Holt Institute of Medicine: A Revolution in the Teaching of Natural Medicine

Natural Ways to Healthy Immune

Stephen Holt, MD, MRCP (UK), FRCP (C), FACP, FACG, FACN, FACAM, Little Falls, NJ, contact: info@naturesbenefit.com.

The Body’s Bio-defenses

The immune system is the body’s bio-defense. Immune function involves a complex cascade of events involving intelligent communications between all tissues of the body. Alterations of the balance of the immune function are responsible for the cause or progression of many common diseases including: cancer, chronic inflammatory disorders, arthritis and specific auto-immune disease. People talk about boosting immune function but most often they really mean balancing immune function.

A Simple Overview of Immune Function
White cells in the body of various types aggregate to form lymphatic tissues which are the pivotal structures of the immune system. A complex series of chemical messengers are shared among cells involved in immune defense and normal cells. Antibody production by specific types of white cells is responsible for clearing the tissue fluids of harmful intruders, e.g. antigens or microorganisms.
The bio-defenses within the immune system are not simple in their structure or function. Elaborate mechanisms of bio-defense are present in entry sites into the body including the nasal passages, throat and entire gastrointestinal tract.
Understanding the complexity of the body structure and functions involved in immunity is a difficult task for even the most knowledgeable health caregiver. The complexity of the cascade of events that occur during immune functions makes it highly unlikely that any single agent be it food or a drug or a dietary supplement will have an efficient effect on balancing or promoting immune function.
Recommendations for single dietary supplements to “boost” immunity are somewhat misguided. “Boosting” certain aspects of the complex events in immune-related diseases may, on occasion, be more harmful than good. The additive benefits and versatile nature of many different natural agents that can work on different aspects of immune events are quite desirable in dietary supplement formulations.

Self-Reliance for Self-Management of Immune Function
Many people are seeking natural substances that will help to deliver optimal immune function in the body and control unwanted inflammatory responses. Modern research on remedies of natural origin has pointed to a number of remedies of natural origin that have complex actions on immune function and actions at many different sites in the overall cascade of immune events. Again, I stress that using more than one natural agent that works on different aspects of immune function is the optimal approach. This has led to the use of synergistic formulations of dietary supplements where many different dietary supplements are combined to get a more global and complete overall effect on immunity. The word “synergy” means that each natural component in a dietary supplement may have an added benefit when mixed together.

Advanced Supplement Formulations for Immune Support
Single-agent approaches with one herb or nutrient possess disadvantages and limitations. For example, sterolins or mushroom extracts are valuable immune stimulators but they have focused and limited effects on only certain aspects of immune function. There is a way of producing a dietary supplement that combines nutrients, herbals and botanicals for a greater effect and potential benefit on immunity. Table 1 is a list of dietary supplements that can be used in combination to stimulate immune function in a reasonably global manner. Such combinations do not rely upon an isolated component of the immune cascade.

Andrographis paniculata
Acanthopanax Senticosa
Green tea
Turmeric
Grapeseed extract
Zinc
Vitamin C
Ashwagandha
Oregon grape
Shiitake mushroom
Echinacea purpurea
Goldenseal
Goldenthread
Aloe vera
Garlic
Astragalus
Korean ginseng
Coriolus versicolor
Active Hexose Correlate Compound
(AHCC)
Beta glucan

Table 1: A list of nutrients, herbs and botanicals with good scientific agreement of nutritional benefits for immune function.

Any natural agent that exerts an antioxidant function can be potentially valuable in promoting healthy immune function, because oxidative stress (free-radical damage) to components of the immune system is a common reason for disordered immunity. In particular, the following antioxidants are of great value for immune well-being, including: Vitamin C, zinc, green tea, turmeric, grapeseed extract and antioxidants found in a variety of herbs and botanicals (Table 1).
Botanical agents with specific immune-enhancing power include several species of mushrooms, plant sources of beta glucan, various types of Echinacea and the potent and versatile herb Andrographis paniculata (AP). Recent research implies that AP may be a very powerful stimulator of immune function by its specific actions on chemical signals in certain cells, and it has anti-cancer and anti-viral properties.

