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Available online at ajdhs.com 

Asian Journal of Dental and Health Sciences 
Open Access to Pharmaceutical and Medical Research 

Copyright  © 2022 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 
which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the 

original author and source are credited 
 

 

 

Immunostimulants: Concepts, Types and Functions 

Prince Jain, Pratik Darji, Bhupendra Singh Thakur, Anushree Jain, Prateek Kumar Jain, Basant Khare* 

Adina College of Pharmacy, ADINA Campus Rd, Lahdara, Sagar, MP, 470001 

Article Info: 
_______________________________________ 
Article History: 

Received 06 Sep 2022      
Reviewed 11 Nov 2022 
Accepted 28 Nov 2022 
Published 15 Dec 2022 

_______________________________________ 
Cite this article as:  

Jain P, Darji P, Thakur BS, Jain A, Jain PK, Khare 
B, Immunostimulants: Concepts, Types and 
Functions, Asian Journal of Dental and Health 
Sciences. 2022; 2(4):26-34 

DOI: http://dx.doi.org/10.22270/ajdhs.v2i4.22  

_______________________________________

*Address for Correspondence:   

Basant Khare, Adina College of Pharmacy, 
ADINA Campus Rd, Lahdara, Sagar, MP, 470001 

Abstract 
___________________________________________________________________________________________________________________ 
The proper functioning of human immune system is essential for organism survival against infectious, 
toxic and oncogenic agents. The concept of immunomodulation was proposed by Edward Jenner, while 
working on polio vaccine in 1796. A brawny, fine-functioning immune system is the keystone of 
excellent health. Immune replies are the consequence of an effectual interaction among innate (natural 
and non-specific) and acquired (adaptive and specific) components of the immune system. Inequity or 
failure of the immune systems is connected with a variety of chronic illness counting allergies, 
autoimmune diseases, cancers and furthers. Immunomodulators are natural or synthetic materials that 
regulate the immune system and induce innate and adaptive defense mechanisms. These substances are 
classified into two types, immunostimulants and immunosuppressants. Immunostimulants can enhance 
body's resistance against various infections through increasing the basal levels of immune response. 
These agents could increase the oxidative activity of neutrophils, augment engulfment activity of 
phagocytic cells and stimulate cytotoxic cells as necessary defense mechanisms. The researchers 
classified the immunostimulants using their origin and mode of action such as bacterial products, 
complex carbohydrates, vaccines (antigens and adjuvants), cytokines, immunoenhancing drugs, 
nutritional factors, animal extracts, and plant extracts. The link between immune system with diet, 
exercise, sleep, stress, microbial exposure, alcohol, water, hygiene are found to influence the immune 
response to a greater extent. Immunostimulants and some immunity enhancing nutrients improve the 
functioning of the immune system. In addition, some preventive measures such as healthy diet or proper 
nutrition, moderate exercise, sound sleep, drinking adequate water, subclinical exposure to microbes 
and managing stress, good hygiene, are altogether capable of boosting the immune system. In this 
review, the concepts, types and functions of immunostimulants will be described as a therapeutic 
approach against different diseases. 

Keywords: Immunomodulators, Immunostimulants, Adjuvant, Mechanism, Immune system. 

 

Introduction 

Humans and other vertebrates reside in a world that is 
occupied by a huge range of pathogenic microbes and toxic 
substances that menace normal homeostasis; and immunity is 
a specialized form of host defense mechanism that works 
particularly in relation to the causes and prevention of 
diseases1. Manifestation of disease due to the pathogen 
depends on its virulence and capability of the immune system; 
and to achieve resistance against disease, the most important 
is strengthening the immune system2. If the immune system 
fails become under or over active, or hits the wrong target it 
can vent a variety of adverse consequences. Under-activity of 
the immune system lead to loss the defensive mechanism 
against infections; extreme immune failure results HIV 
disease, certain cancer, etc. whereas over-activity can lead to 
autoimmune diseases, including arthritis, inflammatory bowel 
disease, inflammatory lung disease, connective tissue disease, 
autoimmune endocrine diseases, multiple sclerosis, etc. So, 
proper understanding and strictly regulating the immune 
system has become mandatory. Two main compounds are able 
to enhance immune responses including adjuvants and 
immunostimulants. An adjuvant is a substance combined with 
an antigen for increasing its immune response, but an 
immunostimulant can induce the immune response without 
injection with an antigen3. There are several types of 
stimulants with different mechanisms and functions such as 
bacterial products, complex carbohydrates (e.g., glucans, 

schizophyllan, scleroglucan, lentinan, statolon, bestatin, 
acemannan), vaccines, immunoenhancing drugs (e.g., 
Levamisole, Isoprinosine, Fluoroquindone, Avridine, 
Polyribonucleotides), nutritional factors (e.g., vitamins, 
carotenoids, lipids, trace elements, selenium), animal extracts 
(e.g., chitosan from shrimp), cytokines (e.g., macrophage 
activating factor, interferon, interleukin-2, tumor necrosis 
factor), and plant extracts (e.g., Lectins, mitogens such as 
phytohemagglutinin, concanavalin A) 4. Two main approaches 
were determined to evaluate the efficiency of an 
immunostimulant such as in vivo protection against 
pathogens, and in vitro assay of cellular and humoral immune 
mechanisms. In vitro tests should be performed before in vivo 
experiments to clarify the basic mechanisms responsible for 
the protection. In vitro immunostimulant evaluation is usually 
based on some parameters such as serum lysozyme, 
complement, total leucocyte count, 
monocyte/lymphocyte/granulocyte count, antibody titers, 
phagocytosis, respiratory burst and leucocyte proliferation4. 
Immunomodulation can be either specific or non-specific. 
Specific immunomodulation is limited to a single antigen such 
as vaccination, whereas non-specific immunomodulation leads 
to a further change in immune response both in innate and 
adaptive immunity causing altered host reactivity to many 
various antigens5.  

