Mediated LeukotrieneB4-Amplified Neutrophil Chemotaxis Is Essential in Tumor Immunotherapy Facilitated by Anti-Tumor Monoclonal Antibody and beta-Glucan. The journal of Immunology, 2005, 174:7050-7056.
31. Cheung NK, Modak S, Vickers A, Knuckles B. 2002. Orally administered Beta-glucans enhance anti-tumor effects of monoclonal antibodies. CancerInnumon.Immunother:51:557-564.
32. Yan J, Vetvicka V, Xia Y, Coxon A, Carroll MC, Mayadas TN, Ross GD. 1999. beta-Glucan, a “specific” biologic response modifier that uses antibodies to target tumors for cytotoxic recognition by leukocyte complement receptor type 3 (CD11b/CD18). J.Immunol.163 3045-3052.
33. Cheung NK, Modak S. 2002. Oral (133),(134)-beta-D-glucan synergizes with antiganglioside GD2 monoclonal antibody 3F8 in the therpy of neuroblastoma. Clin. CancerRes.8:1217-1223.
34. Yan J, Allendorf DJ, Brandley B. Yeast whole glucan particle (WGP) beta-glucan in conjunction with antitumour monoclonal antibodies to treat cancer. Expert Opin Biol Ther. 2005 May;5(5):691-702.
35. Zhong W, Hansen R, Li B, Cai Y, Salvador C, Moore GD, Yan J. Effect of yeast-derived beta-glucan in conjunction with bevacizumab for the treatment of human lung adenocarcinoma in subcutaneous and othotopic xenograft models. J Immunother. 2009 Sep;32(7):703-12
36. Harnack U, Eckert K, Fichtner I, Pecher G. Oral administration of soluble 1-3, 1-6 beta-glucan during prophylactic surviving peptide vaccination diminishes growth of a B cell lymphoma in mice. Int Innumopharmacol. 2009 Oct;9(11):1298-303.
|Click the links below to see more Relevant Research|