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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5992_Библиотеки_им_академика_М_И_Перельмана.pdf
INTRODUCTION
Immune System
The word immune in Latin refers to ‘protection’. The immune system of body is a built-in protection
against attack by foreign substances known as antigens. An antigen is a substance that causes the
body to attack and induce an immune response. Examples of antigens include bacteria or viruses.
Unfortunately, the immune system does not discriminate between harmful foreign substances (such
as bacteria and viruses) and transplanted organs.
Immunity is defined as the resistance to disease, especially infectious disease. The collection
of cells and molecules that mediate resistance to infection is referred to as immune system. The
coordinated reaction of these cells and molecules to infectious microbe is known as immune
response. The physiological function of the immune system is to prevent infection and to eradicate
established infections.
Edward Jenner (1778) observed that milkmaids, who developed cowpox, were immune to
smallpox. The classic work of Russian scientist Elie Metchnikoff (1845–1916) is credited with
the biological hypothesis that marked a new stage in the history of immunobiology. Louis Pasteur
(1822–95) developed vaccines for anthrax and rabies. Paul Ehrlich (1854–1915) reported that
certain substances in the blood serum secreted by special cells under the influence of microbes and
their toxins contribute to the defence mechanism of human body.
Immunology and Immunological
Preparations
2
CHAPTER
Introduction
How the Immune System Works
Principles
Types of Immune System
Immune Tolerance
Hypersensitivity
Antigen–Antibody Reactions and
Their Applications
Immunomodulators
Applications of Immunomodulators
Vaccines
Questions
Textbook of Pharmaceutical Biotechnology
16
A transplanted organ is seen by the immune system of the body as a foreign substance that needs
to be eliminated. To protect the transplanted organ from attack, medications are used to suppress
or hold back the body’s immune response. These medications are known as immunosuppressants,
e.g. Neoral, Prograf, OKT3, Imuran, prednisone, Cellcept and rapamycin.
HOW THE IMMUNE SYSTEM WORKS
The immune system is able to differentiate between substances that belong to our body and those
that are foreign. Once a substance is recognized as foreign, the immune system tries to eliminate it
from the body. It is therefore a practice that immunosuppressant medications must be administered
after an organ transplant. A basic understanding of the immune system helps us understand why
taking these medications as instructed is critical to the success of organ transplant.
Lymphocytes are white blood cells primarily responsible to defend our immune system. These
are the only cells in the body that have the ability to recognize specific antigens (foreign substances).
There are different kinds of lymphocytes in the body. B lymphocytes react to antigens in solution
such as blood. T lymphocytes react against infected or foreign cells such as a transplanted organ.
The different cells of the immune system working together to resist or overcome an infection in the
body are given in Figure 2.1.
Figure 2.1 Structure of immune system.
Leukocyte
activation
Tolerance
induction
Leukocyte
migration
Immune
system
development
Immune
response
Antigen
processing
and
presentation
Activation
of
immune
response
Somatic
diversification
of immune
response
Leukocyte
homeostasis
Immune
affecters
process
Innate
immune
response
Humoral
immune
response
Inflamma-
tory
response
Immune
response to
tumour cell
Adaptive
immune
response
Organs or
tissue-
specific
response
Immune system process
Biological process
Immunology and Immunological Preparations
17
T and B lymphocytes are present in all the tissues in human body. They remain inactive until
they recognize a specific antigen. The receptors on the surface of lymphocytes bind with the antigen.
When this coupling takes place, the immune response is initiated and the lymphocyte destroys the
antigen. Immunosuppressant agents prevent the lymphocyte and the antigen from binding, therefore
preventing the immune system from destroying the transplanted organ.
Organs of Immune System
A number of organs are involved in the development of an immune response, and they impart
different functions (Fig. 2.2).
Different organs of the body play their roles in the development of an immune system.
Lymphoid System
These organs provide appropriate microenvironment for the development and maturation of
antigen-sensitive lymphocytes. Maturation of T lymphocytes occurs in the thymus, whereas that
of B lymphocytes takes place in the bone marrow. Secondary lymphocytes are the sites for the
initiation of immune response, e.g. spleen, tonsils, lymph nodes, appendix, etc.