Immune system 

                       Open Access                                                                                                                                                                                                          Review Article                                                                           

http://jddtonline.info/
http://dx.doi.org/10.22270/ajdhs.v2i4.22


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The immune system consist of a complex network of 
specialized cells, tissues, molecules and biological processes 
within an organism that watches out the continually to protect 
it against attacks by foreign antigens or invaders (basically 
microbes-infection causing organisms such as bacteria, 
viruses, parasites, and fungi or any injury, and disease) 6. The 
different organs of human immune system are shown in 
Figure 1. Some of the potentially infectious agents includes: (a) 
Viruses, which are sub-microscopic non-living entities that 
replicates only inside the host cells (living organism) and often 
results in serious diseases. Examples include influenza virus, 
human immunodeficiency virus (HIV), herpes simplex virus 
(HSV, which can cause cold sores or genital ulcers), a newly 
discovered virus named coronavirus (causes infection in the 
upper respiratory tract). (b) Bacteria are single celled 
microbes capable of causing disease when get entry into the 
body through water, air, soil and also through physical contact. 
Examples include Staphylococcus and Streptococcus that 
cause acute infections such as abscesses and sore throats, 
Escherichia, Salmonella that cause food poisoning and 
Mycobacteria that cause chronic infections such as 
tuberculosis and leprosy. (c) Fungi, eukaryotic, 
nonphototrophic organisms with rigid cell walls, they can be 
unicellular or multicellular. Examples include Aspergillus that 
causes allergic disease, Candida that causes thrush, 
Cryptococcus that causes meningitis and meningo-encephalitis 
in patients with HIV infection and AIDS. (d) Parasites, which 
are eukaryotic organisms that live off other organisms, or host, 
to survive. Some are them are single-celled protozoa that 
cause diseases for example, malaria; others are large, 
multicellular organisms (metazoa) example, worms that can 
be seen with the naked eye. In order to prevent disease, the 
immune system must able to scan, recognize and attack the 

foreign invaders by distinguishing self from non-self 
substances2. Self-molecules are those components that 
belongs to an organism's body which the immune system can 
distinct from foreign substances. Autoimmunity is an immune 
response in opposed to its own healthy cells and tissues, 
which may lead to various diseases7. Non-self-molecules are 
those recognized components that do not belong to an 
organism’s body, they are foreign invaders. One example of 
non-self-molecules is antigens that cause the immune system 
to promote the generation of antibodies against it and then 
combine specifically with them to induce an immune 
response8. 

Innate and adaptive immunity 

Defence against infection is divided into two main forms 
namely innate immunity and adaptive immunity. Its 
components are shown in Figure 2. Some of the differences 
between innate and adaptive immunity are shown in Table 1. 

Innate immunity 

Innate immunity regarded as the first line of defense from 
both external and internal attack, also known as natural or 
native immunity. It is a nonspecific and antigen-independent 
defensive mechanism which responds immediately and within 
minutes or hours of meeting an antigen9. Its host defense 
mechanisms are encoded as their mature form by the germ-
line gene of the host1. This type of immune response is lack in 
memory to recognize the pathogen, if the same pathogen 
invades for second time as they cannot generate that 
immunologic memory. Innate immunity consists of two major 
components: Humoral (include complement cells) and Cellular 
(includes neutrophils, macrophages, adnatural killer cells).

  

 

 

Figure 1: Organs of the human immune system 



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Figure 2: Flowchart of basic components of human Immune system 

The defensive barriers of  innate immunity are of four types: 

 Anatomical barriers e.g., skin and mucous membrane, the 
epithelial cell layers offers tight junction so there is tight 
cell to cell contact, the mucus layers over the respiratory, 
gastrointestinal and genitourinary tract, and when foreign 
particles are inhaled, the mucus layer get contaminated 
which are constantly discarded by the epithelial cilia. 

 Physiological barriers e.g., temperature, low pH and 
chemical mediators 

 Endocytic and phagocytic cells (neutrophils, 
macrophages), dendritic cells, natural killer (NK) cells and 
other innate lymphoid 

 Inflammatory barriers e.g., a series of events occurs in 
inflammation process that plays an important role to 
destroy or inactivate microbes. 

Adaptive immunity 

Adaptive immunity is also known as specific or acquired 
immunity which means the resistance acquired by human 
during their lifetime. It is antigen-dependent and antigen-
specific defensive mechanism and, thus delays the time of the 
antigen to get expose and to produce the maximal response. 
The advantage of adaptive immunity is their capacity to 
generate memory which permits the host to elicit a more 
rapid, stronger and efficient immune response against 
consecutive exposure to the antigen10. This type of immunity 
provides the basis for effectual immunization facing infectious 
diseases. The two major components of adaptive immunity are 
Humoral (comprises of antibodies formed by B lymphocytes) 
and Cellular (mediated by T lymphocytes). B lymphocytes and 
T lymphocytes are two kind of lymphocytes found in this type 
of immunity that impart long lasting immunity against specific 
antigens by proliferating into memory cells. Lymphocytes are 
generated from the bone marrow and the type that mature in 
bone marrow turns into B lymphocytes whereas the type that 
leave the bone marrow and migrate to thymus gland get 
mature into T lymphocytes and based on ‘cluster of 
differentiation’ (CD) molecules on their surface they acquire 
certain genetic and immune surface characteristics which 

determines their different functions11. B lymphocytes are 
responsible for formation of specific antibodies by 
differentiating into plasma cells while T lymphocytes get 
activated in presence of appropriate antigens presented by 
macrophages like APC and Histocompatibility Complex (MHC). 
The function of B lymphocytes are like military intelligence 
system, they find out the target and organise defensive action, 
while T lymphocyte perform like soldiers, they destroy the 
invading substance identified by the intelligence system i.e. B 
lymphocytes12. Antigen specific receptors are encoded by 
genes that are assembled by somatic rearrangement of germ-
line gene to form intact T cell receptor (TCR) and 
immunoglobulin (B cell antigen receptor; Ig) genes. Millions of 
different antigen receptors are formed from the collection of a 
few hundred germ-line-encoded gene elements assembly of 
antigen receptors, each of which are potentially unique and 
antigen specific1. The advantage of this diverseness of 
receptors helps adaptive immunity to identify any kind of 
pathogen13. They are of two types i.e., naturally   acquired 
adaptive immunity and artificially acquired adaptive 
immunity. 

Naturally acquired adaptive immunity: In naturally acquired 
active adaptive immunity, antigens enter the body naturally 
then the bodies develop antibodies and specialized 
lymphocytes whereas in naturally acquired passive adaptive 
immunity, antibodies passes from mother to foetus/infant 
through placenta/mother’s milk. Naturally acquired active 
adaptive immunity lives longer than naturally acquired 
passive adaptive immunity. 

Artificially acquired adaptive immunity: In artificially acquired 
active adaptive immunity, antigens are introduced into the 
body through the use of vaccines then the bodies generate 
antibodies and specialized lymphocytes against it whereas in 
artificially acquired passive adaptive immunity, preformed 
antibodies in immune serum are introduced into the body by 
injection. Artificially acquired active adaptive immunity lives 
longer than artificially acquired passive adaptive immunity 
but, when there is very less time to develop active immunity 
then passive type is more effective as it can prevent the 
infection in any stage and its process is rapid.



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Table 1: Differences between innate and adaptive immunity 

Feature Innate Immunity Adaptive Immunity 

Cells involved Dendritic leukocyte, Natural killer cells, Mast cell, 
Granulocytes/ Macrophages, Basophils, etc 

Killer CD8+ T-cells, Helper CD4+ T-cells, B-
cells, Antigen presenting cells, etc. 

