Ethnopharmacological review of traditional medicinal plants as immunomodulator

Medicinal plants play significant roles in the prevention of human beings from various pathogenic microorganisms and diseases. The immunomodulators are agents used to modulate the immune system and can be obtained from both natural as well as synthetic origin from plants and chemicals. Alteration within the system is often achieved by immunomodulatory agents from a plant source, low molecular weight compounds like alkaloids and other nitrogen-containing compounds, terpenes, phenols, and high molecular weight compounds like lectins, polysaccharides. The Immune system is a part of the body to detect the pathogen by using a specific receptor to produce an immediate response by the activation of immune components cells, cytokines, and chemokines and also release of an inflammatory mediator. This review also discusses various ethnopharmacological information of traditional medicinal plants being used as immunomodulators.


Introduction
Today, worldwide a novel coronavirus disease (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has emerged as havoc to humanity.The disease has unfolded globally and caused more than three lakh casualties.Worldwide many efforts and measures have been taken by the countries to control this pandemic but it is ceaselessly spreading.Now the dimension of pandemic forces us to explore the available options present in all knowledge systems practicing globally [1,2].A ray of hope has come from China wherever they used Traditional Chinese Medicine (TCM) to treat COVID-19 cases and to seek out better recovery results.This can also draw the attention of the scientific community to Ayurveda classics and their experimental knowledge to get explored for finding a cure for this pandemic [3].
Nowadays, the use of plants or parts thereof is being used worldwide, and in the COVID-19 situation, WHO recommending to use of herbal medicines for treatment or prophylactic use in the prevention of diseases or disorders.There are thousands of plants that are being used throughout the world as medicinal plants [4][5][6][7][8][9][10].According to the World Health Organization, around 80% of the world population uses herbal medicines for primary health care, particularly across South Asia and Europe.Research studies indicate that along with building up the body's immunity, they also have anti-inflammatory properties and relatively have fewer side effects [11][12].
The System is one of the foremost complex biological systems within the body.At the time of infection, the immune system goes under the attack of a large number of viruses, bacteria, and fungi.Modulation of immune functions by utilizing medicinal plants and their products as a possible therapeutic measure has become an accepted therapeutic approach.Plants and minerals have been used since ancient times for the treatment of many infirmities and diseases.It is now being that immunomodulation of immune response could provide an alternative to conventional chemotherapy for a variety of disease conditions, especially when the host's defense mechanism has to be activated under conditions of impaired immune responsiveness or when a Particular immunosuppressant has to be induced in a situation such as autoimmune disorders or organ transplantation.Immunity is a homeostatic process a series of finely balanced complex, multicellular and physiologic mechanisms that allow an individual to distinguish foreign material from "self" and neutralize and/or eliminate the foreign matter [13][14].

Immune system
The immune system is multi-layered, with defenses on numerous levels.The most primary is the skin, which is the first barrier to infection.Another one is a physiological condition such as pH and temperature provide living conditions for foreign organisms.Once pathogens enter the body, they deal with the innate immune and acquired or adaptive immune system.Both systems are composed of a mess of cells and molecules that interact in a complex manner to detect and eliminate pathogens.Both detection and elimination of pathogen depend upon chemical bonding: surfaces of immune system cells are engulfed with various receptors, some of them chemically bound with pathogens and some of which bind to other immune system cells or molecules to delegate the complex system of signaling that mediates the immune response [15][16][17] (See Fig. 1).

Innate immune system
The term "innate" refers to that part of the system, with which we are born; that means, it doesn't change or adapt to specific pathogens like an adaptive system.The innate system gives a rapid first line of defense, to keep the early infection in check, giving the adaptive immune system time to build up a more specific response [18].Innate immunity comprises primarily of a chemical response system called complement, and the endocytic and phagocytic systems, which involve roaming "scavenger" cells, such as macrophages, that detect and immerse extracellular molecules and materials, clearing the system of both debris and pathogens [19].