A Very Important Message
Recent research links excessive intake of simple sugars in the diet with depressed immunity in both the short and long term. Who would have thought that America’s love affair with sweet foods would open the door for chronic disease in a manner that has been unsurpassed in medical history? Seventy million Americans have the metabolic syndrome or Syndrome X, which is the combination of obesity, high blood pressure, and high blood cholesterol as a consequence of insulin resistance.
Simple sugar intake in the diet is promoting the development of Syndrome X. Syndrome X is the most important public health initiative facing Western society, and the dietary supplement industry has still not waken up to the importance of Syndrome X as a death and disability risk from all causes of disease. The risk of Syndrome X is humungous.

While Syndrome X has components that people can identify with cardiovascular disease, Syndrome X also causes liver disease, cancer and diminished immune function. Syndrome X is a forerunner to the development of maturity onset diabetes mellitus. People with diabetes or Syndrome X may present themselves with the consequences of diminished immune function. Early signs of diabetes in many people include recurrent infections, e.g. yeast, Candida. The reduction of refined sugar in the diet may be a simple intervention to help restore balance to the immune system. The far-reaching health consequences of Syndrome X have resulted in a redefinition of Syndrome X as “Syndrome X, Y and Z….”

Conclusion
I believe that nutritional support for immune function must be multifaceted and formulations of dietary supplements that contain several different natural ingredients are the optimal way to provide nutritional support for immune function.

Resources:
Holt S, Miracle Herbs, Carol Publishing, Secaucus, NJ, 1998
Holt S, Combat Syndrome X, Y and Z…, Wellness Publishing, Newark, NJ, 2002

Reavley N, Vitamins etc., Bookman Press, Australia 1998
www.naturesbenefit.com

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Immune Senescence: A Key Anti-Aging Initiative
Stephen Holt, MD, LLD(Hon.) ChB., PhD, ND, FRCP (C), MRCP (UK), FACP, FACG, FACN, FACAM, OSJ

The therapeutic use of dietary supplements in Complementary medicine practice is threatened by legislation in several states. This legislation is pending and its content is often quite threatening to the use of dietary supplements or nutritional support for the promotion of well being. State agencies provide different recommendations to various healthcare professionals who contribute to the important specialty of Integrative Medicine. For example, licensed medical practitioners continue to have questions about usual and customary treatment methods in their practice of Integrative Medicine and one state has attempted to place legislation that is designed to limit recommendations for dietary supplement use by Certified Nutritionists.

It is clear that different specialties or types of healthcare professionals in the Integrative Medicine field should attempt to communicate among each other and represent their best interests in a collective manner. While the use of supplements in a professional context is challenged, increasing pressure is being placed on the retail segment of the dietary supplement industry, which is increasingly regulated. There is inadequate communication and cooperation between professional organizations in Integrative Medicine and professional organizations or trade associations that advocate the use of dietary supplements for health. These circumstances must change if the nature of the Dietary Supplement Health Education Act (DSHEA, 1994) can survive.
Upon reflection, the practice of Integrative Medicine must be represented by an eclectic group of healthcare professionals, not just one discipline. It is a shame that some professional societies limit their forum to single types of healthcare givers. Integrative Medicine can only survive if integration occurs in a manner that medical practice becomes pluralistic.

These challenging times are clear, but new events are surfacing to challenge the future. First, regulatory agencies at the state and federal level are demanding that good scientific agreement be placed behind supplement claims or recommendations. Just as a medical practitioner is expected to match a drug to a disease, the practitioner of Integrative Medicine must match an evidence based, alternative approach to wellness promotion. Every one is challenged by the legal enigma that dietary supplements are not to be used to prevent or treat disease, but these are the reasons why healthcare practitioners or their clients use supplements, of their own volition. How can we live in a democratic society that legislates against the healthcare consumers own self-reliance to seek simple, gentle and natural options to maintain wellness?