 

Molecules involved 

 

Cytokines, Complement cells, Interferon, Acute phase 
reactants/ proteins  

Antibodies, Cytokines 

 

Receptors Germline encoded 

No somatic rearrangement  

Non-clonal distribution 

Encoded in gene segments Somatic 
rearrangement necessary   

Clonal distribution 

Action time Immediate effector activation Delayed effector activation 

Response Rapidly occurs (0-6 h ours) Occurs over days to weeks 

Order of  defense 

 

It is the first line of defense of immune system Action against pathogens that are able to 
evade or overcome innate immune defense 

Immunological 
memory 

None Confer Immunological memory 

Types of          Immune 
response 

Inflammation, Complement mediated killing, 
Phagocytosis 

Antibodies generation, microbial destruction 
by Helper T cells and Cytotoxic T cells  

Subsequent exposure 

 

Immune response does not get alter on repeated 
exposure 

Immune response get improves with 
subsequent exposure 

Reason behind  
immune evasion 

Caused by pathogenic virulence Caused by mutation of the recognized 
antigen 

Allery or 
hypersensitivity  

reaction 

 None Immediate and delay hypersentivity 

Potency Lower Higher 

Physioanatomicalcal 
barriers 

Skin, Mucous membranes, Temp, pH, chemicals, etc Lymph nodes, spleen, mucosal associated 
lymphoid tissue 

Functions (a) Recruiting immune cells to 

site of infection; (b) Activation of complement cascade to 
identify antigens; (c) Identification & removal of foreign 
substances present in organs, tissues, blood and lymph; 
(d) Activation of adaptive immune system through 
antigen presentation; (e) Acting as physical & chemical 
barrier to infectious agents. 

(a) Recognition of specific “non- self” 
antigens during the process of antigen 
presentation; (b) Generation of responses 
that are tailored to maximally eliminate 
specific pathogens or infected cells; (c) 
Development of immunological memory, 
through memory B cells and memory T cells. 

 

Functioning of immune system 

The immune system comprised of cells and proteins that 
uphold the body from the foreign invaders14. These cells 
emanate from the pluripotent stem cells of bone marrow. Of 
the two pathways - (I) the myeloid pathway, in presence of IL-
3, becomes excited giving rise to the production of platelets, 
erythrocytes, monocytes and granulocytes. (II) the lymphoid 
pathway, in presence of IL-7, becomes excited giving rise to 
the production of innate and adaptive lymph cells 
(Lymphocytes). The pathways distinction relies on the 
chemical signals in the surrounding area15,16. When pathogens 
invade the host body, innate immunity provides the first line 
of defense. Leukocytes like dendritic cells, monocytes, 
neutrophils, macrophages, eosinophils, mast cells, are allowed 
by the pattern recognition receptor (PRRs) to detect and react 
rapidly towards a large population pathogen which is 
structurally similar, known as pathogen associated molecular 
patterns (PAMPs). An example of these is the components of 
bacterial cell wall like lipopolysaccharides (LPS) and double-

stranded ribonucleic acid17. The binding of PRPs with PAMPs 
triggers the release of cellular messenger called cytokines (e.g. 
interleukin) and causes inflammatory reaction. Inflammation 
leads to vasodilation, increased vascular permeability and 
cellular infiltration due to which the microbial cells get 
destroyed. Other cells, like natural killers are the critical 
members of innate immunity as they able to pursue and kill a 
vast number of pathogens along with malignant cells. All the 
cells of immune system are capable to suppress or induce 
inflammation by communicating one another over direct cell 
contact or through generation of cytokines. Again a complex 
systems of proteins known as the complement system also 
induces inflammatory response that aid to fight infection. This 
type of immunity also aid to remove dead cells or foreign 
substances from different organs, blood and lymph13. The 
adaptive response takes over when the innate immune 
response becomes ineffective to eliminate pathogen. In 
adaptive immunity at first antigen presenting cell (APC) like 
macrophages and dendritic cells recognizes, engulfs and 
process the antigen; and displays the specific part of antigen 



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on its surface then present it to T- cells. T-cells receptors are 
there that bind with the specific antigenic sites and triggers 
proliferation and differentiation processes in lymphoid 
tissues2. There are two classes of T-cells namely, helper T-cells 
and Cytotoxic T-cells which can be discriminate by their 
presence of some molecules on their surface like CD4+ and 
CD8+ respectively. T-helper cells aid the immune response in 
recognition of antigen and then activate other T and B-cells by 
secreting cytokines whereas Cytotoxic T-cells aid the immune 
response by killing pathogen infected cells or tumor cells. One 
other class of T-cells, known as suppressive T-cells are able 
to secret suppressive cytokines that can inhibit the actions 
of other T-cells. Antigen binding and helper T-cell can trigger 
the differentiation process of B-cells into plasma cells and 
secret antibodies which circulate in the blood and causes 
destruction or inactivation of the antigen18. 

Immunostimulants 

Immunostimulants (or immune stimulants) are biologically 
active substances obtained from natural or synthetic sources 
with different chemical characteristics and mechanism of 
action that modulate the immune system of host to increase 
resistance against various infections [19]. They interact with 
specific receptors and cellular components of innate and 
adaptive response to modulate the immune response. They 
used during suppressed immunity condition like cancer 
disease, AIDS, SARS etc. to improve the host’s resistance19. 

Concept of immunostimulant 

Immunostimulants known as immunostimulators are 
attractive substances that activate the immune system of 

humans and animals for prevention of diseases and 
improvement of the body’s natural resistance to various viral 
and bacterial infections. These biologically active substances 
are the products derived from natural sources or synthetically 
made with different chemical properties and mechanisms of 
action. In general, immunostimulants induce synthesis of 
specific antibodies and cytokines for treatment of infectious 
diseases. Two major groups of immunostimulants contain a) 
specific immunostimulants acting as antigen for stimulation of 
immune responses (e.g., vaccines), and b) non-specific 
immunostimulants without antigenic properties enhancing 
immune responses to other antigens (e.g., adjuvants and non-
specific immunostimulators). Moreover, immunostimulants 
were classified based on their origin and mode of action20. 

Functions of immunostimulants 

Immunostimulants activate different elements of the immune 
system in humans and animals. They develop the non-specific 
immunotherapy and immunoprevention by stimulating the 
major factors of the immune system including phagocytosis, 
properdin and complement systems, protective secretory IgA 
antibodies, α- and γ-interferon release, T- and B-lymphocytes, 
synthesis of specific antibodies and cytokines, and synthesis of 
pulmonary surfactant. There are several reasons for using the 
immunostimulants in the control of various infectious diseases 
including: a) antibiotic resistance of the bacteria; b) allergic 
reactions to antibiotics; c) immunosuppressive effects of 
antibiotics; and d) Poor effects of the antibiotics in viral 
infections19. Figure 3 shows some types of immunostimulants 
and their general functions. 