Adaptive immune system
The adaptive immune system adapts or "learns" to concede specific kinds of pathogens, and retains a "memory" of them for speeding up future responses.The learning occurs during a primary response to a kind of pathogen not encountered before by the system.The primary response is slow, often first only becoming apparent several days after the initial infection, and taking over three weeks to clear an infection.After the primary response clears an infection, the immune system keeps a memory of the kind of pathogen that caused the infection.Should the body be infected again by the equivalent kind of pathogen, the system doesn't need to re-learn to acknowledge the pathogens, because it remembers their specific appearance, and will mount a way more rapid and efficient secondary response [20].
The secondary response is often quick enough so that there are no clinical indications of a re-infection.Immune memory can confer protection up to the lifetime of the organism (measles is a good example in this regard).The adaptive immune system primarily consists of certain types of white blood cells, called lymphocytes, which circulate the body via the blood and lymph systems [21].

Classification of immunomodulators
The immune system may be a complex system that involves an interwoven network of biochemical mechanisms.The modulation of immune response by various agents to diminish the disease has been of interest for many years, to modulate and potentiate the weapons of your immune system keeping them in a highly prepared state for any threat it may confront with this balancing effect, all subsequent immune responses improve [22].When your immune system is in this highly prepared state, the invading organisms do not have the time to build up force and strength before the immune system attack demolishes and/or weakens the invader.Immunomodulation is the process of improving immune response in a positive or negative approach by the administration of a drug or compound.Many proteins, amino acids, and natural compounds have shown a huge potential to manage immune responses including interferon-γ (IFN-γ) and steroids.These substances, which can stimulate, suppress, or modify any of the immune systems, including both adaptive and innate arms of the immune response.Clinically, immunomodulators can be classified into the following three categories (See Fig. 2) [23][24].These agents are used to increase the efficacy of vaccines and, therefore, could be considered specific immunostimulants.Immunoadjuvants act as true modulators of the immune response [25].

Immunostimulants
Immunostimulants are inherently non-specific as they are envisaged as enhancements to a body's resistance to infection.They can act through innate and adaptive immune responses.In healthy individuals, Immunostimulants are expected to serve as prophylactic and promoter agents by boosting the basic level of an immune response.In the individual with impairment of immune response, they are expected to act as immunotherapeutic agents [26].

Immunosuppressants
These 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 [27].

Methods for testing immunological factors
The routine method for screening is to extract one ingredient and single distilled fraction from flavoring medicine and verify its bioactivity by the classic medical specialty means that.the total animal model is that the foremost classic medical specialty screening model, which is extraordinarily vital within the facet of drug analysis as a result of it will answer to the efficaciousness, facet impact, and toxicity of medicines as a full.Though this methodology is high value and low potency, it's still a primary due to drug discovery and analysis [28].
Many in-vitro and in-vivo strategies of medical specialty screening of healthful plants having immunomodulatory activity are listed below:

In-Vitro Methods
(i)Inhibition of histamine release from mast cells, (ii) Mitogen induced lymphocyte proliferation, (iii) Inhibition of T cell proliferation, (iv) Chemiluminescence in macrophages PFC (plaque-forming colony) test in vitro, (v) Inhibition of dihydro-orotate dehydrogenase.

Pharmacology of immunomodulatory plants
There is associate excessive would like for understanding plant-based drug medical specialty profile, administration, and dosage, since high doses tend to be immunological disorder and low doses of constant, tend to become immunostimulatory.Finally, it ought to be noted that the bulk of in vitro or in vivo models are not adequate or not straightforward enough to form certain that the same is commonly used as a drug.Several phytoconstituents from plants like polysaccharides are taken into consideration to be biological response modifiers and are reportable to bolster varied immune responses, like complement activation, a proliferation of lymphocytes, and stimulation of macrophages [29].
The immunopharmacological activities of phenolic are complicated and are still not fully understood.In-Vitro study does not forever settle for as true with observations in vivo study.Moreover, the consequences of various flavonoids could also be antagonistic; in some cases, they're an immunological disorder, and in others, an immunostimulatory.Varied flavonoids a square measure seen to influence the performance of protein systems that a square measure critically concerned at intervals the immunologic response, and at intervals the generation of inflammatory processes, particularly within the transduction of cellular activation signals [30].The Asteraceae family is the largest flowering plant having immunomodulatory activity.This family consists of about 900 genera and some 13,000 species [31].Different plants having immunomodulatory activity are listed in Table 1.Ocimum sanctum Lamiaceae Leaf

