Identifying the best ways to stimulate the immune system to fight infectious diseases and cancer makes eminent sense and could provide highly attractive benefits. But it is not easy to do. Here is a list of category-leading immunostimulants, followed by a discussion of the issues involved.
Cytokines: IL-2 has shown itself to be an effective general immunostimulant in scores of clinical trials against different indications and appears promising against HIV (Cohen and Powderly, 2004). Used in high doses, IL-2 has significant side effects, so it is best used as a low-dose adjuvant. Other cytokines of proven general merit include G-CSF and GM-CSF, both for hematopoiesis. Interferons may work in specific cases, but their side effects make them less suitable as broad-spectrum adjuvants.
Microbial fragments/toxins: Of the large number of candidates, beta-glucans (also found in plants) are the most frequently investigated as an approach to provoking a general immune response (Wagner, 1999).
Herbs: Echinacea is the only herb that thus far has been shown, in controlled clinical trials, by itself regularly to stimulate the immune system, though even Echinacea is not completely reliable and the benefits are often marginal (Wagner, 1999). Other promising immunostimulants include astragalus, garlic, ginseng, Guduchi (Tinospora cordifolia), maca, and Reishi mushrooms (Ganoderma lucidum), or extracts from them. The popular, mainly mushroom-based RM-10 combination (Garden of Life) contains selenium, so one must take care not to avoid an overdose.
Probiotics: Lactobacillus rhamnosus GG interacts with GI tract lymphoid foci and stimulates the immune system, e.g., in malnourished children (Gill and Cross, 2002; Clancy, 2003). Lactobacillus (L.) and Bifidobacterium (B.) have a history of safe use in dairy products and are present in the gut microbiota. They boost mucosal immunity and shorten respiratory and gastrointestinal infections (Wu, 2019)
Antioxidant Vitamins: Vitamin C has often been shown to convey an immunostimulative effect. Vitamin D boosts innate and adaptive immunity (Wu, 2019). Even though Vitamin E is not, strictly speaking, an immunostimulant, its antioxidant action does protect the immune system. Together, Vitamins C and E have been found to slow or stop disease progression in HIV/AIDS (Hughes, 2002; Allard et al., 1998). Recent studies have found that intake of high-dose Vitamins C and E over extended periods of time can have harmful effects in cardiovascular patients, but there is no evidence of these effects when they are used in HIV/AIDS and respiratory disorders.
Minerals: Zinc has proven immunostimulative effects (Prasad, 2002; Wu, 2019). Iron plays an immunity-boosting role for iron-deficient individuals (Kuvibidila and Baliga, 2002). Transdermal zinc and iron may be more immunostimulative than oral dosing (Microminerals). Salt concentrated by the body in the skin has a stimulative effect on T-cells and macrophages (Minton, 2015). This effect suggests that hypertonic saline gargle may do likewise in the throat.
Animal Products: Propolis (bee gum), collected by bees from the exudates of various trees and plants, is used to provide antimicrobial defense of hives. Its powerful antibiotic, antiviral, and antifungal effects have been deployed for millennia to fight infections both by direct antimicrobial action and by general immunostimulation. Propolis is especially indicated in oral and respiratory infections (Sforcin, 2007).
Phototherapy: Biophotonic Therapy, the leading phototherapeutic treatment of infectious diseases, has a tested and well-characterized immunostimulative effect (Dillon, 1998, 2003, 2008).
CAM Therapies: Homeopathy has repeatedly outperformed other CAM therapies in controlled clinical trials as an adjuvant treatment of HIV (Ullman, 2003). Opinions vary regarding homeopathy’s mechanisms of action. One view is that they are informational; another is that they resemble those of Biophotonic Therapy.
DISCUSSION: Given the exceptional benefits that identifying several first-rate approaches to stimulating the immune system would convey, one could reasonably ask why we seem not to have such a good idea of what they might be. Part of the answer stems from the confusion caused by the term “immunomodulator”, which in recent years has become much more widely used than the word “immunostimulant”. Immunomodulatory interventions that stimulate or suppress the immune system, depending on circumstances and doses, have drawn far more scientific attention and funding than the simple notion of immunostimulation. But in fact it is quite easy to suppress the immune system. Countless drugs, various negative emotions, and other factors can readily do so. A reasonably reliable stimulatory effect is less common, and thus it deserves to be separated out from the obfuscatory umbrella term of “immunomodulation” and given special attention.
Another part of the answer involves determining the criteria for selecting leading immunostimulants. What should these criteria be? How can we compare apples and oranges? What works against ovarian cancer might not work against tuberculosis, or even against breast cancer. Can we rely on clinical trial data? In most cases, these data are patchy or unreliable. Rarely do they include the kind of head-on-head comparative framework that would make selecting the best easier. Also, considerations of convenience and cost play a role. A hi-tech intravenous approach scores much lower than simple nutritional supplements in these regards, but it might prove somewhat more effective. Dose and the acceptability of side effects also are factors.
