Immunostimulants

Immunostimulants are substances that activate or increase the activity of any element of the immune system and are divided into two types: specific and non-specific. Specific immunostimulants are those that induce immunity against a specific antigen, the most widely used being vaccines. Conversely, non-specific immunostimulants such as adjuvants, prompt an immune response without antigen specificity. These substances can be either endogenous or synthetic.

Common endogenous and synthetic immunostimulants that are administered for medical purposes include proteins such as lymphokines, particularly IL-2 which induces proliferation of CD4⁺ cells, and CSF for macrophages and granulocytes. More importance are interferons which are commercially available, and are currently being used in medicine for the treatment of certain types of cancer like leukemia and Karposis sarcoma.^1-2 These endogenous and synthetic substances are categorized as non-specific, usually given to immunocompromised patients.

Adjuvants, typically aluminum salts, are another example of non-specific immunostimulants, used along with vaccines as immunological boosters.³ Vaccines, being specific immunostimulants, are preparations of antigens which can either be dead, attenuated microorganisms, or products or derivatives of such organisms. ⁴ Adjuvants are important because they aid in the stabilization of vaccine-induced immune responses.  As a result, less of the antigen is required for effective antibody production, avoiding the administration of large quantities of a pathogen that could potentially lead to infection. Some childhood vaccines that contain adjuvants are those for hepatitis A, B and C, DTP, and HPV. Viral vaccines against measles, mumps, and chicken pox do not contain adjuvants and neither do seasonal flu vaccines.³

Recently, a great deal of effort is being invested in the development of studies that shed light on the effectiveness of immunostimulants in the prevention and treatment of disease.  This is of particular importance within the developing industry of immunostimulant nutrients. Such nutrients obtained from food or plants can be easily incorporated into our diets.⁵ These effects have been identified in many vitamins and minerals like vitamins A, B-6, C and E, magnesium, zinc, selenium and folate.  As most of these substances are obtained from vegetables, fruits, nuts, seafood and meat, their incorporation into the agriculture and aquaculture industries is of particular importance. For example, folate is one of the most common nutritional deficiencies seen among many segments of the world’s population.⁶ It is obtained mostly from foods that contain wheat.  The usage of folate in the developing stages of wheat products can prevent viral and bacterial infiltration into the crop and ultimately provide a healthier product without the need of chemical preservatives.

 Immuostimulants represent a powerful tool in our constant battle with pathogens.  Their properties allow them to act in favor of our immune system, increasing leukocyte activity, antibody formation and response, non-specific infection resistance, interferon production and macrophage activity.  Also, they could oppose cancer, activate neutralization and complement systems and prevent atrophy caused by stress, injury, surgery, aging and infection.⁶  Further knowledge of immunostimulants can paint a promising picture of a future where the human defense system is powerful enough to fight infections, immunodeficiencies, autoimmunity and neoplasms.⁷

Clinical Correlations

Immunostimulation can be achieved by a natural process, such as an infection by bacteria or virus. It can also be achieved by human intervention, such as a vaccine, intervention with immunoglobulins, or with immunostimulants that are derived from bacteria or nutritional components. There are various useful ways to use immunostimulants such as for treatment of respiratory infections, cancer, for the prevention of allergic reactions and minimization of antibiotic resistance.

            Recurrent respiratory infections in children can predispose them to more respiratory diseases in the future. This is one of the mayor causes of morbidity and mortality in children. One of the main ways that micro-organisms invade the body is through epithelial surfaces and mucosa. In a similar pattern, bacterial immunomodulators are also administered orally. This activates the Peyer’s patches of GALT, and generates an immune response. In figure 1, the mechanism of oral stimulation is described.   M cells, found in Peyer's patches, have microfolds where T cells and B memory cells reside. They are responsible for the trapping of molecules and there transfer to the subepithelial region. Here they are processed by macrophages and dendritic cells in the mucosa, and they are presented to lymphocytes. Also, plasmocytes, which produces IgA, are generated. Then, lymphocytes are transported the thoracic duct were they return to MALT associated structures.  One of the bacterial immunomodulators that researchers are studying is called OM-85 BV. It has been considered to treat respiratory tract infections on pediatric patients. OM-85 BV (Broncho-Vaxom) is an immunostimulant used to prevent recurrent tract infections.⁸ It stimulates the terminal maturation of dendritic cells thus leading to an enhanced T cell stimulation. It has been proved that OM-85 BV can affect innate immunity by stimulating macrophages, neutrophils and cytokine production, as well as the acquired immune response by synthetizing immunoglobulins and lymphocyte activation.⁹ Several studies also demonstrate up regulation of oxidative metabolism, super oxide and nitric oxide production.⁹ Moreover, it increases expression of adhesion molecules on monocytes and granulocytes. In general, OM-85 BV has the potential of enhancing specific immunity as well as humoral immunity, and it also can increase levels of IgA. This immunoglobulin deficiency is related to frequent respiratory infections. Hence, the number of episodes of acute respiratory tract infections can be reduced and their duration shortened.

