Immunomodulators: Immune System Modifiers

 

Sukhbir Lal Khokra, Bharat Parashar, Hitesh Kumar Dhamija* and Manju Bala

Department of Pharmacy, Manav Bharti University, Solan, Himachal Pradesh

Corresponding author: hiteshkumardhamijagju@gmail.com

 

ABSTRACT:

Immunomodulators are becoming very popular in the worldwide natural health industry as people start to realize the importance of a healthy immune system in the maintenance of health and the prevention and recovery of disease. Help the immune system, and the body helps itself - often quite considerably. An immunomodulator, also known as an immunotherapy is a substance (e.g. a drug) which has an effect on the immune system. Immunotherapy is an approach that has been actively investigated in recent years as a method for disease prevention. It does not involve recognition of a specific antigen or targeting the immune response towards a specific pathogen, but causes an overall immune response that hastens recognition of foreign proteins. This review gives a brief introduction of various immunomodulators.

 

KEYWORDS: Amino acids, Immunomodulation, Immune response, Proteins, Therapeutic activity

 


INTRODUCTION:

Immunomodulation is the process of modifying an immune response in a positive or negative manner by administration of drugs or various preparations. Many proteins, amino acids, and natural compounds have shown a significant ability to regulate immune responses, including interferon-γ (IFN-γ) 1-4, steroids 5-7, DMG 8-11 and various other extracts.

 

The survival of an organism in this environment, teeming with a multitude of potentially harmful micro-organism, depends upon its ability to resist a wide variety of infections. The vertebrate animals, therefore, as a means of protection from the destructive effect of these parasitic organisms have developed an elaborate system of lymphoreticular cells, the immune system. In mammals, it has evolved as an integrated network of interacting cells and cell products that coordinately recognize and react to any component which may be considered ‘non-self’ and therefore, foreign to it12. Although immunological surveillance and competent immunological response of a host to foreign intrusion depends on the integrity of the system13, these processes, nevertheless, are susceptible to both strong and subtle genetic, therapeutic and environmental influences that result in wide variations in the expression of the immune system 14-16.

 

Recently, progress in clinical immunology has unrivalled the involvement of the immune system in the pathogenesis of several disease conditions. A large number of agents capable of modifying the relationship between the disease and host’s response to disease termed as the biological response modifiers. These agents which have also been referred to as immunomodulators, immunostimulators or immunorestoratives in accordance with their mode of action, include crude bacterial preparations, mixed bacterial vaccines, polysaccharides of bacterial and fungal origin or synthetic chemicals 17-19.

 

An immunomodulator is any substance that helps to regulate the immune system. This "regulation" is a normalisation process, so that an immunomodulator helps to optimise immune response. Give an immunomodulator to someone with a low immune system, and it can help raise that immunity; give a modulator to someone with a healthy immune system, and it will have little effect in the body; and give a modulator to someone with an overactive immune system, and can help to normalize that overactive immune system. So immunomodulators do not used to boost immunity, but to normalize it.

 

Working of Immunomodulators:

How immunomodulators work in the body is still largely a mystery. Part of their benefit appears to be their ability to naturally increase the body's production of messenger molecules, such as cytokines, which mediate and regulate the immune system. Some of them, like Biobran, can also decrease the production of inflammatory cytokines. Overall, the effect is a more efficient immune system.   Most people using substances like Biobran MGN-3 do so because they have weak immune systems. Increasing cytokine production in this case can significantly help raise the immune response. This site focuses, therefore, on the effect of immunomodulators in helping to increase immune function.

 

A Standard Immunomodulatory Response:

The graph given in Fig-1 depicts the effectiveness of a typical immunomodulator at three different arbitrary dosages on individuals with weak immune systems.

