Rice Bran Arabinoxylan for Regulation of the Immune System
By Jay Udani, MD, and Mary L. Hardy, MD, Dr. Udani is Assistant Clinical Professor at UCLA David Geffen School of Medicine, and Medical Director of the Integrative Medicine Program at Northridge Hospital, Northridge, CA; Dr. Udani has received clinical research support from Daiwa Pharmaceuticals, the manufacturer of BioBran. Dr. Hardy is Associate Director, UCLA Center for Dietary Supplement Research: Botanicals, and Medical Director, Cedars-Sinai Integrative Medicine Medical Group, Los Angeles, CA; she reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.
Background: The Immune System
Inflammation is a necessary immune system defense function that can be triggered by endogenous or exogenous factors. The inflammation cascade is a complex system that involves positive and negative signaling factors that must exist in homeostasis. When this system is out of balance, the result can be a depressed immune system leading to susceptibility to infections, or overstimulation leading to damage to the host.
Chronic inflammation is particularly worrisome as it can lead to premalignant and malignant conditions. Some examples of this are inflammation associated with Helicobacter pylori colonization leading to gastric cancer, Barrett's esophagitis leading to esophageal cancer, sun burn leading to skin cancer, HPV infection and resultant inflammation leading to cervical cancer, and hepatitis B or C leading to hepatocellular carcinoma.
BioBran
Rice bran arabinoxylan (beta-1,4-xylopyranose hemicellulose) is treated with a hyphomycetes mycelia extract (Shiitake mushrooms). The chemical structure is an arabinoxylan with a side chain polymer and a xylose on the main chain. The product also contains polysaccharides, including beta-glucan.
Daiwa Pharmaceuticals manufactures a rice bran arabinoxylan product called BioBran. This product was previously sold in the United States under the trade name MGN-3 until the FDA permanently restricted the distributing company (Lane Labs) from selling the product due to unlawful claims that it was indicated for the treatment of cancer.1 The product is now distributed by Daiwa Health Development under the trade name PeakImmune4.
Mechanism of Action/Laboratory Studies
In vitro studies have shown that BioBran appears to stimulate the production of inflammatory cytokines IFN-gamma, TNF-alpha2 and IL-6.3,4 It also has been shown to increase the release of nitrous oxide from macrophages and the overall phagocytic activity of macrophages.3 The product may have antioxidant properties and has been shown to scavenge free radicals in a dose-dependent manner.5
The ability to increase natural killer (NK) cell cytotoxicity is one of the other often mentioned immunomodulatory abilities of BioBran. In a series of studies available only as abstracts or in abbreviated form, Ghoneum et al showed an improvement in NK activity following treatment with BioBran in a group of 32 cancer patients, all of whom exhibited lower than normal NK cell function at study outset.6 Ghoneum also examined the effect of BioBran on NK cell activity in a series of 24 individuals using 15-45 mg/kg/d for two months.7 NK activity was enhanced at all concentrations used, and BioBran acted in a dose-dependent fashion to increase NK cell activity significantly over the duration of the study.
Ghoneum et al also found baseline NK cell activity to be low in patients with varied advanced cancers: BioBran led to a significant increase in NK cell activity after 1-2 weeks and was reportedly sustained for up to five years with continued administration.8 A decrease in tumor markers and long-term stabilization of disease also were reported, though again, only through abstracted or abbreviated publication.
While a detailed discussion of the merits and methods for measuring NK cell cytotoxicity are beyond the scope of this article, in vitro studies have demonstrated that both BioBran and IL-2 can increase NK cell cytotoxicity in a dose-dependent manner. Combining BioBran and IL-2 appears to increase NK cell cytotoxicity even further.4
Anti-inflammatory Properties
In vitro studies also reveal a possible maximum dose for increasing NK activity. One study showed that while peripheral blood lymphocytes (PBLs) with lower initial NK cell cytotoxicity demonstrated increases in this marker when incubated with BioBran, PBLs with initially high amounts of NK cytotoxicity showed a decrease in activity with the addition of Biobran.9 This provides a basic mechanism for the hypothesis that Biobran may exert anti-inflammatory properties under certain circumstances.