These political, medical and social initiatives aside, healthcare professionals are increasingly challenged in their dispensation practice of dietary supplements by being supplied so-called “professional dietary supplements” that are often freely available for purchase in retail, at substantial discount. It is not possible for a healthcare giver to operate a dispensary with narrow margin on product sales because of practice overhead. However, when clients are dispensed a dietary supplement at a premium cost and the dietary supplement is available in a discounted retail circumstance, e.g. the internet, amazon.com etc., then there is a major disturbance in the relationship between healthcare giver and client. This has led to claims by patients that some healthcare givers are “price gouging.” Healthcare givers are best served by
using products that are backed by science, preferably product-specific science and such products should not be available in retail markets. These emerging problems are amenable to solution by a healthcare practitioner selecting only those products that are suitable for professional dispensation and proprietary to a healthcare giver. In this volume 1 number 1 of the Natural Clinician e-zine, attempts to address these issues of product specific research are made in the important area of use of nutrients or herbs or botanicals in the support of immune function.

Clinical Immune Modulator™ (Biodefense®) – Product-Specific Science and Comparison by Independent Laboratory Studies

Introduction: An attempt to promote or modulate immune function with natural substances has been of major interest in the practice of alternative medicine. The threats to humankind posed by chronic insults to the immune system or viral infections are not addressed to a major degree in preventive medicine using conventional medical interventions, with the exception of vaccines or anti-viral drugs of variable efficacy. It makes complete sense to have all patients with chronic debilitating disorders or acute medical challenges prepared by a bolstering of innate immune function, in the absence of specific types of auto-immune problems.

Product-Specific Research. Manufacturers of products that allege an ability of their supplement to stimulate immune function often use borrowed science or market with exaggerated statements of efficacy without performing product-specific research. Natural Clinician LLC has taken a lead in the research of professional dietary supplements by commissioning independent studies through its Scientific Advisory Board. In this case, the feature of recent research has been immune stimulation or modulation with the product Clinical Immune Modulator™ (Natural Clinician LLC).
Introducing Comparative Research. In the attached abstract, Formulation A is Clinical Immune Modulator™ (Biodefense®)* and Formulation B is MGN-3*, now called PeakImmune4* (in retail) and BRM-4* (in professional practice). MGN-3 was, at one time, the best selling immune stimulator in the modern history in the practice of Integrative Medicine in the United States. The product was withdrawn under the label MGN-3 because of exaggerated treatment claims, but it continues to be marketed as PeakImmune4 or BRM-4.
Attached to this communication shows extremely intricate in-vitro and in-vivo studies that demonstrate clearly enhanced versatility and potency of Clinical Immune Modulator™ in comparison with MGN-3 or BRM-4 or PeakImmune4. Also attached is the comprehensive, patented formula of Clinical Immune Modulator™ which demonstrates its content of many different nutrients, herbs and botanicals that have an evidence base to support immune function. Clinical Immune Modulator™ also contains modest amounts of AHCC and its effects appear to be more versatile than described with AHCC (ImmPower™*, ImmunoMax™*, AHCC, Immuno Complex™* etc.) Other immune stimulators such as Epicor™* have emerged with distinct similarity to MGN-3(PeakImmune4 or BRM-4) in its actions, but some attempt to produce in-vitro studies.

Natural Clinician LLC is proud to present its compelling research data to show the superiority of synergistic formulation of multiple herbs, botanicals and nutrients (Clinical Immune Modulator™) over other immune stimulators that are sold in the market. The studies of Natural Clinician challenge purveyors of supplements in the professional market to supply a clear evidence base for the action of their product by undertaking specific research with their own products. Upon information and belief, most products containing AHCC alone merely take borrowed science to promote their brand. In contrast, Natural Clinician can show the efficacy of their product in independent laboratory studies by testing actual product in circulation in clinical practice. The efforts of Natural Clinician are part of the new model to support an evidence base for therapeutics in Integrative Medicine, without reliance on marketing data or sales hype.

