INTRODUCTION:

The use of medicinal plants as a treatment policy for various disease caused by bacteria, fungi, viruses etc. have been in human history since long term. Since the time immemorial natural products have been a backbone of traditional system of healing throughout the globe. The chemicals present in these plants are responsible for their effects that work in the same manner as other drugs. Apart from the positive effects these plants have harmful and undesirable toxic effects which can be reduced by processing plants crude product by the process of maceration, infusion, percolation and decoction. These plants are currently in considerable significance view due to their special attributes as a large source of therapeutic phytochemicals that may lead to the formation of new drugs. Ethnobotany is the study of traditional knowledge of plants including classification, cultivation and medicinal properties in order to discover future medicines^[1,2,3,4].

More than 300 plants yielding about 122 chemicals have been found to have medicinal effects and are used commercially. For e.g. the coca plant is very rich in cocaine and is commercially used as local anaesthetic. Also the purple foxglove (Digitalis purpurea) is rich in digitoxin and is used for cardiotonic action. Nature is the master of craftsmen of molecule and created almost an inexhaustible of molecular entities. Some common drugs which are derived from the plant sources are caffeine, aspirin, digitalis, morphine, codeine etc. The use of these medicinal plants as modulator for complex immune system is growing very rapidly. Through a numerous researches conducted in an area it has been claimed that many phytochemicals such as alkaloids, lactones, polysaccharides and glycosides products are responsible to modify the immune response or functioning of the immune system and act as immunomodulator. In other words, these chemicals are liable to cause modification in the immunomodulatory properties. There is much growing interest to use herbal medicine as a multicomponent agent to modulate the complex immune system in the prevention of infection rather than treating and curing the disease. Taking this into account, this review will give an overview of widely investigated plant derivative component and their potent effects as immunomodulators^[2,5,6,7].

IMMUNITY:

Immunity is defined as the balanced state of multicellular organisms having sufficient biological defences to fight infection, disease etc. while having adequate tolerance to avoid allergy and other disease. Specifically it is body’s defence system against any disease or disorders. Extraordinarily advanced among vertebrates, this complex immune system is made up of specialized cells, tissues and organs to destroy span of infection and other invaders. Immunomodulators are the class of drugs or medication used to help, regulate or normalize the immune system. It modifies the immune response or the functioning of the immune system. Immunomodulation is a part of immunotherapy, in which immune responses are induced, amplified or prevented according to therapeutic goals. Moreover Immunostimulators and immunosupressor are two types of immunomodulators in practice. Immunostimulators are the substances that stimulate the immune system by activation of any of its components. The use of immunostimulators in treatment of various immune deficiency conditions, chronic infection or cancer in order to activate innate immunity and promote release of endogenous immune mediators (eg. Cytokines) Immunosupressor are the drugs that partially or completely supress the immune system of vertebrates and are used to treat autoimmune disease. Immunology is the study of immune system and is one of the most rapidly developing fields of medical and biological science^[1,7,8]. The immunomodulatory characteristics of plant based therapeutics have gathered attention of researchers. Every aspect of immunity and host defence is dependentupon proper supply and balance of nutrients. The primary forms of host defence are termed as innate or non-specific immunity. They may be active or passive in nature. The secondform of host is termed as adaptive and this is delivered by immune system itself. When immune system is weakened by the virus HIV, it is mostly a group of T-cells reduced in number. Then the body is usually prone to infections .Due to the lack of T-cells the immune system has difficulties in coordinating the fight against pathogens. Cells called B-lymphocytes help the T-cells doing their work. They produce specific antibodies to fight off bacteria, virus, fungi and other substances. These cells originate and mature in bone marrow where they become specialized defence cells. Besides defence cells cytokines contribute to in the elimination of the pathogens. These cytokines are released by many cells of the immune system. These communicate with one another and thus ensure that the infected cells are recognised and eliminated^[9,10,11].

To transform this lead molecule with least toxicity and maximum selectivity and potency with respect to its target, its further design and development through chemical modification to make it therapeutically fit is nowadays gaining much interest. There are a number of medicines derived from plants such as vinblastine, vincristine, Madagascar periwinkle, capsaicin

CLASSIFICATION OF IMMUNOMODULATORS:

Immunomodulators can be classified into the following three categories:

Immunoadjuvants:

These are the substances used to enhance the efficacy of vaccines and therefore could be considered specific immune stimulants. Immunoadjuvants hold the promise of being the true modulators of the immune response ^{[1,6,12,13,14]}.