 

Fig 1: Typical Modulator Response with Dosage

 

From this it was concluded that after a period of time on a particular dose, this typical modulator modulates the immune system to a characteristic level that is independent of dosage (provided of course we are dealing with effective dosage ranges). The difference between dosages is that higher doses tend to modulate quicker, and although the difference might only be small, as in this case, it is very significant to those who are seriously unwell and need immune system help as fast as possible.   After a period of time, there is little benefit staying on a high doses, which is why lower “maintenance” dose are usually recommended.

 

Comparing Immunomodulators:

The graph given in Fig-2 gives a comparison between Modulator X and Modulator Y. In this diagram we can see that Modulator X is significantly more effective than Modulator Y.

 

Fig 2: Schematic comparison between two immunomodulators

Even high doses of Modulator Y cannot compete with any dose of Modulator X after the "lsoading period". Modulator X is more effective to immune system to a high level.

 

A few of the agents capable of modulating the immunological network and which have undergone significant clinical development have been reviewed as under:

 

Levamisole: is an anthelminthic and immunomodulator belonging to a class of synthetic imidazothiazole derivatives. It was discovered at Janssen Pharmaceutical in 1966. Levamisole has been used in humans to treat parasitic worm infections, and has been studied in combination with other forms of chemotherapy for colon cancer, melanoma, and head and neck cancer. The drug was withdrawn from the U.S. and Canadian markets in 2000 and 2003 respectively, due to the risk of serious side effects and the availability of more effective replacement medications 20. Levamisole, the levoisomer of the tetramisole 21 acts primarily upon cellular rather than humoral immune responses and restores the immunocompetency of impaired hosts without hyper stimulating the normal. It augments macrophage chemotaxis22, phagocytosis and promotes interaction with other immunoregulatory lymphoid cells 23. The compound also promotes T-cell proliferation, cytolysis, lymphokines production and antibody formation 24. Levamisol may function as a thymic hormone to induce precursor cells to become functionally mature T-lymphocytes. Alternatively, the compound may serve as an anti-oxidant to prevent the formation of free radicals and peroxides which negatively interfere with neutrophils activity or may increase the polymerization of microtubulin in cellular membranes, resulting in an alteration in leukocyte function 25. Finally Levamisol may increase cyclic GMP and decrease cyclic AMP in lymphocytes resulting in immunopotentiation. In the aged mice, Levamisole treatment activates macrophages and restores the delayed type hypersensitivity reaction and antibody response to T-cell-dependent antigens. It prevents the appearance of suppressor cells, in this respect acting antagonistically to cyclosporine, and, like BCG, prolongs the mouse life span. In young healthy mice, Levamisole is inactive. Levamisole has been developed and launched for use in cancer and rheumatoid arthritis in several countries. Clinical efficacy of Levamisol has been evaluated in various types of immunodeficiency, herpes infection, rheumatoid arthritis, LE, Scleroderma and Reiter’s syndrome in addition to cancer 26.

 

Liposaccharide: Also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals. LPS induces a strong response from normal animal immune systems which promotes the secretion of proinflammatory cytokines in many cell types but especially in macrophages27. It comprises three parts: O antigen (or O polysaccharide), Core oligosaccharide and Lipid A. O antigen is exposed on the very outer surface of the bacterial cell, and, as a consequence, is a target for recognition by host antibodies. The Core domain always contains an oligosaccharide component that attaches directly to lipid A and commonly contains sugars such as heptose and 3-deoxy-D-mannooctulosonic Acid (also known as KDO, keto-deoxyoctulosonate) 28. Lipid A is, in normal circumstances, a phosphorylated glucosamine disaccharide decorated with multiple fatty acids. When bacterial cells are lysed by the immune system, fragments of membrane containing lipid A are released into the circulation, causing fever, diarrhea and possible fatal endotoxin shock (also called septic shock).The process of exposing a subject to an LPS that may act as a toxin, produces many types of mediators involved in septic shock. Humans are much more sensitive to lps than other animals. Dose of 1 µg/ kg induces shock in humans, but mice will tolerate a dose up to a thousand times higher 29-31.