 

 

Figure 3: Schematic representation of some types of immunostimulants and their general functions 

Types of Immunostimulants 

For simplification, we divided the types of immunostimulants 
as 7 groups such as bacterial products, complex 
carbohydrates, vaccines (antigens and adjuvants), cytokines, 
immunoenhancing drugs, plant extracts, and animal extracts 
as mentioned below: 

Immunostimulatory drugs 

A few immunostimulatory drugs (Endogenous 
immunostimulants or Synthetic immunostimulants) have been 
developed to induce humoral or cellular immune responses or 
both of them against bacterial or viral infections, 



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immunodeficiency diseases, and cancer. They were classified 
as follows:  

a) Levamisole (Ergamisol): Levamisole is a synthetic drug 
inducing B and T lymphocytes, monocytes, and macrophages. 
It was used in adjuvant therapy with 5-fluorouracil after 
surgical resection in patients with Duke’s stage C colon cancer. 
Its disadvantages are allergy, nausea, flu, and muscle pain. 
Levamisole has been successfully used in combination with 
polymers for treatment of dermatologic disorders. For 
example, it was combined with cimetidine for treating 
recalcitrant warts, and with prednisolone for treating 
aphthous ulcers of the mouth21,22.  

b) Thalidomide: Thalidomide or Immunoprin (C13H10N2O4) is 
an immunomodulatory drug. Thalidomide could decrease 
circulating TNF-α in patients with erythema nodosum 
leprosum. In contrast, it increased TNF-α in HIV-seropositive 
patients. Furthermore, its therapeutic effects were determined 
in severe rheumatoid arthritis and angiogenesis21. 

c) Isoprinosine (Inosiplex/ Imunovir): Isoprinosine 
(C52H78N10O17) is a combination of inosine, acetamidobenzoic 
acid, and dimethylaminoisopropanol. Isoprinosine could 
enhance the levels of cytokines including IL-1, IL-2, and IFN-γ. 
It increased the proliferation of lymphocytes against mitogenic 
or antigenic stimuli. Moreover, Isoprinosine augmented active 
T-cells and induced T-cell surface markers on prothymocytes. 
It was used to treat Herpes simplex infections, Epstein-Barr, 
and Measles viruses. Its disadvantages are minor CNS 
depressant, transient nausea, and increased level of uric acid 
in serum and urine21.  

d) Immunocynin: Immunocynin is a stable form of 
haemocynin, a copper-containing protein, found in molluses 
and arthropods. It was used to treat urinary bladder cancer 
with poor side effects such as rare-mild fever21.  

e) Bestatin: Bestatin, a dipeptide [(2S, 3R)-3-amino-2- 
hydroxy-4-phenylbutanoyl]-L-leucine, is an immunostimulant 
with low toxicity which binds to the cell surface of 
lymphocytes and macrophages and enhances both humoral 
and cellular immune responses. It is a leucine aminopeptidase 
and aminopeptidase-B inhibitor. Bestatin possesses antitumor 
activity and also increase the antitumor activity of bleomycin 
and adriamycin. Bestatin efficiently prevented the metastasis 
of P388 leukemia when the antibiotic was constantly injected 
after tumor inoculation23. The dipeptide was 
immunorestorator in the elderly and cancer patients and HIV-
infected subjects. It stimulated granulocytopoiesis and 
thrombocytopoiesis in vitro and could restore them in myelo-
hypoplastic man24. 

Bacterial products 

The immunostimulatory effects of bacteria and bacterial 
products are due to the release of cytokines. Live bacillus 
Calmette-Guerin (BCG) is an attenuated, live culture of the 
bacillus of Calmette and Guerin strain of Mycobacterium bovis. 
Its mechanism of action includes: a) induction of a 
granulomatous reaction at the site of administration, and b) 
prevention and treatment of carcinoma types. Furthermore, 
BCG enhances both B and T cell-mediated responses leading to 
phagocytosis and resistance to infection. Its disadvantages are 
hypersensitivity, fever, shock, and immune complex disease21.  

Recombinant cytokines 

Several interferons and interleukins are suggested to 
stimulate effective immune responses. Interferons could be 
obtained from trout leucocytes after stimulation with 
mitogens. It was able to cause an in vitro resistance against 
pancreatic necrosis virus in trout cells. In mammalian, low 
doses of interferon could induce stable positive results 

without side effects. On the other hand, vaccination of animals 
with the recombinant IL-2 against different infections 
increased the protective effects. However, IL-2 was a very 
toxic compound in high doses causing side effects such as 
fever and diarrhea. The purified cytokines showed 
unsatisfactory results in clinical trials, because the immune 
responses were produced by a mixture of cytokines generated 
by the immune cells, but not against a single cytokine. Thus, 
the enhancers of nonspecific cytokine synthesis may improve 
immune responses and solve this problem4. Thus, 
recombinant cytokines are produced recently in different 
expression systems (e.g., plants) and used in clinical trials such 
as interferons, TNF-α and IL-225. Complex carbohydrates 

Several types of the complex carbohydrates were described as 
follows: 

a) Glucans: An important class of immunostimulants is the β-
(1→3)-linked chain of glucose units. The main chain has β-
(1→6)-branched glucose units. The β-glucans were obtained 
from highly conserved structural components of cell walls in 
fungi, algae, yeast, and have a broad range of molecular 
weights from 5 to 200 kDa. The length and frequency of these 
branches vary depending on different sources. β-glucan was 
used to stimulate anti-tumor mechanisms (e.g., increased 
macrophage activity) and to enhance host resistance to a 
variety of microbial pathogens in mammalian. Glucan might 
also be helpful to prevent the carcinogenic effects of aflatoxin. 
β-glucan was consideredas a stimulator of cellular immunity. 
Indeed, mammalian macrophages or monocytes have specific 
receptors for β- glucans and produce mediators such as 
cytokines (e.g., IL-1, IL-9, TNF-α) and prostaglandins in the 
presence of glucans26, 27. In Japan, the β-glucans such as 
Lentinan derived from the Shiitake mushroom and 
Polysaccharide-K derived from Coriolus versicolor were 
licensed as anti-cancer drugs28. Lentinan could induce 
protective Th1 immune responses to control the proliferation 
of malaria parasites red blood cells by stimulating maturation 
of DCs, increasing the expression of MHCII, CD80/CD86, Toll-
like receptors (TLR2/TLR4) and the level of IL-12, and 
preventing the adverse effects of Tregs29,30. The main roles of 
glucans were detected in cancer treatment, infection 
immunity, stress reduction, and restoration of damaged bone 
marrow. A mixture of polysaccharides isolated from the cell 
walls of Saccharomyces cerevisiae named as zymosan could 
potently stimulate macrophages and induce the release of 
cytokines from neutrophils. Indeed, β-glucan in zymosan was 
identified as its effective component for non-specific 
immunomodulation. In addition, β-glucan could reverse 
myelosuppression generated by chemotherapeutic drugs via 
targeting the C3 fragment of complement and circulating 
antibodies. The recent studies have shown that daily therapy 
with soluble or insoluble β-glucan led to a 70%-95% reduction 
in tumor size. Indeed, after the binding of antibodies on the 
surface of cancer cells, C3 fragments of complement could coat 
the cancer cells. Then, β-glucan-primed cells, such as blood 
neutrophils, macrophages, and NK cells specifically recognized 
these complement-antibody complexes and killed the tumor 
cells. In fact, the cooperation of β-glucan with anti-tumor 
antibodies is an effective approach in combination therapy28.  