Boerhaavia diffussa
Boerhaavia diffusa, (Punarnava; Family Nyctaginaceae), could also be a crawl weed found profusely each ever India.In Indian ancient medication, roots of this weed are used for the treatment of indigestion, jaundice, enlargement of spleen, abdominal pain, and associate degree as an anti-stress agent.Extraction of Boerhaavia diffusa in methane series, chloroform & grain alcohol solvents, they isolated two different compounds, i.e.Bd-I (eupalitin-3-O-h-Dgalactopyranoside) and Bd-II (eupalitin) by Flash action.The methane series extract stifled considerably PHAstimulated proliferation of human peripheral blood mononucleate cells at the concentration of ten µg/ml, whereas chloroform and grain alcohol extract offer this activity at the concentration of fifty µg/ml.The suppression by Bd-I and Bd-II is dose-dependent and ranged from 63 to 98 you have to attempt a five hundred µg / milliliter to 7-14 attempt five µg /ml.On the opposite hand, the impact of chloroform extract on NK cell is eighty-four, the ethanolic extract is forty-eighth however, the Bd-I & Bd-II is incredibly low [32].

Curcuma longa
Curcumin could be a main active constituent of Curcuma longa Linn belonging to the family Zingiberaceae.Asian nations are the largest country that produces turmeric (about ninetieth of the whole output of the world).Liliopsid genus is also a genus of concerning seventy species of stalk herbs distributed in South East Asia particularly China, Thailand, and Asian nation.Curcumin is employed for the treatment of medicine, antiarthritic, common colds & coughs, jaundice [33].
The inhibition of IL-2 induced proliferation of cells was dose-dependent; since the increasing suppressive effect was observed at increasing concentration of curcumin from 6.25 to 25 mol/L.IL-2 induced proliferation of spleen cells was completely inhibited by curcumin at 25 mol/L (See Table 2).

Rhododendron spiciferum
The plant Rhododendron spiciferum belonging to the Ericaceae.They will be widely used as a medicinal plant due to their active constituent's proanthocyanidin A-1 (PAA-1) is very used for health.Proanthocyanidin A-1 (PPA-1) is used attributable to the unconventional scavengers, anti-bacterial agents, and effective protein inhibitors.They conjointly exhibit the activity of vasodilators, anti-allergic, medicinal drug, cardio-protective, immune-stimulating, antiviral, and sex hormone activities [34][35].

Caesalpinia bonducella
Caesalpinia bonducella belonging to the Caesalpiniaceae.It's commonly referred to as Nata Karanja.It's anindigenous plant of India but also found to be Myanmar, Sri Lanka.The Caesalpinia prickly shrub, globular-shaped seeds with a smooth shining surface.The Seeds of those plants contain thick, brittle shells with a yellowish-white bitter fatty kernel.Caesalpini bonducella has employedthe shows following therapeutic activity like antipyretic, antidiuretic, anthelmintic and antibacterial, anti-anaphylactic and antidiarrheal, antiviral, antiasthmatic, antiamoebic, and anti-estrogenic.
Within the treatment of liver disorder and tumor, bonduc has been traditionally used.Extraction of Caesalpinia bonducella by the recent extraction process using ethanol as a solvent.This extract is employed for the activity of immunomodulatory within the mouse.The oral administration of Caesalpinia bonducella (ethanolic extract) withinthe mouse the effect of this is often given below (see Table 3) [36].

Tinospora cordifolia
Tinospora cordifolia belonging to the family of Menispermaceae.This is often a perennial climber distributed throughout the tropical Indian subcontinent.It's categorized as in Ayurveda and documented for its adaptogenic and immunomodulatory activity in fighting infection.The activity of this drug appears to flow from to alkaloid.The drug shows immunomodulatory activity.It's shown to be effective against various sorts of experimental induce infection [37].
In Tinospora cordifolia extract is referred to as a-d-glucan RR1.The recent extraction process employed for the extraction.In the extraction process the methanol, trichloracetic acid is employed as a solvent .thecompound RRA-1 is isolated from this extract by the tactic of chromatography & lyophilization process [38].
They have according to that the result of Tinospora cordifolia extracts on leucocyte activation.The dose of the extract is one hundred µg/ml can offer the result of leucocyte activation i.e. the activation of β-cells is thirty-ninth, T-cells one hundred and fifth, and NK cells is 331% severally.Throughout this result the result of the extract on the NK cells is high; this might be vital|a crucial|a vital|a very important feature as a result of the NK cells square measure important effectors of innate immune system [39].