 

Cytokines: There are a few reports and an increasing interest in studies of lymphotoxins 32-34. The major interest at the present time is in interferon, which stimulates both NK cells and lymphokine production, but also has a cytostatic activity 35, 36. It is clear that interferon has a certain clinical effect on lymphoma, IgG (but not IgA) myeloma, acute lymphatic leukemia, and chronic lymphatic leukemia 37, 38.

 

Interferon’s (IFNs): Interferones are proteins made and released by lymphocytes in response to the presence of pathogens- such as viruses, bacteria, or parasites or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors. IFNs belong to the large class of glycoproteins known as cytokines. Interferones are named after their ability to "interfere" with viral replication within host cells. IFNs have other functions: they activate immune cells, such as natural killer cells and macrophages; they increase recognition of infection or tumor cells by up-regulating antigen presentation to T lymphocytes; and they increase the ability of uninfected host cells to resist new infection by virus. Certain host symptoms, such as aching muscles and fever, are related to the production of IFNs during infection. About ten distinct IFNs have been identified in mammals; seven of these have been described for humans. They are typically divided among three IFN classes: Type I IFN, Type II IFN, and Type III IFN. IFNs belonging to all IFN classes are very important for fighting viral infections. All Interferones share several common effects; they are antiviral agents and can fight tumors. Interferon type I: All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chains. The type I Interferones present in humans are IFN-α, IFN-β and IFN-ω 39.  Interferon type II: Binds to IFNGR. In humans this is interferon: Signal through a receptor complex consisting of IL10R2 (also called CRF2-4) and IFNLR1 40-42.

 

Tuftsin: Tuftsin is a naturally occurring tetra peptide generated in the serum by two enzymatic cleavages of the parent molecule, a cytophilic immunoglobulin. It augments several functions of macrophages, monocytes and granulocytes including the stimulation of motility of PMNs phagocytosis and bactericidal activity and augments antibody responses as well as tumoricidal activity. The peptide exhibits antitumor activity in animals against a number of tumors 43. It has been proposed that the antitumor effect of tuftsin resides in its ability to stimulate macrophages.

 

BCG:  In young healthy mice, BCG, the best studied of the immunomodulators, can under certain dose and time conditions activate the phosphatase activity and the cytostatic effect of macrophages, potentiate antibody responses and antibody-dependent cell-mediated cytotoxicity and induce nonspecific suppressor cells. BCG also stimulates the secretory activity of thymic epithelium. It may increase the lymphocyte number in the spleen and reduce that in mesenteric lymph nodes 44.

 

Glucan: Glucan, b-1-3 polyglucose from yeast, is a classic macrophage stimulator in animals, but there are few reports in humans.

 

Cyclosporine: Cyclosporine, isolated from a fungus, has antimalarial, antischistostomal, and T-suppressor cell stimulating, or possible T-helper- inhibiting activity 45, 46. It is not cytostatic and no marrow toxicity. The T-suppressor cells seem to arrest B cells in the G0 or G1 phase, so that IgM, IgG, IgE production is inhibited 47-49.

 

Cyclophosphamide:  It is nitrogen mustard alkylating agent 50 from the oxazophorines group. It is used to treat various types of cancer and some autoimmune disorders. It is a "prodrug"; it is converted in the liver to active forms that have chemotherapeutic activity. The main use of cyclophosphamide is together with other chemotherapy agents in the treatment of lymphomas, some forms of leukemia 51 and some solid tumors.  It is a chemotherapy drug that works by slowing or stopping cell growth. A 2004 study showed that the biological actions of cyclophosphamide are dose-dependent 52. At higher doses, it is associated with increased cytotoxicity and immunosuppression, while at low continuous dosage it shows immunostimulatory and antiangiogenic properties 53.