b) Trehalose: Trehalose dimycolate (TDM), Muramyl 
dipeptide (MDP), and Lipopolysaccharides (LPS) as the 
bacterial products promote the production of antibody, 
stimulate activation of lymphocytes, and elicit specific 
immunity against different bacterial infections. Trehalose 
dimycolate, a glycolipid present in the cell wall of 
Mycobacteria is a potent immunostimulant that limits tumor 
growth and enhances resistance against bacterial, parasitic, 
and viral infections. It can interact with membranes due to its 
amphipathic properties. TDM primes murine macrophages to 



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generate nitric oxide (NO) and to develop anti-tumoral 
activity. As an adjuvant, TDM enhances both cellular and 
humoral immunity, but elicits a stronger cellular response. 
TDM could induce potent immune responses against malaria 
antigens in mice as compared to groups immunized with 
malarial antigens and Freund’s adjuvant. The reports showed 
that the protective effect of TDM is reduced in macrophage-
depleted mice injected with silica particles indicating the role 
of macrophages. T lymphocytes were not necessary for TDM 
to prime peritoneal macrophages. Trehalose diesters could 
induce IL-12p40 and IFN-γ mRNA31,32. 

 c) Prebiotics: Prebiotics are indigestible fibers that increase 
beneficial gut commensal bacteria resulting in improvement of 
the host's health. Prebiotics, such as fructooligosaccharide, 
mannanoligosaccharide, inulin, or β-glucan, are called 
immunosaccharides. They directly enhance innate immune 
responses including phagocytic activation, neutrophil 
activation, activation of the alternative complement system, 
and increased lysozyme activity. Immunosaccharides directly 
activate the innate immune system by interacting with pattern 
recognition receptors (PRR) expressed on innate immune 
cells. They can also associate with microbe associated 
molecular patterns (MAMPs) to activate innate immune cells. 
Indeed, probiotics activate the innate immune system in two 
ways: a) by directly stimulating the innate immune system and 
b) by enhancing the growth of commensal microbiota33.  

Immunostimulants used in vaccines 

Vaccines contain a wide range of immunostimulants. For 
example, an adjuvant heat-labile enterotoxin from Escherichia 
coli (LT), administered as an immunostimulant (LT-IS) patch 
on the skin may further enhance immune responses to 
influenza vaccine in the elderly34. Also, the immune activation 
mediated by LT-IS improved the potency of generating 
Alzheimer's disease (AD)-specific vaccination responses as an 
adjuvant in the clinical trial35. Co-administration of a potent 
adjuvant in IS patches containing heat-labile enterotoxin from 
E. coli placed on the skin at the site of DNA vaccination 
significantly increased anti-influenza antibody immune 
response36. Adjuvants enhance and modulate immune 
responses to antigens. This is important when the purified 
antigens do not elicit the effective innate or adaptive immune 
systems. Adjuvants are different in the types and levels of 
immune responses. Expected advantages of adjuvants contain 
stronger immune priming, effective immune responses in low-
response populations (e.g., the elderly or immuno-
compromised patients), the use of smaller amounts of the 
antigen, and safety profile37. New adjuvants have already 
applied to more efficient influenza vaccines, as well as 
vaccines targeting hepatitis B (HBV) and human 
papillomavirus (HPV) 38. On the other hand, CpG 
oligonucleotides and imiquimod drugs (an antiviral agent) 
could activate dendritic cells, induce in situ maturation and 
migration of DCs, and augmented both humoral and cellular 
immune responses39. The unmethylated CpG motif in bacterial 
DNA was identified as a B-cell stimulating adjuvant, and 
synthetic oligodeoxynucleotides (ODNs) containing the CpG 
motifs were shown to induce potent therapeutic activities in 
different infections and tumor animal models. Imiquimod was 
topically used for patients with anogenital warts as well as 
basal-cell carcinoma. The studies indicated that CpG ODNs and 
imiquimod (resiquimod) drugs act as synthetic ligands for 
TLR9 and TLR7, respectively, and both stimulate efficiently DC 
maturation39.  

Plant-derived immunostimulants 

Natural plant product promote various activities such as anti-
stress, growth promotion, appetite stimulation, 
immunostimulation, aphrodisiac and antimicrobial properties, 

due to the active substances such as alkaloids, flavanoids 
pigments, phenolics, terpenoids, steroids, and essential oils. 
Medicinal plants have been known as immunostimulants, 
growth promoters, immune enhancers, where they act as 
antibacterial and antiviral agents to the host immune system. 
Unfortunately, the mechanisms were not understood40. Some 
medicinal plants were described as following: 

a) Ocimum sanctum (Tulsi): Leaves of O. sanctum containing 
water-soluble phenolic compounds and various other 
constituents may act as an immunostimulant. Leaves extract of 
O. sanctum affected both specific and nonspecific immune 
responses. It stimulated both antibody response and 
neutrophil activity5,41. 

b) Phyllanthus emblica (Amla): P. emblica has antioxidant, 
anti-fungal, anti-microbial, and anti- inflammatory activities. 
Amla fruit pulp contains a large amount of vitamin C as an 
immunostimulant5,41. 

c) Azadirachta indica (Neem): A. indica possesses antihuman 
immunodeficiency virus, anti-tumor, and antimicrobial 
activities. Azadirachtin, a triterpenoid derived from A. indica, 
enhanced respiratory burst activities, the leukocyte count and 
the primary and secondary antibody responses against SRBC 
(sheep erythrocytes) in tilapia5,41. 

d) Solanum trilobatum (Purple Fruited Pea Eggplant): The 
herbal extract of S. trilobatum possesses a broad spectrum of 
antibiotic, antibacterial and anticancer activities. A study 
showed that the water-soluble fraction of S. trilobatum 
significantly enhanced the production of reactive oxygen and 
decreased the percentage of mortality following a challenge 
with Aeromonas hydrophila5,41. 

e) Eclipta alba (Bhringraj): E. alba possesses several 
medicinal properties. The methanol extracts of E. alba 
significantly increased the phagocytic index, antibody titer and 
WBC count in mice5,41.  