Immunostimulants:

Immunostimulants are inherently non-specific as they are envisaged as enhancements to a body’s resistance to infection. They can act through innate as well as adaptive immune responses. In healthy individuals, the immunostimulants are expected to serve as prophylactic and promoter agents, i.e., as immunopotentiators, by enhancing the basic level of immune response. In the individual with impairment of immune response, they are expected to act as immunotherapeutic agents.

Figure 1: Classification of immunomodulators

Immunosuppressants:

Immunosuppressants are a structurally and functionally heterogeneous group of drugs, which are often concomitantly administered in combination regimens to treat various types of organ transplant rejection and autoimmune diseases.

SIDE EFFECTS OF ALLOPATHIC IMMUNOMODULATOR DRUGS:

There are various side effects associated with the use of allopathic drugs as immunomodulator i.e. Pulmonary toxicity, Myelosuppression, Alopecia, Increased risk of infection, Hepatic fibrosis, Lymphoma (Epstein–Barr virus associated), Nephrotoxicity, neurotoxicity (tremor, headache, motor disturbances and seizures), GI complaints, hypertension, hyperkalemia, hyperglycemia, and diabetes, Renal dysfunction, tremor, hirsutism, hypertension, hyperlipidemia, gum hyperplasia, hyperuricemia, hyper cholesterolemia, nephrotoxicity, hypertension, diabetogenic, Elevated LDL cholesterol etc^[15-18].

IMMUNOMODULATION BY MEDICINAL PLANTS:

Immunomodulatory therapy could provide an alternative to conventional chemotherapy for a variety of diseased conditions, especially when host’s defence mechanisms have to be activated under the conditions of impaired immune responsiveness or when a selective immunosuppression has to be induced in a situation, like inflammatory diseases, auto-immune disorders ad organ/bone marrow transplantation.A number of medicinal plants and various ‘Rasayana’ have been claimed to possess immunomodulatory activity. Some of these plants are Withania somnifera, Tinospora cordifolia, and Mangifera indica. A lot more are still to be explored and offer scope for further investigation^{[1,3,4,7,8,11,12,16,18]}.

Table 1: A brief description of common plant-derived immunomodulators

Botanical (Family)	Ayurvedic/Common name	Part used	Chemical constituents
Aloe vera Tourn.ex Linn. (Liliaceae)	Kumaari	Gel from leaves	Anthraquinone glycosides
Eclipta alba L. (Compositae)	Bringraja	Leaves	Triterpenoid glucoside
Ocimum sanctum Linn. (Labiateae)	Tulasi	Entire plant	Essential oils such as eugenol, cavacrol, derivatives of ursolic acid, apigenin
Evolvulus alsinoides Linn. (Convolvulaceae)	Shankhpushpi	Herb	Alkaloids
Andrographis paniculata Nees (Acanthaceae)	Kaalmegha	Leaves	Diterpenes
Asparagus racemosus Wild. (Liliaceae)	Shatavaari	Roots	Saponins, sitosterols
Picrorhiza scrophulariiflora Benth. (Scrophulariaceae)	Kutki	Roots	Iridoid glycosides, amphicoside
Abutilon indicum linn. (Malvaceae)	Atibalaa	Whole plant	Flavonoids, triterpenoids
Nyctanthes arbor-tristis L. (Oleaceae)	Paarijaata	Leaf, seeds	Iridoid glucosides
Genus Ardisia (Myrsinaceae)	Marlberry	Shrub, Branches and leaves	Peptides, saponins, Isocoumarins, quinones and alkyl phenols
Camellia sinensis L. (Theaceae)	Tea	Leaves	(-)Epigallocatechin gallate, quercetin, gallicacid
Echinacea angustifolia (Asteraceae)	Cone flower	Flowers	Polysaccharide

CYTOKINE MODULATION CAUSED BY HERBAL PLANTS:

Cytokines are soluble proteins secreted by different cells of our body in response to various stimuli. Their main role is in activation and strengthening of immune system. Presently, about 200 cytokines have been identified broadly in following categories:

1. Interferons (IFN)

2. Interleukins (IL)

3. Tumour necrosis factor group (TNF, cachectin)

4. Transforming growth factor (TGF)

5. Colony stimulating factor (CSF)

6. Growth factors (e.g. platelet-derived growth factor PDGF, epidermal growth factor EGF, fibroblast growth factor FGF, endothelial-derived growth factor EDGF, transforming growth factor TGF).