            Another useful way that scientists and doctors are using immunostimulants is for the treatment of cancer. Many oncologists already use monoclonal antibodies as passive immunotherapy. One of the most promising approaches being used is the manipulation of the tumor micro-environment. According to Ruttinger et al, “…the use of immune-stimulating antibodies, and the manipulation of immune suppression and immune microenvironment hold out great hope for achieving clinical benefit” ¹⁰. To manipulate the cancer micro-environment, scientists have to act upon T_reg lymphocytes, which can be found in high levels in cancer patients and are thought to be related to a negative prognosis. The use of toxin Ontak® (denileukin difitox) has showed a regression in melanoma and ovarian cancer. Ontak® is an interleukin (IL-2)-toxin molecule that binds to the IL-2 receptor on T_reg cells.¹⁰ Another way immunostimulants are being utilized is by using the anti-CTLA-4 antibody ipilimumab. CTLA-4 is a member of the immunoglobulin superfamily that is expressed in activated CD4 T cells and sends inhibitory signals to cytotoxic T cells. The use of ipilimumab has led to 1, 2, and 3 year survival rates for IV melanoma patients at a resected stage, and 30% of patients treated experienced survival benefits.¹⁰ In the future, there is a possibility that immune-stimulatory antibodies can 

become the preferred treatment for cancer patients. 

A third mode in which immunostimulants have proven to be successful is in the prevention of allergic  reactions^.11 Research has shown success in the use of polybacterial immunostimulants as a way to activate mechanisms of the immune system in humans. They work in the promotion of nonspecific immunoprevention that boosts phagocytosis, the properdin complement systems and synthesis of IgA, as well as contribute to the formation of new lymphatic nodules.¹¹ Via this process, allergic reactions are prevented and antibiotic use will not be as frequent in individuals undergoing this treatment, since its excessive use has proven to have an immunosuppressive effect on the host.¹¹ Finally, the increase in antibiotic resistance from multiple bacteria strains has created scientific enigmas.  In some species, antibiotic resistance has reached as high as 40% of the total bacterial strains..¹¹ Bacterial resistance to treatments proves to be detrimental, yet novel immunostimulant techniques promise to offer a prospective and less prejudicial means to increase survival rates for immunodeficiency patients

Multiple Choice Questions

1)      Refer to the graphic 2 to answer this question. In this graphic, t-cell uptake of H-Thymidine is used to quantify t-cell proliferation on the presence of increasing amounts of IL-2.  Considering the graph results, what is the mechanism through which IL-2 could be considered an immunostimulant?

a)      IL-2 acts as a post-trancriptional factor which up regulates receptors involved in its proliferation.

b)      IL-2 is a cytokine messenger which promotes t-cell proliferation acting through IL-2 receptor, thus having.

c)      IL-2 promotes the formation of different peptides that will activate the proliferation cascade.

d)     IL-2 acts as a second messenger that phosphorylates PKA and eventually initiates DNA transcription.

Explanation: IL-2 is a cytokine which promotes T-cell proliferation when bound to IL-2 receptor. IL-2/IL-2R complex stimulates the growth and survival of selected cytotoxic T-cells.

Answer: B

2)      A 29 years old pregnant woman went to a health fair, where she received a H1N1 vaccine. Why can a vaccine of H1N1 be considered an exogenous immunostimulant?

a)      Protects the fetus against H1N1.

b)      Ameliorates her pregnancy symptoms.

c)      Dilates the lung bronchioles preventing from collapse.

d)     Enhances her response to the H1N1 virus.

Explanation: H1N1 vaccine enhances the host response to the virus by stimulating the production of specific immunoglobulins which will prevent an infection by H1N1 virus.

Answer: D

3)      In case of an infection, macrophages and other immunological cells are capable of secreting proteins that can be considered immunostimulants. Which of the following is the best choice as an immunostimulant?

a)      Promegapoietin

b)      TGF-β

c)      GM-CSF (granulocyte macrophage- colony stimulant factor)

d)     TNF-α

Explanation: GM-CSF is a protein secreted by immune system’s cells which stimulates stem cell differentiation into granulocyte and monocytes.