f) Zingiber officinale (Ginger): The extracts of Z. officinale 
contain polyphenol compounds which have a high antioxidant 
activity. Moreover, it showed a significant increase in 
proliferation of neutrophils, macrophages, and lymphocytes, 
as well as it enhanced phagocytic, respiratory burst, lysozyme, 
bactericidal and antiprotease activities5,41. 

g) Echinacea (purple coneflowers) and Allium sativum 
(garlic): Echinacea and A. sativum improved the gain in body 
weight, survival rate and resistance against challenge infection 
of Aeromonas hydrophila. Both compounds developed 
resistance to cold stress during the winter season5,41. 

h) Camellia sinensis (Green tea): Green tea extracts possess 
biological activity including antioxidant, antiangiogenesis, and 
anti-proliferative activities that are related to the prevention 
and treatment of various forms of cancer5,41. 

i) Aloe vera: Oral administration of A. vera could enhance the 
specific and non-specific immune responses and increase 
lysozyme activity, serum bactericidal potency, and the total 
protein and IgM levels5,41.  

j) Cynodon dactylon (Bermuda Grass): The antiviral activity of 
C. dactylon was confirmed to prevent white spot syndrome 
virus (WSSV) infection with no mortality and no signs of WSD 
(White spot disease) 5,41. 

k) Achyranthes aspera (Prickly Chaff Flower): A. aspera 
showed both specific and non-specific immunity revealed by 
higher levels of serum antibody and also serum antiproteases 
in fish. Moreover, the level of serum globulin and RNA/DNA 
ratio of the spleen were also significantly enhanced in the fish 
fed with A. aspera5,41. 



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m) Nyctanthes arbortristis (Night-flowering Jasmine): N. 
arbortristis possesses hepatoprotective, anti-leishmanial, 
antiviral and antifungal activities. The extract of N. arbortristis 
significantly enhanced serum lysozyme, complement activities 
and cellular reactive oxygen species (ROS), reactive nitrogen 
intermediate (RNI) and myeloperoxidase (MPO) 
production5,41. 

n) Fermented vegetable product (FVP): The phagocytic 
activities, the activity of lysozyme, and superoxide generation 
of peritoneal leukocytes enhanced in fish fed with the FVP 
supplemented diet5,41. 

o) Saffron: Saffron, a spice derived from the flower of Crocus 
sativus, is rich in carotenoids. Carotenoids are lipophilic 
molecules accumulating in lipophilic compartments including 
lipoproteins and/or membranes. Two main natural 
carotenoids of saffron, crocin, and crocetin, are responsible for 
its color42. Saffron and its components were suggested as 
promising candidates for cancer prevention43. The 
mechanisms underlying cancer chemopreventive activities of 
carotenoids contain modulation of carcinogen metabolism, 
regulation of cell growth and cell cycle progression, inhibition 
of cell proliferation, antioxidant activity, immune modulation, 
enhancement of cell differentiation, stimulation of cell-tocell 
gap junction communication, apoptosis and retinoid 
dependent signaling. The immunomodulatory activity of 
saffron was determined on driving toward Th1 and Th2 limbs 
of the immune system42. Carotenoids increase the proliferative 
response of T and B lymphocytes to mitogens, the activity of 
natural killer cells, the number and activity of cytotoxic T-cells, 
macrophage tumor-killing activity and also induce the 
secretion of TNF-α in an animal model. These effects are 
involved in preventing tumor growth, killing tumors and 
lowering tumor burden. Different carotenoids were used as 
main phytonutrients to inhibit the development of tumors in 
vitro and in vivo44. For example, a single treatment with crocin 
significantly decreased tumor size in a mouse model43. 

Animal originated immunostimulants 

There are some immunostimulants derived from animals. For 
example, chitin and chitosan are the non-specific 
immunostimulators which are protective against infections for 
a short time. Also, fermented products of chicken egg (EF203) 
containing immunoactive peptides showed 
immunomodulatory effects when administered orally to 
rainbow trout, Oncorhynchus mykiss. Fish treated with EF203 
displayed an increased resistance to both natural and 
experimental β-haemolytic streptococcal infection41. 
Moreover, chitosan, the deacetylated derivative of chitin, has 
shown strong anti-microbial activity depending on its degree 
of deacetylation and molecular weight. Both oligomers of 
chitin and chitosan were effective in enhancing the migratory 
activity of macrophages. Furthermore, chitosan could activate 
the production of cytokines such as IL-1β, TNF-α, and reactive 
oxygen intermediates to promote the defense system against 
microbial infections45. On the other hand, glycated chitosan 
(GC) as an immunoadjuvant was used in combination with 
phototherapy for cancer treatment in animal models. In vitro 
studies also showed that after incubation of GC with 
macrophages, it could significantly stimulate the secretion of 
TNF-α46. 

Conclusion 

Immunomodulators are divided into several groups including 
physiological products, cytokines, host defense peptides, 
microbial products, probiotics, synthetic chemical compounds, 
herbal products, adjuvants, and polysaccharides. 
Immunostimulants represent a promising class of drugs for 
the treatment of infectious disorders and cancer. Herbal 

extracts and animal originated product have a potential 
application as an immunostimulant, because they can be easily 
obtained, are not expensive and act against a broad spectrum 
of pathogens. Most of the herbs and herbal extracts can be 
given orally, which is the most convenient method of 
immunostimulation in a dose dependent approach. Recently, 
carbohydrate-based immunostimulants that target Toll-like 
receptor 4 (TLR-4) and cluster of differentiation 1D (CD1d) 
receptors as vaccine adjuvants are underway. Also, the 
incorporation of immunostimulants into nanomaterials has 
shown a novel approach to enhance the immunostimulation 
properties. However, further studies are needed to identify 
effective immunostimulants without adverse side effects and 
determination of their mechanism of action. 