 

Some Immunomodulatory Plants are:

Aloe vera: Aloe vera (Family: Aloeaceae). The true Aloe vera plant is called Aloe barbadensis Miller, otherwise called the Curacao aloe, and is the most medicinally potent of the 300 (and more) varieties found around the world 54. Two new dihydrocoumarin derivatives have been isolated from Aloe vera and their structures had been determined by X-ray crystallographic diffraction analysis and extensive 1D, 2D NMR spectroscopic data 55. Both of them evidently showed antioxidant activity against superoxide and hydroxyl radicals. Only compound exhibited immunomodulatory activity in relation to increasing the phagocytic activity and stimulating the production of superoxide anions in the oxygen respiratory burst of rat peritoneal macrophages 56.

 

Asparagus racemosus: Immunomodulating property of Asparagus racemous (Liliaceae) has been shown to protect the rat and mice against experimental induced abdominal sepsis. Oral administration of decoction of powdered root of A. racemosus has been reported to produce leucocytosis and predominant neutrophilia along with enhanced phagocytic activity of the macrophages and polymorphs 57. Percentage mortality of A. racemosus treated animals was found to be significantly reduced while survival rate was comparable to that of the group treated with a combination of metronidazole and gentamicin. Since A. racemosus is reported to be devoid of antibacterial action, so protection offered by it against sepsis by altering function of macrophages, indicates its possible immuno-modulatory property 58. Alcoholic extract has been found to enhance both, humoral and cell mediated immunity of albino mice injected with sheep red blood cells as particulate antigen 59.

 

Curcuma Longa: Turmeric is the dried rhizome powder of Curcuma longa, a perennial herb of the Zingiberaceae family. The major chemical principles of turmeric are curcuminoids, which impart characteristic yellow color to it. The curcuminoids can be separated from turmeric by ethanol extraction and it usually contains 0.3–5.4% curcumin (one of the major curcuminoids) depending on the season of its harvest. Vogel and Pellatier first reported molecular formula of curcumin and which was later identified as diferuloylmethane. The IUPAC name of curcumin is (1, 7- bis (4-hydroxy-3-methoxy-phenyl) hepta-1, 6-diene-3, 5-dione). Curcumin has been found to modulate the growth and cellular response of various cell types of the immune system. Numerous lines of evidence suggest that curcumin can modulate both the proliferation and the activation of T cells. Curcumin inhibited the proliferation induced by concanavalin A (Con A), phytohemagglutinin (PHA), and phorbol-12- myristate-13-acetate (PMA) of lymphocytes derived from fresh human spleen. In another study curcumin inhibits the proliferation induced by PMA and anti-CD28 antibody or that induced by PHA of T lymphocytes isolated from healthy donors. Also reported that curcumin can suppress the PHA-induced proliferation of human peripheral blood mononuclear cells (PBMCs) and inhibit IL-2 expression and NF-κB 60.

 

Desmodium gangeticum: Desmodium gangeticum (Leguminosae) is a small perennial shrub growing throughout India and commonly known as salparni. The active principal from Desmodium gangeticum glucosyl glycerolipid (pentadecanoicacid-3-(6- minomethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yloxy)-2-pentadecanoyl-oxy propyl- ester) and glycosphingolipid  cerebroside) exhibited in vitro antileishmanial and immunomodulatory activities, as it enhanced nitric oxide (NO) production and provided resistance against infection established in peritoneal macrophages by the protozoan parasite Leishmania donovani 61.