Answer: C

 Discussion Questions

1)      Describe the two types of immunostimulants. Mention an example where they are both used together.

Specific immunostimulants are those that induce immunity against a specific antigen, the most popular and most widely used examples are the contents of a vaccine.

Non-specific immunostimulants, such as adjuvants, prompt an immune response without antigen specificity. A perfect example of both used togheter is when an adjuvant is included along with a vaccine.

2)      What is the purpose of vaccines? Why is using an adjuvant an advantage?

Vaccines are use to stimulate the immune system to create antibodies without the need of a primary symptomatic infection. Adjuvants aid in the stabilization of vaccine-induced immune responses so that less antigen is required for effective antibody production, thus avoiding the administration of large quantities of a pathogen that could lead to a potential infection.

3)      Discuss the importance of immunostimulant nutrients. Mention an example.

Immunostimulant  nutrients can be obtained from food or plants, such as vitamins and minerals, can be easily incorporated into our diets and can provide stimulatory effects on the immune system. The usage of immunostimulant substances in the developing stages of wheat products can prevent viral and bacterial diseases among the species and ultimately provide us with a healthier product without the need of chemical preservatives. One of the most common immunogenic nutritional deficiencies seen among many segments of the world’s population is folic acid deficiency.⁶It is obtained mostly from foods that countain wheat.

 References

1. Vardanyan, R. and Hruby, Victor. Synthesis of Essential Drugs. San Diego : Elsevier B.V., 2006. pp. 420-421.

2. Stanford University. Immunostimulants. PharmGKB. [Online] [Cited: March 27, 2011.] http://www.pharmgkb.org/do/serve?objId=PA164712819&objCls=Drug#tabview=tab0.

3. CDC. Vaccine Safety. Center for Disease Control and Prevention. [Online] March 19, 2010. [Cited: March 27, 2011.] http://www.cdc.gov/vaccinesafety/concerns/adjuvants.html#4.

4. FDA. Consumer Updates. U.S. Food and Drug Administration. [Online] March 28, 2011. [Cited: March 27, 2011.] http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm048750.htm#BenefitsandRisks.

5. Lloyd, E. What are immunostimulants? [Online] [Cited: March 28^th, 2011.] www.wisegeek.com/what-are-immunostimulants.htm.

6. Kumar Pati, A. Power-Boosting Your Immune System: Immunostimulant Nutrients [Online] October 26^th, 2010. [Cited March 28^th, 2011.] www.prlog.org/10940666-power-boosting-your-immune-system-immunostimulant-nutrients-drabhay-kumar-pati-haywood-ca-usa.htm

7. Eichler, F., Krueger GR. Effects of non-specific immunostimulants (echinacin, Isoprinosine, and thymus factors) on the infection and antigen expression in herpesvirus-6 exposed human lymphoid cells. 8(4): 565-75. [Online] July-August 1994. [Cited: March 28^th, 2011]. www.ncbi.nml.nih.gov/pubmed/7534493.

8. Schaad U. OM-85 BV, an immunostimulant in pediatric recurrent respiratory tract infections: a systematic review. World journal of pediatrics. 2010; 6. [Cited March 26^th, 2011.]http://www.wjpch.com/article.asp?article_id=361.

9. Rozy A, Chorostowska-Wynimko J. Bacterial immunostimulants—mechanism of action and clinical application in respiratory disease. Pneumonol Alergol Pol. 2008; 76: 353-359.  [Cited March 26^th, 2011.]http://www.ncbi.nlm.nih.gov/pubmed/19003766

10. Rüttinger D, Winter H, van den Engel N, et al. Immunotherapy of cancer: key findings and commentary on the Third Tegernsee Conference. The Oncologist. 2010; 15: 112-118. [Cited March 27^th, 2011.] http://theoncologist.alphamedpress.org/cgi/reprint/15/1/112. 

11. Petrunov B, Nenkov P and Shekerdjiisky R. The role of immunostimulants in immunotherapy and immunoprophylaxis. Biotechnology and biotechnological equipment. 2007; 4: 454-462.  [Cited March 27^th, 2011.] http://www.diagnosisp.com/dp/journals/view_abstract.php?journal_id=1&archive=1&issue_id=16&article_id=443. 

12. Arrington, J, McMurray, D, Switzer, K, Fan, Y, & Chapkin, R. Docosahexaenoic acid suppresses function of the cd28 costimulatory membrane receptor in primary murine and jurkat t cells. The Journal of Nutrition, 131(4). [Cited: March 28^th, 2011]. http://jn.nutrition.org/content/131/4/1147/F4.expansion.html