IMMUNOSTIMULANTS
Immunostimulants are substances (drugs or nutrients) that increase the ability of the immune system to fight infection and disease (USIH). Typically, immunostimulants are divided into specific and non-specific categories. Specific imunostimulants stimulate an immune response to one or more specific antigenic types. This highly specific adaptive response begins when the patient is infected for a first time. The immune system reacts to the new pathogen and develops permanent protection by T and B lymphocytes. These immune cells will protect the body when subsequently met by the same pathogen. This immune response is mounted when macrophages engulf the foreign antigens and present them in the lymph nodes. These antigens are then recognized by T-helper, T-Killer, or B cells. B cells enlarge to produce plasma cells that produce antibodies, impeding the microbes and marking them to be engulfed by macrophages. When the virus is removed, memory cells are formed by T- and B cells so when there is re-exposure a quick response ensues. Vaccines, another type of specific immunostimulant, also mimic natural infection preparing the system for a quick response to re-exposure (Figure 1) Adjuvants also enhance the response of the immune system specifically. Some mechanisms of action for adjuvants through noncovalent binding are: prolonging the stimulus through a delay in the release of immunogen; enhancing the uptake of immunogen by antigen-presenting cells; inducing co-stimulatory molecules; and stimulating the Toll-like receptors on the surface of macrophages, which in turn induces the cytokine production that enhances the response of T cells and B cells to the antigen (Levinson).
Non-specific immunostimulants do not have any antigenic specificity, but rather act as general stimulants that enhance the function of certain types of immune cells. In non-specific immunostimulation, a primary augmentation of the immune response is by the anatomical and mechanical barriers that are associated with chemical and biological agents. (Medzhitov, R., Janeway, C. 2000). Cytokines, or interleukins, mediate non-specific immunostimulation signal by affecting cells’ behaviors. In addition to inducing growth, differentiation, and apoptosis, the upregulation of these mediators increase the immune response and helps to contain different infectious agents (Vinderola, C. et al. 2006). Cytokines therefore provide a strong defense in several clinical cases that would potentially cause serious damage to the host. For example, granulocyte-macrophage colony stimulating factor (GM-CSF) is a cytokine secreted by macrophages, T cells, mast cells, endothelial cells and fibroblast that effectively stimulates stem cells to produce granulocytes and monocytes (Crawford J. 1991). GM-CSF’s are used as medications to stimulate the production of white blood cells following chemotherapy. This non-specific immunostimulant has also been considered a potential vaccine adjuvant in HIV-infected patients and is waiting for FDA approval (Lieschke GJ. 1992).
Endocrine hormones such as PRL, GH and thyroid hormones have been demonstrated to have a role in immunostimulation as well. These hormones exert their effect indirectly as anabolic and stress-modulating hormones affecting cells of the immune system (Dorshkind and Horseman 2000). These endocrine signals modulate immunosuppression associated with glucocorticoids. The positive effects of these hormones on the immune system occur as an adaptation to stress (Figure 2); therefore, they are not required for the generation of an immune response in healthy individuals (Dorshkind and Horseman 2000). Immunostimulants are also found in the form of food derivates. Vitamins, minerals, and fatty acids generate a proliferation in antigen-specific antibody (Figure 3). Vitamins, minerals, oligosaccharides and lactic bacteria also augment T cells and amplify their propagation during an immune reaction and elevate phagocytic and NK cells action (Shuichi, K. and Masanobu, N. 2004).