References 

1. Chaplin DD. Overview of the Immune Response. J Allergy Clin 
Immunol. 2015; 125:1-41. 

2. Meagher MW. Immune system structure and function. Encyclopedia 
of Health Psychology. 2014; 1-9. 

3. Carter D, Reed SG. Role of adjuvants in modeling the immune 
response. Curr Opin HIV AIDS. 2010; 5 (5):409-13. 
https://doi.org/10.1097/COH.0b013e32833d2cdb 

4. Galeotti M. Some aspects of the application of immunostimulants 
and a critical review of methods for their evaluation. J Appl 
Ichthyol. 1998; 14 (3-4): 189-99. https://doi.org/10.1111/j.1439-
0426.1998.tb00641.x 

5. Dhama K, Saminathan M, Jacob SS, Singh M, Karthik K, Amarpal, 
Tiwari R, Sunkara LT, Malik YS, Singh RK. Effect of 
immunomodulation and immunomodulatory agents on health 
with some bioactive principles, modes of action and potent 
biomedical applications. Int J Pharmacol. 2015; 11 (4):253-90. 
https://doi.org/10.3923/ijp.2015.253.290 

6. Schultz KT, Grieder F. Structure and Function of the Immune 
System. Toxicol Pathol. 1987; 15(3):262-264. 
https://doi.org/10.1177/019262338701500301 

7. Rajasekaran A, Venkatasubramanian G, Berk M, Debnath M. 
Mitochondrial dysfunction in schizophrenia: Pathways, 
mechanisms and implications. Neurosci Biobehav Rev. 2015; 
48:10-21. https://doi.org/10.1016/j.neubiorev.2014.11.005 

8. Marshall JS, Warrington R, Watson W, Kim HL. An introduction to 
immunology and immunopathology. Allergy, Asthma Clin 
Immunol. 2018; 14:49-59. https://doi.org/10.1186/s13223-018-
0278-1 

9. Cruvinel WDM, Júnior DM, Antônio J, Araújo P, Tieko T, Catelan T. 
Fundamentals of innate immunity with emphasis on molecular 
and cellular mechanisms of inflammatory response. Bras J 
Rheumatol. 2010; 50(4):434-461. 
https://doi.org/10.1590/S0482-50042010000400008 

10. Marshall JS, Warrington R, Watson W, Kim HL. An introduction to 
immunology and immunopathology. Allergy, Asthma Clin 
Immunol. 2011; 7:1-8. https://doi.org/10.1186/1710-1492-7-S1-
S1 

11. Nielsen HG. Exercise and Immunity. In: Current Issues in Sports 
and Exercise Medicine. 2016. p. 121-42. Available from: 
https://www.intechopen.com/books/advanced-biometric-
technologies/liveness-detection-in-biometrics. 

12. Advances in Exercise Immunology - UQ eSpace. Available from: 
https://espace.library.uq.edu.au/view/UQ:145869. 

13. Turvey SE, Broide DH. Innate Immunity. J Allergy Clin Immunol. 
2010; 125:24-32. https://doi.org/10.1016/j.jaci.2009.07.016 

14. Sattler S. The Role of the Immune System beyond the Fight against 
Infection. 1003rd ed. London: Springer International Publishing; 
2017. p. 3-14. https://doi.org/10.1007/978-3-319-57613-8_1 

15. John H Humphrey SSP. Evolution of the immune system. Encycl Br. 
2020; 1-3. 

https://doi.org/10.1097/COH.0b013e32833d2cdb
https://doi.org/10.1111/j.1439-0426.1998.tb00641.x
https://doi.org/10.1111/j.1439-0426.1998.tb00641.x
https://doi.org/10.3923/ijp.2015.253.290
https://doi.org/10.1177/019262338701500301
https://doi.org/10.1016/j.neubiorev.2014.11.005
https://doi.org/10.1186/s13223-018-0278-1
https://doi.org/10.1186/s13223-018-0278-1
https://doi.org/10.1590/S0482-50042010000400008
https://doi.org/10.1186/1710-1492-7-S1-S1
https://doi.org/10.1186/1710-1492-7-S1-S1
https://doi.org/10.1016/j.jaci.2009.07.016
https://doi.org/10.1007/978-3-319-57613-8_1


Jain et al                                                                                                                                        Asian Journal of Dental and Health Sciences. 2022; 2(4):26-24 

[34]                                                                                                                                                                                                                                                 AJDHS.COM 

16. Travis J. On the Origin of the Immune System. Science. 2009; 
324(5927):580-582. https://doi.org/10.1126/science.324_580 

17. Panda S, Ding JL, Alerts E. Natural Antibodies Bridge Innate and 
Adaptive Immunity. J Immunol. 2015; 194:13-20. 
https://doi.org/10.4049/jimmunol.1400844 

18. Janeway CA JR, Travers P WM. Immuno biology: The Immune 
System in Health and Disease. 5th ed. New York: Garland Science; 
2001. 1-884 pp. 

19. Petrunov B, Nenkov P, Shekerdjiisky R. The role of 
immunostimulants in immunotherapy and immunoprophylaxis. 
Biotechnol & Biotechnol Eq. 2007; 21(4):454-63. 
https://doi.org/10.1080/13102818.2007.10817494 

20. Labh SN, Shakya SR. Application of immunostimulants as an 
alternative to vaccines for health management in aquaculture. Int J 
Fish Aquat St. 2014; 2 (1):153-6. 

21. Patil US, Jaydeokar AV, Bandawane DD. Immunomodulators: A 
pharmacological review. Int J Pharm Pharm Sci. 2012; 4 (1):30-6. 

22. Biswajit D, Suvakanta D, Chandra CR, Jashabir C. An overview of 
levamisole hydrochloride with immunostimulant activity. Am J 
Pharm Health Res. 2014; 2(4):1-9. 

23. Jain M, Jain A, Khare B, Jain DK, Khan R, Jain D. An Update on the 
Recent Emergence of Candida auris. Asian Journal of Dental and 
Health Sciences. 2022; 2(1):14-9. 
https://doi.org/10.22270/ajdhs.v2i1.11 

24. Mathe G. Bestatin, an aminopeptidase inhibitor with a 
multipharmacological function. Biomed Pharmacoter. 1991; 
45:49-54. https://doi.org/10.1016/0753-3322(91)90122-A 

25. Sirko A, Vanek T, Gora-Sochacka A, Redkiewicz P. Recombinant 
cytokines from plants. Int J Mol Sci. 2011; 12 (6):3536-52. 
https://doi.org/10.3390/ijms12063536 

26. Sahoo PK, Mukherjee SC. Effect of dietary β-1, 3 glucan on immune 
responses and disease resistance of healthy and aflatoxin B1-
induced immunocompromised rohu (Labeo rohita Hamilton). Fish 
Shellfish Immunol. 2001; 11 (8):683-95. 
https://doi.org/10.1006/fsim.2001.0345 

27. Madrigal-Bujaidar E, Morales-González JA, Sánchez- Gutiérrez M, 
Izquierdo-Vega JA, Reyes-Arellano A, Álvarez- González I, Pérez-
Pasten R, Madrigal-Santillán E. Prevention of aflatoxin B1-induced 
DNA breaks by β-D-glucan. Toxins (Basel). 2015; 7 (6):2145-58. 
https://doi.org/10.3390/toxins7062145 

28. Vetvicka V. Glucan-immunostimulant, adjuvant, potential drug. 
World J Clin Oncol. 2011; 2 (2):115-9. 
https://doi.org/10.5306/wjco.v2.i2.115 

29. Zhou LD, Zhang QH, Zhang Y, Liu J, Cao YM. The shiitake 
mushroom-derived immuno-stimulant lentinan protects against 
murine malaria blood-stage infection by evoking adaptive 
immune-responses. Int Immunopharmacol. 2009; 9(4):455-62. 
https://doi.org/10.1016/j.intimp.2009.01.010 