Cells of the Immune System (Fig. 2.3)
Two types of lymphocytes occur, namely B cells and T cells.
1. B lymphocytes (B cells): B cells are produced in the bone marrow. They constitute a major
class of lymphocytes producing immunoglobulin, and they are primarily involved in humoral
Tonsils and
adenoids
Lymph
nodes
Appendix
Bone
marrow
Lymphatic
vessels
Lymph
nodes
Peyer’s
patches
Spleen
Thymus
Lymph
nodes
Lymphatic
vessels
Figure 2.2 Organs of immune system in human body.
Textbook of Pharmaceutical Biotechnology
18
immunity. The B cells possess the capability to specifically recognize each antigen and
produce antibodies against it.
2. T lymphocytes (T cells): T cells are also produced in the bone marrow but leave the bone
marrow and mature in the thymus. T cells belong to a group of white blood cells known as
lymphocytes that play a crucial role in the cell-mediated immunity. They can be differentiated
from other lymphocyte types, such as B cells and natural killer cells (NK cells), by the presence
of a special receptor on their cell surface T-cell receptor (TCR). The abbreviation T in ‘T cell’
represents thymus, which is the principal organ responsible for the maturation of T cells.
T cells are broadly of the following four types:
a. Inducer T cells: These cells mediate the development of T cells in the thymus. Suppressor–
inducer T cells are a specific subset of CD4
+
T helper cells that ‘induce’ CD8
+
cytotoxic T
cells to become ‘suppressor’ cells. Suppressor T cells are also known as CD25
+
–Foxp3
+
regulatory T cells (nTregs), and they reduce inflammation.
b. Cytotoxic T cells: These cells are capable of recognizing and killing the infected or abnormal
cells. Cytotoxic T cells (T
C
cells or CTLs) destroy virally infected cells and tumour cells
and are also implicated in transplant rejection. These cells are also known as CD8
+
T cells,
since they express the CD8
+
glycoprotein at their surface.
c. Helper T cells: These cells initiate immune response. They assist other white blood cells
in immunologic processes, including maturation of B cells into plasma cells and activation
of cytotoxic T cells and macrophages. These cells are also known as CD4
+
T cells as they
express the CD4 protein on their surface. On activation, these cells divide rapidly and
secrete small proteins known as cytokines that regulate or assist in the active immune
response. These cells can differentiate into one of several subtypes, including T
H
1, T
H
2,
T
H
3, T
H
17 or T
FH
, which secrete different cytokines to facilitate a different type of immune
response.
d. Suppressor T cells: These cells, also known as regulatory T cells, mediate the suppression
of immune response and play a critical role in the vertebrate immune system. They
are specialized subpopulation of T cells that act to suppress activation of the immune
system and thereby maintain immune system homeostasis and tolerance to self- antigens.
The immunosuppressive potential of these cells can be harnessed therapeutically to
treat autoimmune diseases and also to facilitate transplantation tolerance and in cancer
immunotherapy.
B lymphocytes (B cells)
Inducer T cells Cytotoxic T cells Helper T cells Suppressor T cells
T lymphocytes (T cells)
Cells of immune system
Figure 2.3 Cells of immune system.
Immunology and Immunological Preparations
19
Human Immunoglobulins
Immunoglobulins are group of proteins capable of mediating humoral immunity. Immunoglobulins
are of five different types (Table 2.1).
1. Immunoglobulin A ( IgA): It occurs as a single or double unit held together by J chain. It
is mostly found in the body secretion, such as saliva, tears, sweat, milk, etc. It is capable of
preventing the foreign substances from entering into the body cells.
2. Immunoglobulin D (IgD): It is composed of a single Y-shaped unit. It is present in a low
concentration in the circulation, and it functions as B-cell receptor.
3. Immunoglobulin E ( IgE): The molecules of IgE tightly bind with mast cells that release
histamines and cause allergy. It is normally present in very low concentration in blood.