A lot of studies in vitro and in vivo shown that herbal Medicine can influence cytokines activity in different ways. Tumor necrosis factor- (TNF-) α and chemokine (C-C motif) ligand 2 (CCL2) are key inflammatory mediators in diseases like rheumatoid arthritis and atherosclerosis, respectively. Some studies on herbal plants found in Brazil shows that The extracts of Caryocar brasiliense, Casearia sylvestris, Coccoloba cereifera, and Terminalia glabrescens inhibited TNF-α production in a concentration-dependent manner^[11,17,19]. Inhibitory activities of the methanol extracts from 20 different medicinal plants on the release of pro-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs) were evaluated. paniculata (Hydrangea paniculata, the panicled hydrangea, is a species of flowering plant in the family Hydrangeaceae native to southern and eastern China, Korea, Japan and Russia) extract and its major compound andrographolide strongly inhibited the release of IL-1α.

In vitro studies were done to evaluate the role of extracts of Hypericum triquetrifolium (an herbaceous perennial plant and one of the Iranian native) and Peganum harmale (a eastern Iranian native Plant) effect in the role of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) in the observed anti-inflammatory effect, usefulness in different neurological conditions, analgesic effect. But due to its severe side effect such as Abortion, numbness, vomiting etc its dose related usefulness is still under studies.

Astragalus membranaceus (a native herbal plant found in china) used in various diseases and for boosting Immune system. The root extract of the plant was found to lower IL-6. IL-6 is an interleukin that acts both as a pro-inflammatory cytokine and an anti-inflammatory myokine.

Garlic or Allium sativum has great potential as antimicrobial potential, anti-inflammatory due to an inhibitory effect on IL-1, IL-6, TNF, IL-8 and boosting effect on IL-10. IL-1, IL-6, TNF, IL-8 and IL-10 act as an anti-inflammatory, hypocholesterolemic, antioxidant, and also angiotensin-converting enzyme inhibitor ^{[18,20,21,22,23]}.

EFFECT OF MEDICINAL PLANTS ON IMMUNE COMPONENTS:

It has been seen from various researches that herbal medicines have an immense modulatory effect on various components of the immune system. Studies on various immunomodulatory activities of herbal plants suggeststhat, the secondary plant metabolites can play a leading role in the development of immunomodulators in the future for therapeutic use. A number of experiments performed on animal models recommends that there is a variety of plant immunomodulators which can be indicated in various allergic allergic diseases including asthma, esophagitis, allergic rhinitis, and eosinophilic ^{[3,6,9,14,
24,25]}.

EFFECT ON INNATE IMMUNE SYSTEM:

IL-4/IL-13 receptors are the most promising targets for immunomodulatory therapy in allergic reactions. therefore assessment of herbal plant activity should be emphasized on immunoglobulin E (Ig E) (main effectors molecule in allergic response), for targeting the aforesaid receptors as well as for hiking in the ratio of TH1/TH2 balance. Human trials on various such phenotypes enlights (though not upto the mark) the way of careful understanding of their mechanism, which aims at blocking critical TH2 cytokines activity to inhibit decrease excessive TH2 cells. IL-10 is a cytokine which shows potent anti-inflammatory properties, by activating macrophages that represses the expression of inflammatory cytokines such as IL-6 and IL-1 and TNF-α.

Some studies showed that on use of Ganoderma lucidum, Glycyrrhiza uralensis, and S. Flavescens, decreases eosinophil infiltration of lungs and airway hyperresponsiveness pertaining to level of IgE and associated cytokines IL-5, IL-4, and IL-13. Components of the innate immune system involved in immunomodulation are types of cells that includes T-cells , macrophages, natural killer (NK) cells, NKT-cells, granulocytes (neutrophils, eosinophils, and basophils), and dendritic cells while B-cells naïve CD4+ T-cells, differentiated CD4+ T-cells including helper T-cells, induced regulatory T-cells, and natural regulatory T-cells^[7,18,19].