Capparis zeylanica
Capparis zeylanica, family Cappridaceae is typically mentioned as Indian caper, perhaps an ascent bush found throughout Republic of India and has been used as a 'Rasayana' drug at intervals the standard in Northern India; the leaves square measure wide used as counter-irritant, medicine and as a plaster, in swellings, boils, and piles.The varied Fig. 6 Capparis zeylanica species of Capparis square measure helpful at intervals the treatment of cough, asthma, inflammation, fevers, and infectious disease and additionally helpful as poultice in urarthritis [40].
The result of immunomodulatory activity of ethanolic and water extracts of Capparis zeylanica leaves.This extract was used to the determination of cellular and body substance reaction victimization white blood corpuscle adhesion take a look at, somatic cell activity in sheep RBCs.The solvent used for the extraction fossil fuel ether, ethanol, and so the processes square measure hot extraction (Soxhlet).A big (P < zero.05)increase within the in vitro white blood corpuscle adhesion to nylon fibers by water extract (at a dose of three hundred mg/kg, oral).However, ethanolic extract (150-300 mg/kg) doesn't show any important increase in white blood corpuscle adhesion [41].

Nelumbo nucifera
Nelumbo nucifera is a plant belonging to the family of Nymphaeaceae.This plant could also be a well-known aquatic healthful plant that has been used as a typical medication in The Republic of India.The stalk extract of the sacred lotus, be employed for the activity of symptom, antidiarrheal, antimicrobial, diuretic, antipyretic, pharmacological medicine, medication.The seed of this plant is in addition, used for resultant activity as well as an anti-ischemic, inhibitor, hepatoprotective, antiproliferative, medication.The plant contains betulinic acid and hormone pentacyclic triterpenoid.Every extract of this plant is utilized for immunomodulatory activity [42].
The immunomodulatory effect of the plant extracts Nelumbonucifera, in Swiss albino mice.The extract (NNSE and NNRE) of rhizome and seeds was extracted with 70% ethanol by cold maceration process.It has been reported the activity is dose-dependent, i.e. the improvement of NBT (Nitro blue tetrazolium reduction test) a reduction was determined additional considerably at higher doses of each the extracts, three hundred mg/kg NNSE, P < 0.001; NNREP < 0.01) and then that of their lower dose 100 mg/kg when compared to control 100 mg/kg (P < 0.01), 300 mg/kg (P < 0.001) [43].
During their study, they were determined that adherence of neutrophils to the nylon fiber was augmented in each NNRE and NNSE treated teams as compared to the management and ended that hydroalcoholic extracts of a rootstock and seeds of a lotus showed stimulation of weapons system by modulating the medicine parameters and shows potential therapeutic edges of the plant components on immunomodulation [44].

Allium sativum
Allium sativum a crucial medicinal plant having immunomodulatory effects.Three proteins showing immunomodulatory were discrete from garlic by Q-Sepharose chromatography of 30 kD ultrafiltrate of raw garlic extract of these proteins shows the mitogenic activity towards human peripheral blood lymphocytes, murine splenocytes, and thymocytes [45][46].
The extraction of garlic was prepared by blending the bulbs in phosphate buffer saline (pH, 7.4).Followed by ammonium sulfate precipitation and were isolated by ultra-filtration, and anion exchange chromatography using Q-Sepharose (High Performance) column taking unbuffered 20 mm 1, 3-diamino propane taken in 1:10 ratio (w/v), Tris-HCl buffer, pH 8, and NaCl.The eluted fractions were monitored by absorbance at 280 nm [47].The richly present garlic ImPs, QR-1 and QR-2, identified in the present study agglutinins ASA II and ASA I, was found to be potent mutagenic activity having potential utility in therapeutic immunomodulation [48].Many other plants show immunomodulation activities (See Table 4)

Conclusion
From this discussion, it's evident that many medicinal plants exert an immunomodulatory effect in experimental models at a specific dose.Different types of in vivo and in vitro screening methods are employed in determining their pharmacological activity.Some medicinal plants may stimulate the system like Ocimum sanctum, Tinospora cordifolia and a few of them may suppress the immune responses (Eg.Alternanthera tenella).The review also reveals an update of the present immunomodulator plants and their pharmacological aspects.Thus successful results are achieved by following an appropriate screening approach.

Figure 2
Figure 2 Classification of immunomodulators

Table 1
List of plants having immunomodulatory activity

Table 3
Phagocytic response of extract in mouse

Table 4
A brief descriptions of common plant-derived immunomodulators