4. Immunoglobulin G ( IgG): It is the most abundant (75–80%) class of immunoglobulin. It is
the only immunoglobulin capable of crossing the placenta and transferring the immunity of
mother to the developing fetus.
5. Immunoglobulin M (IgM): It is the first antibody to be produced in response to an antigen
and is the most effective against attacking microorganism. It is the largest immunoglobulin
composed of five Y-shaped units held together by a polypeptide chain.
PRINCIPLES
Innate Immunity
Innate immunity is a type of host defence that is always present in healthy individuals. It is prepared
to block the entry of microbes and rapidly eliminate them if they succeed in entering host tissue. The
main components of innate immunity are physical barriers, soluble mediators capable of directly
inhibiting foreign microorganisms and specialized cells endowed with recognition receptors and
the ability to phagocytise and kill microorganisms.
Physical barriers are sometimes underestimated as part of the immune system. An intact skin
offers very effective protection from infection. The superficial wounds can be easily colonized
by foreign invaders. In addition to skin, the other physical barriers are (1) the blood coagulation
system that stops bleeding and forms a protective clot over wounds and (2) internal mucosae that
is protected by mucus and continuously cleansed by the action of ciliated cells that sweep away
bacteria and other materials. The mildly acidic pH of skin inhibits bacterial proliferation, and very
acidic pH of stomach juices sterilize ingested material.
Table 2.1 Human immunoglobulins: Types, molecular weight and functions
Type Molecular weight (Da) Major function
IgA 1,60,000 Protect the body surface
IgD 1,80,000 B-cell receptor
IgE 1,90,000 Humoral sensitivity and histamine release
IgG 1,50,000 Mostly responsible for humoral immunity
IgM 9,00,000 Humoral immunity, serves as first line of defence
Textbook of Pharmaceutical Biotechnology
20
The varieties of soluble molecules present on the skin, in secretions, in blood and throughout
the body kill bacteria and inhibit viral infections. The important examples are (1) defences (natural
antibiotics), (2) the lysozyme (an enzyme that lyses the wall of some bacteria), (3) complement (a
cascade of proteins activated by bacterial components that make holes in bacterial membranes), (4)
opsonins (complement fragments and other proteins that coat bacteria and facilitate phagocytosis)
and (5) some ancient cytokines such as type I interferons that are released by virus infected cells
and induce an antiviral state in neighbouring cells.
The basic cellular mechanisms of innate immunity are cellular migration towards invaders and
phagocytosis followed by intracellular destruction of the ingested microorganism. If phagocytes
release lytic substances in the environment, extracellular killing is also possible. In mammals, the
two main cell types are granulocytes that contain lytic substances packed in intracellular granules
(also known as polymorphonuclear cells because nucleus is of irregular shape) and macrophages.
Neutrophil granulocytes have an important role in defence against bacterial infections, and
basophils have an antiparasitic role. Macrophages derive from circulating monocytes that
emigrate to practically all tissues and organs, sometimes under different names (e.g. Kupffer cells
in the liver). In addition to immune functions, macrophages play important roles in the turnover
of aging cell components, like red blood cells that are continuously phagocytosed by splenic
macrophages. Natural killer (NK) cells are nonphagocytic elements that kill virus-infected cells.
It is worth noting that the evolution of NK cells is relatively recent and goes in parallel with the
evolution of lymphocytes, to which NK cells closely resemble morphologically.
Recognition in innate immunity is mediated by interactions with pathogen-associated
molecular patterns as expressed by microorganisms. The cellular receptors are referred to as
pattern recognition receptors and include toll-like receptors (TLRs), mannose receptors (MRs)
and seven-transmembrane spanning receptors (TM7s). TLR recognizes bacterial and viral nucleic
acids, flagellin, bacterial peptides, lipopolysaccharide (LPS) and other bacterial components.
MRs are capable of binding carbohydrate moieties on several pathogens, such as bacteria, fungi,
parasites and viruses. TM7 receptors are usually activated by bacterial peptides or by endogenous
chemokines.