EFFECT ON ACQUIRED IMMUNE SYSTEM:

Many herbal products have been found to posses immunomodulatory effects on acquired immune system as well. Chlorophytum borivilianum root extract improves humoral as well as cell-mediated immunity. It helps to improve defensive response as well as provide nonspecific immunological response against infections. Both aqueous and alcoholic extract of glycerrhiza glabra can stimulate humoral response response by acting various level of immune mechanism such as release of mediators of hypersensitivity reactions, antibody production etc.

PRESENT SENARIO OF IMMUNOMODULATOR RESEARCH:

From historical times, through all ages, plants-based medicines have been frequently used in the treatment and prevention of diseases. In fact, researchers are attracted toward plants-based therapeutics. The current research is based on the search for some plant biochemicals in the form of the single compound which is like lead molecule concerned with particular target linked with disease. To transform this lead molecule with least toxicity and maximum selectivity and potency with respect to its target, its further design and development through chemical modification to make it therapeutically fit is nowadays gaining much interest. There are a number of medicines derived from plants such as vinblastine, vincristine, Madagascar periwinkle, capsaicin from chili pepper, and paclitaxel from Pacific yew while few chemically altered lead molecules derived from plants are dicoumarol (warfarin), artemisinin (artemether), camptothecin (irinotecan and topotecan), morphine, and salicylic acid (acetylsalicylic acid). Plant-derived chemicals in the form of terpenoids, steroids, phenolics, flavonoids, etc., are all manifesting worth mentioning immunomodulatory activities. In India, more than 70% of the total population is dependent on non-allopathic system of medicine, namely, Ayurvedic, Yoga, Unani, Siddha, Homeopathy, and Naturopathy which also maximally use herbal drugs as a tool to treatment. Hence, these systems of medicines are not mere folklore or traditional herbal practices, but there is some basis established to logically prescribe the herbal drugs.

The term “Reverse Pharmacology” for the first time being proposed by Vaidya to understand the mechanisms of action of herbal drugs at multiple levels and to optimize safety, efficacy, and acceptability of the leads from natural products, basedon relevant science. With expanding knowledge of herbal therapeutics, newer pharmacophores may evolve for new targets with an involvement of unique innovative techniques. The contribution of combinatorial chemistry in search for a novel pharmacophore using varied chemical modifications and optimizations of the herbal lead molecule is appreciating. Curcumin or Haldi in Indian parlance has been chemically modified and optimized to have drug candidate with efficient efficacy and therapeutic action using combinatorial chemistry approach. Various drug research concerns in India are working in the direction to detect the novel activities of plant-derived products^{[6,9,16,17,19,21]}. A number of herbal-based projects looking for formulation for diabetes, arthritis, malaria, cancer, etc., are running at global level under the Council for Scientific and Industrial Research. Industries are working on medicinal plants in collaboration with academia and government bodies in the direction. However, despite a huge amount of work done, so far, no systemic review or database is available in our country. Even there is no proper mention of our work which is published in Indian journals and in international databases. This study suggests for revision of the work done in varied fields such as ethnobotany, phytochemistry, pharmacology, and pharmacognosy at the global level.

Some future suggestions and developments are desirable and worthy of consideration:

· Improvement of the study design of clinical studies to establish herbal drug safely for therapeutic use.

· International cooperation and pooling of research data from different parts of the world.

· Reinforcement of target-based approach using newer innovative techniques to identify the lead molecule.

· More and more research should be focused on existing herbal products to remove therapeutic dilemma.

CONCLUSION:

Some medicinal plants may stimulate the immune system, (e.g., Panax ginseng, Ocimum sanctum, Tinospora cordifolia, and Terminalia arjuna), and some may suppress the immune response (Alternanthera tenella). Many of the chemicals in the form of alkaloids, flavonoids, terpenoids, polysaccharides, lactones, and glycoside products are responsible to cause alterations in the immunomodulatory properties.

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Received on 14.05.2020 Revised on 12.06.2020

Asian J. Pharm. Tech. 2020; 10(4):273-277.

DOI: 10.5958/2231-5713.2020.00045.8