30. Sajeevan TP, Philip R, Bright Singh IS. Dose/frequency: A critical 
factor in the administration of glucan as immunostimulant to 
Indian white shrimp Fenneropenaeus indicus. Aquaculture. 2009; 
287(3):248-52. 
https://doi.org/10.1016/j.aquaculture.2008.10.045 

31. Parant M, Audibert F, Parant F, Chedid L, Soler E, Polonsky J, 
Lederer E. Non-specific immunostimulant activities of synthetic 
Trehalose-6, 6'-Diesters (Lower Homologs of Cord Factor). Infect 
Immun. 1978; 20 (1):12-9. https://doi.org/10.1128/iai.20.1.12-
19.1978 

32. Oswald IP, Dozois CM, Petit JF, Lemaire G. Interleukin-12 synthesis 
is a required step in Trehalose Dimycolate-induced activation of 
mouse peritoneal macrophages. Infect Immun. 1997; 65 (4):1364-
9. https://doi.org/10.1128/iai.65.4.1364-1369.1997 

33. Jat D, Thakur N, Jain DK, Prasad S, Yadav R. Iris ensata Thunb: 
Review on Its Chemistry, Morphology, Ethno Medical Uses, 
Phytochemistry and Pharmacological Activities. Asian Journal of 
Dental and Health Sciences. 2022; 2(1):1-6. 
https://doi.org/10.22270/ajdhs.v2i1.9 

34. Frech SA, Kenney RT, Spyr CA, Lazar H, Viret JF, Herzog C, Glück R, 
Glenn GM. Improved immune responses to influenza vaccination 
in the elderly using an immunostimulant patch. Vaccine. 2005; 23 
(7):946-50. https://doi.org/10.1016/j.vaccine.2004.06.036 

35. Davtyan H, Ghochikyan A, Hovakimyan A, Petrushina I, Yu J, Flyer 
D, Madsen PJ, Pedersen LO, Cribbs DH, Agadjanyan MG. 
Immunostimulant patches containing Escherichia coli LT enhance 
immune responses to DNA- and recombinant proteinbased 
Alzheimer's disease vaccines. J Neuroimmunology. 2014; 268 (1-
2):50-7. https://doi.org/10.1016/j.jneuroim.2014.01.002 

36. Mkrtichyan M, Ghochikyan A, Movsesyan N, Karapetyan A, 
Begoyan G, Yu J, Glenn GM, Ross TM, Agadjanyan MG, Cribbs DH. 
Immunostimulant adjuvant patch enhances humoral and cellular 
immune responses to DNA immunization. DNA Cell Biol. 2008; 27 
(1): 19-24. https://doi.org/10.1089/dna.2007.0639 

37. Garçon N, Leroux-Roels G, Cheng WF. Understanding modern 
vaccines: Perspectives in Vaccinology. Elsevier BV. 2011; 1: 89-
113. https://doi.org/10.1016/j.pervac.2011.05.004 

38. Pasquale AD, Preiss S, Da Silva FT, Garçon N. Vaccine adjuvants: 
from 1920 to 2015 and Beyond. Vaccines (Basel). 2015; 3 (2):320-
43. https://doi.org/10.3390/vaccines3020320 

39. Mizumoto N, Gao J, Matsushima H, Ogawa Y, Tanaka H, Takashima 
A. Discovery of novel immunostimulants by dendritic-cell based 
functional screening. Blood. 2005; 106 (9):3082-9. 
https://doi.org/10.1182/blood-2005-03-1161 

40. Khatri S, Jain DK. Autism spectrum disorder (ASD): past, present 
and future. CIBTech Journal of Pharmaceutical Sciences. 2018; 
7(4):1-25. 

41. Bairwa MK, Jakhar JK, Satyanarayana Y, Reddy AD. Animal and 
plant originated immunostimulants used in aquaculture. J Nat 
Prod Plant Resour. 2012; 2(3):397-400. 

42. Bolhassani A, Khavari A, Bathaie SZ. Saffron and natural 
carotenoids: Biochemical activities and anti-tumor effects. 
Biochim Biophys Acta. 2014; 1845:20-30. 
https://doi.org/10.1016/j.bbcan.2013.11.001 

43. Khavari A, Bolhassani A, Alizadeh F. Chemoimmunotherapy using 
saffron and its ingredients followed byE7-NT (gp96) DNA vaccine 
generates different anti-tumor effects against tumors expressing 
the E7 protein of human papillomavirus. Arch Virol. 2015; 160(2): 
499-508. https://doi.org/10.1007/s00705-014-2250-9 

44. Bolhassani A. Cancer chemoprevention by natural carotenoids as 
an efficient strategy. Anticancer Agents Med Chem. 2015; 
15(8):1026-31. 
https://doi.org/10.2174/1871520615666150302125707 

45. Mastan SA. Use of immunostimulants in aquaculture disease 
management. Int J Fish Aquat St. 2015; 2(4):277-80. 

46. Chen WR, Sarker A, Liu H, Naylor MF, Nordquist RE. Effects of 
immunostimulants in phototherapy for cancer treatment. 
Biophotonics and Immune Responses IV. 2009; 71780A. 
https://doi.org/10.1117/12.808019

 

 

 

https://doi.org/10.1126/science.324_580
https://doi.org/10.4049/jimmunol.1400844
https://doi.org/10.1080/13102818.2007.10817494
https://doi.org/10.22270/ajdhs.v2i1.11
https://doi.org/10.1016/0753-3322(91)90122-A
https://doi.org/10.3390/ijms12063536
https://doi.org/10.1006/fsim.2001.0345
https://doi.org/10.3390/toxins7062145
https://doi.org/10.5306/wjco.v2.i2.115
https://doi.org/10.1016/j.intimp.2009.01.010
https://doi.org/10.1016/j.aquaculture.2008.10.045
https://doi.org/10.1128/iai.20.1.12-19.1978
https://doi.org/10.1128/iai.20.1.12-19.1978
https://doi.org/10.1128/iai.65.4.1364-1369.1997
https://doi.org/10.22270/ajdhs.v2i1.9
https://doi.org/10.1016/j.vaccine.2004.06.036
https://doi.org/10.1016/j.jneuroim.2014.01.002
https://doi.org/10.1089/dna.2007.0639
https://doi.org/10.1016/j.pervac.2011.05.004
https://doi.org/10.3390/vaccines3020320
https://doi.org/10.1182/blood-2005-03-1161
https://doi.org/10.1016/j.bbcan.2013.11.001
https://doi.org/10.1007/s00705-014-2250-9
https://doi.org/10.2174/1871520615666150302125707
https://doi.org/10.1117/12.808019