Adaptive Immunity
Adaptive immunity is a system of host defence that is stimulated by microbes that invade tissues.
It adapts to the presence of microbial invaders.
The evolution of adaptive immunity is related to the evolution of vertebrates, starting from
sharks. It is, therefore, deduced that part of the evolutionary success and long lifespans of vertebrates
could be attributed to improved defences against exogenous pathogens. The functions of adaptive
immunity are performed by a new type of cell (the lymphocyte) that recirculates amongst blood,
tissues and a specialized circulatory system (the lymphatic vessels) and resides in specialized
organs (lymphoid organs, which include thymus, spleen and lymph nodes).
The hallmarks of adaptive immune responses are specificity, immune memory and immune
tolerance. A lymphocyte population is made up of millions of clones, each specific for a different
Immunology and Immunological Preparations
21
antigen. Specificity is encoded in clonotypic antigen receptors generated by a process of DNA
rearrangement that includes random events to produce billions of variant molecules from a relatively
small pool of DNA sequences.
Specificity permits a considerable economy in adaptive immune responses to pathogens. It
is because only the clones expressing receptors for a specific microorganism are activated upon
infection, whereas all other clones remain inactive. In addition to the proliferation of specific
lymphocyte clones, the first encounter with a given antigen (primary immune response) leaves
behind a population of memory cells that respond more promptly and more efficiently to subsequent
encounters (secondary immune response). The presence of random events in the generation of
specific antigen receptors implies the risk of producing autoreactive receptors.
Cellular–Humoral Immunity
The humoral immune response (HIR) is an aspect of immunity that is mediated by secreted antibodies
produced in the cells of the B lymphocyte lineage (B cell). The B cells (with costimulation)
transform into plasma cells that secrete antibodies. The costimulation of the B cell can be from
another antigen-presenting cell, like a dendritic cell. This entire process is aided by CD4
+
T helper
2 cells, which provide costimulation. The secreted antibodies are capable of binding to antigens on
the surfaces of invading microbes (such as viruses or bacteria), which flag them for destruction.
Humoral immunity is so named because it involves substances found in the humors, or body
fluids. Humoral immunity refers to antibody production and the accessory processes that accompany
it, including T
h
2 activation and cytokine production, germinal centre formation and isotype
switching, affinity maturation and memory cell generation. It also refers to the effector functions
of antibody that include pathogen and toxin neutralization, classical complement activation and
opsonin promotion of phagocytosis and pathogen elimination.
TYPES OF IMMUNITY
Immunity can be broadly classified into natural and acquired. They can be further classified into
active and passive.
Natural Immunity
Nature has given certain individuals, species and races some advantage by providing them with
immunity against certain disease. Natural immunity is resistance to a disease possessed by an
individual.
Acquired Immunity
Only with the protection offered by natural immunity it is difficult to survive. Hence, immunity is
provided by stimulating an individual’s antibody production. It is also further classified into active
and passive immunity.
Textbook of Pharmaceutical Biotechnology
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1. Active immunity: Active immunization entails the introduction of a foreign molecule into
the body that causes the body itself to generate immunity against the target. This immunity
comes from the T cells and the B cells with their antibodies.
Active immunization occurs naturally when a person comes in contact with a microbe. If the
person has not come into contact with the microbe earlier and has no premade antibodies for
defence (like in passive immunization), the immune system shall eventually create antibodies
and other defences against the microbe. The next time, the immune response against this
microbe can be very efficient. This is the case in many of the childhood infections that a
person only contracts once, but then is immune to that infection.
Artificial active immunization is where the microbe or parts of it is injected into the person.
If whole microbes are used, they are known as pretreated, attenuated vaccine.
2. Passive immunity: In passive immunization, presynthesized elements of the immune system
are transferred to a person. Hence, the body does not need to produce these elements itself.
The antibodies can be used for passive immunization. This method of immunization begins
to work very quickly, but it is short lasting, because the antibodies are naturally broken down.
Moreover, if there are no B cells to produce more antibodies, they subsequently disappear.
