ADJUVANTS
Substances that can enhance the immune response to an immunogen
(antigen) are called adjuvants. They are not antigenic by themselves and
alone cannot initiate any immune response by themselves. Adjuvants have
the capability of stimulating the rapid and sustained production of high
titers of antibodies with high avidity and influencing some properties
of cell-mediated immunity. The use of adjuvants is required for many
antigens which by themselves are weakly immunogenic. The
action of adjuvants include:
- Enhance long-term release of the antigen by functioning as a depot.
Slow release of antigen stimulates the immune system for long
durations.
- Increases the number of cells involved in immune response.
- Adjuvants may act as non-specific mediators of immune cell function
by stimulating or modulating immune cells.
- Provides more efficient processing of antigen.
- Adjuvants may also enhance macrophage phagocytosis after binding the
antigen.
- Increase the rate of synthesis and release of antibodies.
- Stimulates the production of cytokines
Types of adjuvants:
-
Repository adjuvants: These include
aluminum (aluminum hydroxide, aluminum phosphate) and calcium
(calcium alginate) salts. The salts combine with antigen to form
an insoluble complex that slows the release of antigen from the
site of subcutaneous or intramuscular injection. It aggregates
proteins to make them easier for phagocytes to engulf. Most
frequently used as adjuvants for vaccine antigen delivery.
Generally weaker adjuvants than emulsion adjuvants. Best used with
strongly immunogenic antigens. Generally produce mild inflammatory
reactions.
-
Water-in-oil emulsions: The emulsified
adjuvant allows slow release of antigen from oil droplets. Since
there is variety in droplet size, the droplets are degraded at
different rates resulting in prolonged presence of antigen.
Antigen in oil droplet are more easily phagocytosed than soluble
antigen. Example: Freund's incomplete antigen. Incomplete Freund's
adjuvant is used for the booster immunizations following the
initial injection with antigen-CFA. May be used for initial
injection if the antigen is strongly immunogenic. Freund's
complete adjuvant (CFA) is Freund's incomplete adjuvant and 0.5
mg/ml of killed Mycobacteria. The paraffin oil is not metabolized;
it is either expressed through the skin (via a granuloma or
abscess) or phagocytized by macrophages. The Mycobacteria induce
granuloma formation at the site of injection. The granuloma
further slows the release of antigen because it is a physical
barrier. The component of the mycobacteria responsible for the
adjuvant effect is muramyl dipeptide, which probably act mainly by
stimulating cytokine production. This is not recommended for use
in humans because the granuloma may be disfiguring. Montanide
Incomplete seppic adjuvant is a mineral oil adjuvant. Other
water-in-oil adjuvant systems are Ribi Adjuvant System, TiterMax
and Syntex Adjuvant Formulation.
-
Nitrocellulose-adsorbed antigen: The
nitrocellulose is basically inert, leading to almost no
inflammatory response. Slow degradation of nitrocellulose paper
allows prolonged release of antigen. Does not produce as dramatic
an antibody response as CFA.
-
Lipopolysaccharide (endotoxin): Endotoxins
of gram negative bacteria may be used as adjuvant. These agents
enhance the IgM response, the exact mechanism of which is not
known. It is not recommended for human use because it induces
fever.
-
Bordetella pertussis: This bacterium
is another adjuvant that increases the amount of IgM produced. In
addition, Bordetella can mobilize T and B cells to site of
injection, thereby enhancing immune response.
-
Immune-stimulating complexes (ISCOMs) are
antigen modified saponin/cholesterol micelles. Both cell-mediated
and humoral immune responses are elicited and has low toxicity.
They stimulate cellular immune responses by delivering antigen to
the cytoplasm of antigen-presenting cells. Liposomes can also be
used as they are based on similar principle.
-
BCG: Nonspecific immune stimulation of
cancer patients with adjuvants such as BCG has been tried for many
years. Typically, the adjuvant would be injected at the site of
the tumor in hopes of activating macrophages and promoting
macrophage-mediated tumor cell killing.
-
L-tyrosine: A co-precipitate of the amino
acid and antigen has been shown to have excellent adjuvant
properties, even surpassing Freund's complete adjuvant in some
circumstances.
Side-effects: Many of the adjuvants have
the capacity to cause inflammation, tissue necrosis and pain in animals.
Adjuvants are known to be able to break tolerance to antigens including
self antigens. They may also be responsible for production of "adjuvant
diseases" such as allergic disseminated encephalomyelitis. Multiple
exposures to CFA will cause severe hypersensitivity reactions.
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