Abstract: Natural Immune Modulation and Biodefenses
While immune function involves a complex cascade of bio-physiological events, attempts to enhance or modulate immunity, using natural medicines, has often focused inappropriately on the use of single agents of botanical or nutrient origin. Practitioners of Integrative Medicine have placed much confidence in natural substances that may increase Natural Killer cell function (NK cell activity), without sufficient consideration for many other aspects of immunity, such as B cell activity, antibody function and messenger molecule cascades (e.g. interleukins). To test the hypothesis that complex immune functions require synergistic formulations of multiple, herbs, botanicals and nutrients, a complex formulation of natural agents with a variable evidence base for altering immune function (Formulation A, Clinical Immune Modulator™, Natural Clinician) were compared with a less complex version of a natural immune modulating product composed of a blend of fermented rice bran and shiitake mycelium extract the (most popular immune stimulator used in Integrative Medical practice in the past decade) (Formulation B, MGN-3, PeakImmune4 or BRM-4). Formulation A and B were purchased over the counter as dietary supplements and compared in experiments to define effects on several parameters of immune function.

Methods: A selected panel of standard in vitro assays for lymphocyte activation was used on cell cultures of freshly isolated human lymphocytes from healthy donors. Direct NK activation was evaluated by immunostaining and flow cytometry for the NK cell activation markers CD69, CD25, and CD54. Proliferation of B, T, and NK cell subsets in vitro was monitored by a flow cytometric method. Cytokine production was evaluated by intracellular staining for TNF-alpha and Interferon-gamma, as well as enzyme-linked immunosorbent assays for Interferon-gamma.

Results and Conclusions: Culturing of human lymphocytes in the presence of Formulation A resulted in a strong direct activation of NK cells, as evaluated by induction of CD69 on almost 100% peripheral blood NK cells. The effect was concentration-dependent, but substantial NK cell activation was seen over a broad range of dilutions. Formulation B produced a weaker, but consistent, activation of NK cells in vitro. Comparison of serial dilutions of both extracts showed that induction of the CD69 NK activation marker required 10-100 fold higher concentrations of Formulation B extract in order to produce similar activation levels as the Formulation A. Neither of the two extracts possessed mitogenic activity, but Formulation A was able to modulate responses to the known T cell mitogen PHA, by reducing PHA-induced proliferation.

This study supports the notion that versatile changes in immune status require comprehensive combinations of synergistic agents that affect a range of the complex cascades of immune function. Furthermore, these findings demonstrate the need for purveyors of professional dietary supplements to provide specific research information on their products, rather than the promotion of a product by the use of borrowed science or inference.