An animal sepsis model (using lipopolysaccharides to induce sepsis) showed that the addition of BioBran improved survival rate and was associated with a decrease in IL-6 levels and an increase in TNF-alpha.9 The authors' working hypothesis was that BioBran stimulates the release of additional cytokines, which down-regulate the TNF receptors. This study also reported the only known potential side effect of BioBran, which was an increase in proteinuria in mice receiving the highest dose of Biobran. It is known that IFN-gamma can induce renal failure, and it is possible that the appearance of proteinuria was a precursor to this outcome.
Animal models of asthma and atopic dermatitis, disorders with a significant inflammatory component, have been studied as well. The small asthma study demonstrated non-IgE-mediated reductions in asthma signs in the animal model and the skin study showed a reduction in IgE along with a reduction in the progression of skin lesions.9 Neither of the studies measured any inflammatory markers.
Cardiovascular Risk
Animal studies of streptozotocin-induced diabetic rats showed significant reductions in total cholesterol and triglycerides and a reduction in the glucose excursion at 30 minutes in an oral glucose tolerance test.9 The authors claim that these effects are independent of the amount of dietary fiber present in the product.
Clinical Studies
A 2004 randomized, double-blind crossover trial compared the ability of BioBran and rice bran to prevent colds in 50 elderly subjects.10 Study participants were living in an assisted living facility in Japan and received each product for about 30-40 days. Forty-eight subjects received BioBran and 38 subjects received rice bran. No adverse events were reported and safety laboratory values (not specified in the text) did not reveal any significant abnormalities. Incidence and duration of colds were not statistically different between groups; however, the total symptom score was significantly lower in the BioBran group (P = 0.04).
More recently, a randomized, double-blind, placebo-controlled trial evaluated the effectiveness of BioBran to reduce fatigue in chronic fatigue syndrome (CFS) patients.11 Seventy-one CFS patients (assessed using the Centers for Disease Control and Prevention 1994 criteria) who were attending outpatient CFS services received 2 g of BioBran three times daily for eight weeks or a placebo equivalent. The primary outcome measurement was the Chalder physical fatigue score; self-reported fatigue measures, self-assessment of improvement, change in key symptoms, and quality of life, anxiety, and depression measures were determined as secondary outcome measures. Although both groups improved over the course of the study, there were no significant differences between groups. With regard to the primary outcome measurement, the Chalder fatigue score was 0.3 (95% confidence interval, -2.6 to 3.2) lower in the BioBran group.
The only published human data on the potential anti-inflammatory properties of BioBran was an eight-person case series in Japan.12 Eight subjects with rheumatoid arthritis who were on chronic pharmacologic therapy were given BioBran for 6-12 months. Only three of the eight patients showed any clinical response to the product. One subject, a 78-year-old female, showed reductions in rheumatoid factor (from 65 IU/mL to 34 IU/mL) and CRP (from 2.0 mg/dL to 0.6 mg/dL) after six months. The subject was on prednisone and bucillamine during this time and it was not noted whether the dosages of these medications were changed during the study. The second case, a 77-year-old female, was also on steroids when she began BioBran. After one year, her inflammatory markers fell as well (rheumatoid factor fell from 500 IU/mL to 62 IU/mL and CRP fell from 1.8 mg/dL to 1.0 mg/dL). The third case, a 39-year-old woman also taking steroids, saw a decrease in rheumatoid factor from 320 IU/mL to 92 IU/mL and in CRP from 1.6 mg/dL to 1.0 mg/dL after three months. Subjective symptoms were also noted to be improved in all three cases. The dosages used in this study ranged from 1 g/d to 3 g/d. No information was provided regarding the five subjects who did not benefit from treatment and no adverse events were reported.
Another case series of fibromyalgia patients was published in a non-peer-reviewed journal in 2001.13 Ten subjects were given BioBran three times a day, however the dose of BioBran was not reported. Of the 10 subjects, one withdrew due to oral ulcers and a facial rash. One other subject developed cervical lymphadenopathy, which continued throughout the study. Four subjects reported improvements although statistical analysis was not applied to these results. The author attempted sub-group analysis based on the etiology of the chronic fatigue, dividing subjects into viral and non-viral causes of their disorder. The requirements for this division were not provided, but the author reports that the viral group was more likely to show improvement.