A prejudice against theoretical arguments in favor of clinical data, moreover, might lead one to select a mediocre immunostimulatory intervention that has been thoroughly tested over a less tested but–in theory and according to somewhat slender evidence–much more effective one.
In addition, powerful biases skew the picture. For-profit corporations will not fund clinical testing of low-cost interventions like homeopathy, while billions of dollars have been poured into research on cytokines and other immune system molecules by corporations seeking profits and government scientists interested in hi-tech research. Meanwhile, specialists in infectious diseases and patient groups have favored disease-specific new drugs instead of broad-spectrum immunostimulatory adjuvants.
All these are reasons for adopting a category-leader approach that ensures equal billing for interventions from disparate sources. Implicitly, this method accepts the risk that a single category might contain two or three interventions that are superior to the top ones in other categories because thus far clustering of funding and attention, especially regarding cytokines and their ilk, has been egregious and has led to a neglect of competing low-cost and–very plausibly–more effective approaches.
Another consideration: we ought to distinguish between interventions that restore the integrity of the immune system (e.g., iron supplementation of iron-deficient individuals) and those that stimulate a healthy immune system to perform at an even higher level (arguably, Vitamin C, especially in combination with Vitamin E, can do so). Clearly, both types of intervention can benefit a given individual; but only the second one is, strictly speaking, immunostimulatory. Nonetheless, from the perspective of a sick person, both kinds of intervention boost immunity. So in drawing up this list, we have deliberately overlooked the distinction between restoring and stimulating the immune system.
This list leaves out interventions such as physical exercise, therapeutic touch, psychology, religion, etc. on the grounds that their effects are hard to measure and compare. Still, in a future version, it might make sense to include them. In addition, combination approaches may well prove more effective than, for instance, individual herbs. But they are less amenable to reliable testing and explication. Lastly, we need to be aware that immunology textbooks do not fully reflect the more profound aspects of human immunity. The persuasive clinical data regarding the effectiveness of Biophotonic Therapy, for instance, must oblige serious scientists to delve deeper.
Allard, J.P. et al. (1998). “Effects of vitamin E and C supplementation on oxidative stress and viral load in HIV-infected subjects,” AIDS 12, pp. 1653-1659
Clancy, Robert (2003), “Immunobiotics and the probiotic evolution,” FEMS Immunology and Medical Microbiology (August 18), Vol. 38(1), pp. 9-12
Cohen, Jonathan and William G. Powderly (2004). Infectious Diseases. 2nd ed., 2 vols. New York: Mosby, p. 1402
Dillon, Kenneth J. (1998). Healing Photons. Washington, D.C.: Scientia Press
Dillon, Kenneth J. (2003). Close-to-Nature Medicine. Washington, D.C.: Scientia Press
Dillon, Kenneth J. (2008). Intriguing Anomalies: An Introduction to Scientific Detective Work. Washington, D.C.: Scientia Press
Garden of Life (www.gardenoflifeusa.com)
Gill, Harsharnjit S. and Martin L. Cross (2002), “Probiotics and Immune Function,” in Calder, Philip C., C.J. Field, and H.S. Gill. Nutrition and Immune Function. New York: CABI, pp. 251-272
Hughes, David A. (2002), “Antioxidant Vitamins and Immune Function,” in Calder, Philip C., C.J. Field, and H.S. Gill. Nutrition and Immune Function. New York: CABI, pp. 171-191
Kuvibidila, Solo and B. Surendra Baliga (2002), “Role of Iron in Immunity and Infection,” in Calder, Philip C., C.J. Field, and H.S. Gill. Nutrition and Immune Function. New York: CABI, pp. 209-228
Minton K. (2015). “A Pinch of Salt.” Nature Reviews Immunology. 13 March
Prasad, Ananda S. (2002), “Zinc, Infection and Immune Function,” in Calder, Philip C., C.J. Field, and H.S. Gill. Nutrition and Immune Function. New York: CABI, pp. 193-207
Sforcin JM. (2007) “Propolis and the immune system: a review.” Journal of Ethnopharmacology 113(1):1-14
Ullman, Dana (2003), “Controlled Clinical Trials Evaluating the Homeopathic Treatment of People with Human Immunodeficiency Virus or Acquired Immune Deficiency Syndrome,” The Journal of Alternative and Complementary Medicine, Vol. 9, No. 1, pp. 133-141
Wagner, Hildebert, ed. (1999). Immunomodulatory Agents from Plants. Boston: Birkhaeuser
Wu D et al. (2019). “Nutritional Modulation of Immune Function: Analysis of Evidence, Mechanisms, and Clinical Relevance.” Frontiers in Immunology. 9:3160
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Kenneth J. Dillon is an historian who writes on science, medicine, and history. See the biosketch at About Us.