FIGURES:
Figure 2: The interaction between stress and the endocrine system are highlighted here. Glucocorticoids (CORT) have immunosuppressive effects via glucocorticoid receptor (GR) mechanisms as seen on the left. This results in maladaptive response in the immune system. On the right, the expression of prolactin (PRL) and/or growth hormone (GH) on immune cells interact with GR preventing the interaction of STAT and GR, minimizing the negative effects of glucocorticoids on immune cells. (Dorshkind and Horseman 2000)
Figure 3: Manipulation of the immune system by food products. The two systems affected are the innate and adaptive immune system. Lactic acid and vitamins have a direct effect on the innate system by increasing phagocytic activity and NK cells. Vitamins, minerals, fatty acids and oligosaccharides affect the adaptive immune system by increasing T cell response and antibody production. (Shuichi, K. and Masanobu, N. 2004)
CLINICAL CASES:
1. GI TRACT INFECTION: Normal Intestinal Microbiota competition against invading pathogen (Cytokine Interaction in Immunostimulation)
CD is a very healthy woman. Her favorite breakfast is a parfait, with yogurt, fresh fruit and granola. She has it every morning after her daily run. For her birthday she decides to go out for dinner with a couple of friends. She had some pork with mashed potatoes. After a few hours she starts getting abdominal pains and she feels bloated. She has both urinary and fecal incontinence, flatulence and experiences vomiting. She can’t even drink water. She visits her physician and he diagnoses her with food poisoning. He orders her to have small amounts of yogurt and Gatorade to prevent dehydration. After 2 days she is feeling much better. She can eat solid food again and her bowel movements have normalized.
Figure 4: Illustration of the natural defense systems of the intestine (www.customprobiotics.com). The intestine, composed of villi and crypts coated with mucus. At the bottom of the crypts lie Paneth cells that release antimicrobial molecules into the gut lumen. The intestinal flora, present mainly in the colon, forms a natural barrier to pathogens. The intestinal immune system comprises cells disseminated beneath the epithelium, lymphocytes, both B and T. When a lymphocyte is activated, it leaves the mucosa in lymph and enters the bloodstream via the thoracic canal eventually colonizing the same mucosa or other mucosal effector sites.
EXPLANATION: Fermented dairy products (ex. yogurt) contain specific metabolites such as peptides and exopolisacharides that enhance B cell proliferation and increase the secretion of Ig A and Ig G antibodies in the gut mucosa. This leads to prevention of infection from bacteria and other microbes in the GI tract. In recent studies, PMFKM (kefir microflora) proved to increase a number of cytokines such as IL-4, IL-6, IL-10, IL-12, IFNc and TNFa mostly in the small intestine. Cytokine secretion was also observed in blood serum, reflecting the inmunostimulant properties of the PMFKM. This demonstrates a manipulation of the constituents of the intestinal lumen through dietary means, enhancing the health status of the host.
2. Non-specific Immunostimulation Treatment
A 30 year-old man that is a cook was sharpening his cooking knives when one slipped and made a 2.5 inch incision in his arm. He rushes to the hospital because he can’t stop the bleeding. The doctors gave him stitches. After a week, he returns to the hospital because the injury is infected. His CBC shows that he has a low WBC count for someone with an infection. The physician asked if he had omitted anything from his medical history that could explain the abnormal results of the infection. He admitted to being HIV positive. Knowing now that this patient is immuno-compromised, the physician opened the wound and flushed it with WFI and gave him an infusion of tetrachlorodecaoxygen in order to stimulate a proper macrophage phagocytic response. After 2 weeks, his wound healed and he was able to go back to work.
Fig 5: Mechanism of action of WF 10 with chronic inflammation. (biomaxx-sys.com)
Explanation: Tetrachlorodecaoxygen has been commonly used for the treatment of external wounds. WF 10 is an intravenous infusion based on the tetrachlorodecaoxygen (TCDO) drug that stimulates phagocytosis by macrophages (Penpattanagul, 2007). WF 10 inhibits proliferation, IL-2 production of anti-CD3 stimulated PBMC, and the nuclear translocation of NFATc (transcription factor); WF 10 induce cytokines like IL-1β, IL-8, and TNF-α (Giese, 2004). WF 10 was developed as an adjunctive therapy to simultaneously combat antiretroviral and opportunistic infection prophylaxis in AIDS patients. It was also approved by the Thailand government for use in post radiation cystitis in cervical cancer patients (Drugs RD, 2004).
