This document discusses immunostimulants, which are substances that stimulate the immune system. It describes several types of immunostimulants including adjuvants, bacterial products like BCG, recombinant cytokines like interferon and interleukin, complex carbohydrates like glucans, and plant-derived substances. Specific examples are provided for each category along with their mechanisms of action and effects on the immune system. Common immunostimulatory drugs like levamisole and isoprinosine are also explained in detail.

1. IMMUNOSTIMULANT

2. Introduction
• Immunostimulants, also known as immunostimulators, are substances (drugs and
nutrients) that stimulate the immune system by inducing activation or increasing
activity of any of its components.
• 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 antigen.

3. Concept of Immunostimulant
Immunostimulants are 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.
In general, Immunostimulants induce synthesis of specific antibodies and cytokines for
treatment of infectious diseases.
Examples of immunostimulant-
Bacillus Calmette Guerin, Bacterial products act by Enhancement of B and T cell-
mediated responses leading to phagocytosis, and resistance to infection
Levamisole act by Induction of B and T lymphocytes, monocytes, and macrophages
Thalidomide Drugs - Therapeutic effects in rheumatoid arthritis and angiogenesis
Recombinant cytokines - Generation of interferon and interleukins to stimulate effective
immune responses

4. Classification
There are two main categories of immunostimulants:
Specific immunostimulants provide antigenic specificity in immune response,
such as vaccines or any antigen
Non-specific immunostimulants act irrespective of antigenic specificity to
augment immune response of other antigen or stimulate components of the
immune system without antigenic specificity, such as adjuvants and non-
specific immunostimulators.

5. Immunostimulant
Immunostimulatory drugs
Ex- Levamisole,
Thalidomide, Isoprinosin
Bacterial products
Ex- BCG
Recombinant Cytokines
Ex- Interleukin, Interferon
Complex carbohydrates
Ex- Glucans, Trehalose
Prebiotics
Ex-
Fructooligosaccharides,
Inulin
Plant derived
immunostimulant
Ex- Tulsi, Amla, Neem,
Saffron

6. Immunostimulatory Drug
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
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 mouth .
Side effects are allergy, nausea, flu, and muscle pain.

7. Isoprinosine (Inosiplex/ Imunovir)
 Isoprinosine is a combination of inosine, acetamidobenzoic acid, and
dimethylaminoisopropanol.
Isoprinosine stimulates biochemical processes in macrophages, increases the
production of interleukin, increased synthesis of antibodies, enhances the
proliferation of T-lymphocytes, natural killer cells.
It stimulates the chemotactic and phagocytic activity of monocytes,
macrophages and polymorphonuclear cells.
 Isoprinosine inhibits the replication of DNA and RNA viruses by binding with
ribosome cells and changes its stereochemical structure.

8. Indication-
Immunodeficiency, accompanied by the development of diseases, caused by the Herpes
simplex virus, Varicella zoster, measles virus, Epstein-Barr virus,
 the development of subacute sclerosing panencephalitis
 acute viral encephalitis
Side effect
Metabolism: transient increase in uric acid in the serum and urine
digestive system: nausea, vomiting, epigastric pain, constipation, diarrhea, a temporary
increase in liver transaminases.
Dermatological reactions: xerosis.
Allergic reactions: skin rash, itch.
CNS: headache, dizziness, nervousness, sleep disorders (drowsiness, insomnia),
slackness, a feeling of fatigue.
Other: polyuria, joint pain, worsening of gout, weakness.

9. Bacterial products
BCG (Bacillus Calmette–Guérin)
BCG vaccine is primarily used against tuberculosis (TB).
The vaccine was developed over a period of 13 years, from 1908 to 1921, by
French bacteriologists Albert Calmette and Camille Guérin who named the
product Bacillus Calmette-Guérin, or BCG.
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.

10. BCG enhances both B and T cell-mediated responses leading to phagocytosis
and resistance to infection.
BCG is given as a single intradermal injection at the insertion of the deltoid.
If BCG is accidentally given subcutaneously, then a local abscess may form (a
"BCG-oma") that can sometimes ulcerate, and may require treatment
with antibiotics immediately.
Its side effects are hypersensitivity, fever, shock, and immune complex
disease.
Use of the BCG vaccine may provide protection against COVID-19. However,
epidemiologic observations in this respect are ambiguous. The WHO does not
recommend its use for prevention as of 12 January 2021.
As of January 2021, twenty BCG trials are in various clinical stages.

11. Recombinant Cytokines
Cytokines are a group of proteins involved in the innate and adaptive immune
systems.
Recombinant cytokines are generally designed to enhance immunity either by
achieving generalized immunostimulation or stimulating specific immune cells.
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

12. On the other hand, vaccination of animals with the recombinant IL2
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.

13. Complex carbohydrates
Several types of the complex carbohydrates were described as follows
Glucans
Glucans is 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.
Glucan might also be helpful to prevent the carcinogenic effects of aflatoxin.
β-glucan was considered as a stimulator of cellular immunity.

14. 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.
Ocimum sanctum (Tulsi): Leaves of O. sanctum containing water-soluble
phenolic compounds and various other constituents may act as an
immunostimulant.
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 immunostimulant .
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