Withania Sominifera (L): Withania somnifera, commonly known as Indian ginseng, has been an important herb in the Ayurvedic and indigenous medical systems for over 3000 years. It is a small, woody shrub in the Solanaceae family. Withania somnifera has been revealed as an immunostimulator in immunosuppressed animal models and also an immunoregulator in immune inflammation animal models. Administration of Withania somnifera extract was found to significantly reduce leucopenia induced by cyclophosphamide (CP) treatment, indicating Withania somnifera could reduce the CP-induced toxicity and its usefulness in cancer therapy. Methanolic extract of Withania somnifera exhibited radioprotective effect in normal BALB/c mice with increased bone marrow cellularity and reduction in chromosomal damage caused by sub lethal dose of gamma radiation 62. Enhanced levels of interferon (IFN)-gamma, IL-2, and granulocyte macrophage colony-stimulating factor (GM-CSF) in normal BALB/c mice were observed on administration of extract from roots of Withania somnifera. Withanolide glycosides activated murine macrophages, phagocytosis, and increased lysosomal enzymatic activity secreted by the macrophages, while also displaying anti-stress activity and positive effects on learning and memory in rats .The stimulation of macrophages was invoked to explain activity versus experimental aspergillosis in mice 63. The use of W. somnifera as a general tonic to increase energy and prevent disease may be partially related to its effect on the immune system. Glycowithanolides and a mixture of sitoindosides IX and X isolated from WS were evaluated for their immunomodulatory and central nervous system effects (anti stress, memory, and learning) in Swiss mice (15-25 g, 5-6 months old) and Wistar strain albino rats (120-150 g and 250- 300 g) 64.

 

Ocimum gratissimum L. (Labiatae): The ethanolic extract of O. gratissimum leaves has been reported 65 to improve the phagocytic function without affecting the humoral or cell mediated immune responses. Ocimum sanctum L. (Labiatae) 66, 67 have reported the immunostimulant properties of methanol extract and aqueous suspension of O. sanctum. Both methanol extract and an aqueous suspension of O. sanctum leaves have been found to enhance the humoral responses to SRBC and typhoid ‘H’ antigens and to increase the count of E resetting lymphocytes 68, 69.

 

Panax ginseng C. A. Meyer (Araliaceae): Panax ginseng classed as adaptogenic or antistress drug 70, has on oral administration , in combination with 6-MFA (an interferon inducing anti-viral substance of viral origin) been found to significantly enhance the protective effect against Semliki Forest Virus (SFV) as compared to 6- MFA alone 71. Ginseng extract has been shown to augment natural killer (NK) cells and antibody dependent cytotoxic (ADCC) activities 72. It has been shown to enhance antibody titre against SRBC, cell mediated immunity against SFV antigen and NK cell activity in mice. It has also been seen to enhance production of interferon by an interferon inducer MFA 73.

Tinospora cordifolia Miers (Menispermeaceae): The ethanolic extract of T. cordifolia has been reported to enhance the cell mediated immunity and non-specific resistance in mice. T. cordifolia aqueous extract has been found to improve the experimentally induced sepsis in animals and immune function associated with early wound healing in patients perforated peritonitis and localsepsis have reported T. cordifolia to protect rats against coecal ligation induced abdominal sepsis and mice against E. coli peritonitis. The aqueous extract of the plant has also been shown to reduce the mortality due to S. aureus sepsis in neutropenic and hemisplenectomized mice, C. albicans sepsis induced mortality and reverse the myelosuppression induced by a single or multiple doses of cyclophosphamide. The plant induced leukocytes with predominant neutrophillia associated with stimulation of phagocytic and bacterial capacity of neutrophils and macrophages have been reported the restorative effect of aqueous extract of T. cordifolia. In rats administration of aqueous extract for 7 days following cholestasis, has been reported to improve the phagocytic function of peritoneal macrophages and blood PMNL. Clinically similar improvement has been observed in patients suffering from obstructive jaundice 74.

 

CONCLUSION:

Since the progress in  the clinical immunology has unraveled the involvement of immune system in  the pathogenesis of several disease conditions like in arthritis, cancer, chronic and recurrent viral and bacterial infections due to the altered functioning of the immune system. Therefore, this has lead to enormous search for development of the agent which could act on the immune system for the treatment of the disease of an individual. No doubt there are certain agents which are capable of modifying the relation between disease and host’s response to disease, are termed as Biological Response Modifiers (BRM’s).

 

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Received on 11.11.2011          Modified on 25.11.2011

Accepted on 01.12.2011         © RJPT All right reserved

Research J. Pharm. and Tech. 5(2): Feb. 2012; Page 169-174