References
Plat J, Mensink RP. 2005. Food components and immune function. Curr Opin Lipidol. 16(1):31-7
Ogawa K, Takeuchi M, Nakamura N. 2005. Immunological effects of partially hydrolyzed arabinoxylan from corn husk in mice. Biosci Biotechnol Biochem. 69(1):19-25
Garritson BK, Nikaein A, Peters GN, Gorman MA, King CC, Liepa GU. 1995. Effect of major dietary modifications on immune system in patients with breast cancer: a pilot study. Cancer Pract. 3(4):239-46.
deVere White Rw, Hackkman RM, Soares SE, Beckett La, Sun B. 2002. Effects of a mushroom mycelium extract on the treatment of prostate cancer. Urology 60(4):640-4.
Ng ML, Yap AT. 2002. Inhibition of human colon carcinoma development by lentinan from shiitake mushrooms (Leninus edodes). J Altern Complement Med. 8(5):581-9.
Rudinicki V, Wong R Kaneko Y. 1998. A placebo-controlled trial of the immune modulator, lentinan, in HIV positive patients: a phase I/II trial. J Med. 29(5-6):305-30.
Wasser SP. 2002. Medicinal mushrooms as a source of antitumor and immunomodulating polysaccharides. Appl Microbiol Biotechnol. 60(3):258-74.
Kidd PM. 2000. The use of mushroom glucans and proteoglycans in cancer treatment. Altern Med Rev. 5(1):4-27.
Maeda H, Ichihashi K, Fujii T, Omura K, Zhu X, Anazawa M, Tazawa K. 2004. Oral administration of hydrolyzed rice bran prevents the common cold syndrome in the elderly based on its immunomodulatory action. Biofactors 21(1-4):185-7.
Ghoneum M, Matsuura M. 2004. Augmentation of macrophage phagocytosis by modified arabinoxylan rice bran (MGN-3/biobran). Int J Immunopathol Pharmacol.
17(3):283-92.
Ghoneum M, Abedi S. 2004. Enhancement of natural killer cell activity of aged mice by modified arabinoxylan rice bran (MGN-3/Biiobran). J Pharm Pharmacol. 56(12):1581-8.
Ghoneum M, Gollapudi S. 2003. Modified arabinozylan rice bran (MGN3/Biobran) sensitizes human T cell leukemia cells to death receptor (CD95)-induced apoptosis. Cancer Lett. 201(1):41-9
Ghoneum M, Jewett A. 2000. 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. 24(4):314-24.
Hopkins MJ, Englyst HN, Macfarlane S, Furrie E, Macfarlane GT, McBain AJ. 2003. Degradation of cross-linked and non-cross-linked arabinozylans by the intestinal microbiota in children. Appl Environ Microbiol. 69(11):6354-60.
Figueroa-Espinoza MC, Poulsen C, Borch Soe J, Zargahi MR, Rouau X. 2004. Enzymatic solubilization of arabinoxylans from native, extruded, and high-shear-treated rye bran by different endo-xylanases and other hydrolyzing enzymes. J Agric Food Chem. 52(13):4240-9.
Leathers TD. 2003. Bioconversions of maize residues to value-added coproducts using yeast-like fungi. FEMS Yeast Res. 3(2):133-40.
Cyran M, Courtin CM, Delcour JA. 2003. Structural features of arabinoxylans extracted with water at different temperatures from two try flours of diverse breadmaking quality. J Agric Food Chem. 51(15):4404-16.
Leathers TD. 2003. Bioconversions of maize residues to value-added coproducts using yeast-like fungi. FEMS Yeast Res. 3(2):133-40.
Ebringerova A, Kardosova A, Hromadkova Z, Malovikova A, Hribalova V. 2002. Immunomodulatory activity of acidic xylans in relation to their structural and molecular properties. Int J Biol Macromol. 30(1):1-6.
Holt Institute of Medicine™ Press 2007
Zunft HJ, Lueder W, Koebnick C, Imhof D, Meuser F. 2004. Reduction of the postprandial glucose and insulin response in serum of healthy subjects by an arabinoxylan concentrate isolated from wheat starch plant process water. Asia Pac J Clin Nutr. 13(Suppl):S147.
Fischer MH, Yu N, Gray GR, Ralph J, Anderson L, Marlett JA. 2004. The gel-forming polysaccharide of psyllium husk (Plantago ovata Forsk). Carbohydr Res. 339(11):2009-17.
Marlett JA, Fischer MH. 2003. The active fraction of psyllium seed husk. Proc Nutr Soc. 62(1):207-9.
Nandini CD, Salimath PV. 2002. Structural features of arabinoxylans from bajra (pearl millet). J Agric Food Chem. 50(22):6485-9.
O’Neill MA, Selvendran RR. 1985. Hemicellulosic complexes from the cell walls of runner bean (Phaseolus coccineus). Biochem J. 227(2):475-81.
Edashige Y, Ishii T. 1998 Hemicellulosic polysaccharides from bamboo shoot cell-walls. Phytochemistry 49(6):1675-1682.
Ebringerova A, Kardosova A, Hromadkova Z, Malovikova A, Hribalova V. 2002. Immunomodulatory activity of acidic xylans in relation to their structural and molecular properties. Int J Biol Macromol. 30(1):1-6.
Coon JT, Ernst E. 2004. Andrographis paniculata in the treatment of upper respiratory tract infections: a systematic review of safety and efficacy. Planta Med. 70(4):293-8.
Poolsup N, Suthisisang C, Prathanturarug S, Asawamekin A, Chanchareon U. 2004. Andrographis pniculata in the symptomatic treatment of uncomplicated upper respiratory tract infection: systematic review of randomized controlled trials. J Clin Pharm Ther. 29(1):37-45.
Rajagopal S, Kumar RA, Deevi DS, Satyanarayana C, Rajagopalan R. 2003. Andrographolide, a potential cancer therapeutic agent isolated fom Andrographis paniculata. J Exp Ther Oncol 3(3):147-58.
Yoon TJ, Yoo YC, Lee SW, Shin KS, Choi WH, Hwang SH, Ha ES, Jo SK, Kim SH, Park WM. 2004. Anti-metastatic activity of Acanthopanax senticosus extract and its possible immunological mechanism of action. J Ethnopharmacol. 93(2-3):247-53.
Ha ES, Hwang SH, Shin KS, Yu KW, Lee KH, Choi JS, Park WM, Yoon TJ. 2004. Anti-metastatic activity of glycoprotein fractionated from Acanthopanax senticosus, involvement of NK-cell and macrophage activation. Arch Pharm Res. 27(2):217-24.
Oak MH, El Bedoui J, Schini-Kerth VB. 2005. Antiangiogenic properties of natural polyphenols from red wine and green tea. J Nutr Biochem 16(1):1-8.
Greenwald P. 2004. Clinical trials in cancer prevention: current results and perspectives for the future. J Nutr 134(12 Suppl):3507S-3512S.
Crespy V, Williamson G. 2004. A review of the health effects of green tea catechins in in vivo animal models. J Nutr 134(12 Suppl):3431S-3440S
Holt Institute of Medicine™ Press 2007
Clinical Immune Modulator Composition (Patent pending)
Commercial Notes. *Clinical Immune Modulator is a trademark of Natural Clinician LLC (www.naturalclinician.com).*MGN-3 is a trademark of Lane Labs (withdrawn from the market) *PeakImmune4 is a trademark of Daiwa Pharmaceutical Co. Ltd. (same as MGN-3) *BRM-4 is a trademark of Daiwa Pharmaceutical Co. Ltd. (same as MGN-3) *ImmPower is a trademark of American BioSciences, Inc. *ImmunoMax is a trademark of Trace Minerals Research *Immuno Complex is a trademark of Quality of Life Labs, Inc. *Epicor is a trademark of Vitamin Research Products, Inc.
Holt Institute of Medicine™ Press 2007