3. Prophylactic treatment against febrile neutropenia in cancer patients
A patient who was recently diagnosed with cancer is undergoing chemotherapy. As a consequence of this therapy, he develops bone marrow suppression. Within a few days, he develops a febrile neutropenia. A CBC was ordered showing a decrease in neutrophils. The doctor, not wanting to remove him from chemotherapy treatment, prescribes him filgrastim, a G-CSF treatment to reduce his febrile neutropenia. After a week of treatment, the patient goes for a follow up visit. He tells the doctor that he has not had anymore fevers. A follow-up CBC showed that his WBC levels had increased.
Fig. 6: The role of the neutrophil consist of their response to foreign invaders. Once the invaders enter the blood vessels, neutrophils detect them and commence phagocytosis in order to remove the bacteria from the system. (hivandhepatitis.com)
Fig. 7: Administration of G-CSF into the body travel to the bone marrow where it stimulates the formation of granulocytes leading to an increase of neutrophils in the blood system. (probiomed.com.mx)
EXPLANATION:
Cancer patients undergo chemotherapy therapy in order to decrease the tumor burden and prolong survival of the patient. Tumors are more susceptible than normal tissue to chemotherapeutic agents because they have a higher proportion of dividing cells. However, because certain types of normal tissue have a high rate of division rate like the bone marrow, mucosa and epidermis, they are also susceptible to the effects of chemotherapy (Meric-Bernstam). Therefore, treatment with chemotherapeutic agents can produce noxious effects, such as bone marrow suppression, which leads to febrile neutropenia. Other side effects of chemotherapy include stomatitis, ulceration of the GI tract, and alopecia (Meric-Bernstam).
Febrile neutropenia increases infection-related morbidity and mortality; therefore, it is a significant dose-limiting toxicity in cancer treatment. (Aapro, 2006). Cancer patients developing severe or febrile neutropenia (FN) during chemotherapy frequently receive dose reductions and/or delays to their chemotherapy. A reduction or delay in therapy may impact the success of treatment, particularly when treatment purpose is either curative or to prolong survival. Recent analyses have shown that by reducing the risk of FN and chemotherapy dose delays and reductions there is a potential enhancement in survival rates for cancer patients. In order to reduce febrile neutropenia in patients undergoing chemotherapy, there has been an increase in the prophylactic use of granulocyte colony stimulating factors (G-CSFs), such as filgrastim, lenograstim or pegfilgrastim. G-CSFs influence the development of the neutrophils, acting as immunostimulants. G-CSF therapy will increase the level of neutrophils and shorten the length of the cycle sufficiently to prevent recurrent bacterial infections (Hammond et al., 1989).
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QUESTIONS:
1. What is the mechanism by which Prolactin (PRL) modulates the immune system during adaptive stress?
Answer: Prolactin on immune cells interacts with GR preventing the interaction of STAT and GR, minimizing the negative effects of glucocorticoids on immune cells. (Fig. 3)
2. True or False: Lactic acid bacteria and vitamins affects the adaptive immune system by increasing phagocytic activity and NK cells while Vitamins, minerals, fatty acids, and oligosaccharides affect the innate immune system by increasing T cell response and antibody production.
Answer: FALSE. Lactic acid bacteria and vitamins affects the innate immune system by increasing phagocytic activity and NK cells while Vitamins, minerals, fatty acids, and oligosaccharides affect the adaptive immune system by increasing T cell response and antibody production.
3. What are the benefits of the prophylactic treatment against febrile neutropenia in cancer patients?
Answer: It stimulates the formation of granulocytes and eventually increasing the levels of neutrophils in the body.
4. Adjuvants differ from protein carriers in that:
a. form covalent bonds with the immunogen
b. accelerate the release of the immunogen
c. diminish the immune response to an antigen
d. do not form covalent bonds with the immunogen
5. Which line of blood cells is the principal target when G-CSF or GM-CSF is administered?
a. Neutrophils
b. Lymphocytes
c. Red Blood Cells
d. Platelets
6. Once the adaptive immune system is activated, it can trigger the T-cell-mediated immune response and the antibody response, both are carried out by ______________.
A) T lymphocytes
B) B lymphocytes
C) Dendritic cells
D) Effector T cells
E) A and B
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