Dosage and Formulation
There is only one formulation of this proprietary product; it is sold under the brand name PeakImmune4. The recommended dose is 1-3 g/d.
Adverse Effects
Animal toxicity data including acute and chronic toxicity, Ames testing, and guinea pig antigenicity testing have been negative to date.9 The fibromyalgia case series reported three adverse events possibly related to BioBran ingestion including oral ulcers, facial rash, and cervical lymphadenopathy.12 There are also theoretical risks with immunostimulation including IFN-gamma-induced proteinuria. This has not been seen in humans.
Conclusion
Use of BioBran as an immunomodulatory is based on in vitro and ex vivo data that show dose-dependent changes in inflammatory cytokines and natural killer cell cytotoxicity. Interestingly, this product appears to possess anti-inflammatory properties when the immune system is already overstimulated, such as in rheumatoid arthritis. These observations are preliminary and will need to be confirmed in controlled human clinical trials, which have yet to be conducted on this product.
Recommendation
While safety data appear reasonable, human efficacy data for BioBran are lacking. MGN-3, as the product was previously known, was employed by a number of patients with cancer, but with little to suggest benefit in that setting. To this day, the remedy remains without significant evidence of clinical benefit, and with no clear therapeutic indication.
References
1. FDA. FDA News: U.S. District Judge Issues Permanent Injunction Against Lane Labs-USA, Inc. and Orders Firm to Refund Money to Purchasers of Illegally Marketed Unapproved Drugs. July 13, 2004. Available at: www.fda.gov/bbs/topics/news/2004/NEW01086.html. Accessed Sept. 26, 2006.
2. Ghoneum M. Enhancement of human natural killer cell activity by modified arabinoxylane from rice bran (MGN-3). Int J Immunotherapy 1998;XIV:89-99.
3. Ghoneum M, Matsuura M. Augmentation of macrophage phagocytosis by modified arabinoxylan rice bran (MGN-3/biobran). Int J Immunopathol Pharmacol 2004;17:283-292.
4. Ghoneum M, Jewett A. Production of tumor necrosis factor-alpha and interferon-gamma from human peripheral blood lymphocytes by MGN-3, a modified arabinoxylan from rice bran, and its synergy with interleukin-2 in vitro. Cancer Detect Prev 2000;24:314-324.
5. Tazawa K, et al. Scavenging activity of modified arabinoxylane from rice bran (biobran/mgn-3) with natural killer cell activity on free radicals. Biotherapy 2000;14:493-495.
6. Ghoneum M, et al. NK Immunorestoration of cancer patients by MGN-3, a modified arabinoxylan rice bran (study of 32 patients for up to 4 years). Available at: www.dhdeurope.sk/research.htm. Accessed Oct. 18, 2006.
7. Ghoneum M. Enhancement of human natural killer cell activity by modified arabinoxylane rice bran (MGN-3). Int J Immunother 1998;IV:197.
8. Ghoneum M, Manatalla G. NK immunomodulatory function in 27 patients by MGN-3, a modified arabinoxylane from rice bran. Abstract, 87th Annual Meeting of the American Association for Cancer Research; Washington, DC; April 1996.
9. Tazawa K. Biobran/MGN-3 basic and clinical application to integrative medicine. Japan: Iyakushuppan Co.; 2006.
10. Maeda H, et al. Oral administration of hydrolyzed rice bran prevents the common cold syndrome in the elderly based on its immunomodulatory action. Biofactors 2004;21:185-187.
11. McDermott C, et al. A placebo-controlled, double-blind, randomized controlled trial of a natural killer cell stimulant (BioBran MGN-3) in chronic fatigue syndrome. OJM 2006;99:461-468. Epub 2006 Jun 29.
12. Ichihashi K. Experience with administration of modified arabinoxylan from rice bran in patients with rheumatoid arthritis. Clin Pharmacol Ther 2004;14:459-463.
13. Kenyon J. A descriptive questionnaire-based study on the use of biobran in chronic fatigue syndrome. Townsend Letter for Doctors and Patients 2001;(November):48-50.
Udani J, Hardy M. Rice bran arabinoxylan for regulation of the immune system. Altern Med Alert 2006;9(11):125-128.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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