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Natural Immune Modulation and Biodefenses
Stephen Holt, MD, LLD(Hon.), ChB, PhD, DNM, FRCP (C), MRCP (UK), FACP, FACG, FACN, FACAM. Distinguished Professor of Medicine, NYCPM, NY, Gitte S. Jensen, PhD, and Aaron N. Hart, PhD, Research Scientists, NIS Inc., Canada and Oregon

While immune function involves a complex cascade of bio-physiological events, attempts to enhance or modulate immunity, using natural medicines, has often focused inappropriately on the use of single agents of botanical or nutrient origin. Practitioners of Integrative Medicine have placed much confidence in natural substances that may increase Natural Killer cell function (NK cell activity), without sufficient consideration for many other aspects of immunity, such as B cell activity, antibody function and messenger molecule cascades (e.g. interleukins). To test the hypothesis that complex immune functions require synergistic formulations of multiple, herbs, botanicals and nutrients, a complex formulation of natural agents with a variable evidence base for altering immune function (Formulation A) were compared with a less complex version of a natural immune modulating product composed of a blend of fermented rice bran and shiitake mycelium extract the (most popular immune stimulator used in Integrative Medical practice in the past decade) (Formulation B). Formulation A and B were purchased over the counter as dietary supplements and compared in experiments to define effects on several parameters of immune function.

Results and Conclusions: Culturing of human lymphocytes in the presence of Formulation A resulted in a strong direct activation of NK cells, as evaluated by induction of CD69 on almost 100% peripheral blood NK cells. The effect was concentration-dependent, but substantial NK cell activation was seen over a broad range of dilutions. Formulation B produced a weaker, but consistent, activation of NK cells in vitro. Comparison of serial dilutions of both extracts showed that induction of the CD69 NK activation marker required 10-100 fold higher concentrations of Formulation B extract in order to produce similar activation levels as the Formulation A. Neither of the two extracts possessed mitogenic activity, but Formulation A was able to modulate responses to the known T cell mitogen PHA, by reducing PHA-induced proliferation.

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