When antibodies are transferred from mother to fetus during pregnancy, passive immunization
occurs physiologically to protect the fetus before and shortly after birth.
Artificial passive immunization is normally administered by injection. It is used if there
has been a recent outbreak of a particular disease or as an emergency treatment for toxicity
(e.g. for tetanus). Although there is a high chance of anaphylactic shock because of immunity
against animal serum itself, the antibodies can be produced in animals (serum therapy). If
available, humanized antibodies produced in vitro by cell culture are preferred.
IMMUNE TOLERANCE
It is the process by which the immune system does not attack an antigen. It can be either ‘natural’
or ‘self-tolerance’, where the body does not mount an immune response to self- antigens or induced
tolerance, tolerance to external antigens may be created by manipulating the immune system. It is
of three types: central tolerance, peripheral tolerance and acquired tolerance.
1. Central tolerance: Central tolerance occurs during lymphocyte development. It operates in the
thymus and bone marrow. The T and B lymphocytes that recognize self- antigens are deleted
before they develop into fully immunocompetent cells, preventing autoimmunity. This process is
most active in fetal life, but continues throughout life as immature lymphocytes are generated.
In mammals, the process occurs in the thymus (T cells) and bone marrow (B cells), when
maturing lymphocytes are exposed to self- antigens. The self- antigens are present in both
organs due to endogenous expression within the organ and importation of antigen due to
circulation from peripheral sites. In case of T cell central tolerance, additional sources of
antigen are made available in the thymus by the action of the transcription factor AIRE.
Immunology and Immunological Preparations
23
Positive selection occurs initially when naive T cells are exposed to antigens in thymus. For
this, T cells that have receptors with sufficient affinity for self-MHC molecules are selected.
Other cells that do not show sufficient affinity to self- antigens shall undergo a deletion process,
known as death by neglect that involves apoptosis of the cells.
Negative selection of T cells with a very high affinity of self-MHC molecules is induced to
energy or lineage divergence to form T regulatory cells.
2. Peripheral tolerance: Peripheral tolerance is a system of immunological tolerance developed
after T and B cells mature and enter the periphery.
3. Acquired tolerance: Acquired or induced tolerance refers to the immune system’s
adaptation to external antigens characterized by a specific nonreactivity of the lymphoid
tissues to a given antigen. One of the most important natural kinds of acquired tolerance is
immune tolerance in pregnancy, where the fetus and the placenta must be tolerated by the
maternal immune system. In adults, tolerance is usually induced by repeated administration
of large doses of antigen. It is most readily induced by soluble antigens administered
either intravenously or sublingually. Immunosuppression also facilitates the induction of
tolerance.
In clinical practice, acquired immunity is important in organ transplantation, when the body must
be forced to accept an organ from another individual. The failure of the body to accept a foreign
organ is known as transplant rejection. To prevent rejection, a variety of medicines are used to
produce induced tolerance.
Oral tolerance is one of the most important forms of acquired tolerance. The specific suppression
of cellular and/or humoral immune reactivity to an antigen with prior administration of the antigen
by oral route is probably evolved to prevent hypersensitivity reactions to food proteins and bacterial
antigens present in the mucosal flora. It is of immense immunological importance, since it is a
continuous natural immunologic event driven by exogenous antigen. Oral tolerance is evolved to
treat external agents that gain access to the body via natural route. The limitation of oral tolerance
is attributed to the development and pathogenesis of several immunologically based diseases,
including inflammatory bowel disease (Crohn’s disease and ulcerative colitis).
HYPERSENSITIVITY
Not all immune responses against an antigen produce a desirable resistance. When the sensitivity
is beyond limits, it is termed as hypersensitivity. When an adaptive immune response occurs in an
exaggerated or inappropriate form causing tissue damage, the condition is termed as hypersensitivity.
Hypersensitivity (also known as hypersensitivity reaction) refers to undesirable (damaging,
discomfort-producing and sometimes fatal) reactions produced by the normal immune system.
Hypersensitivity reactions require a presensitized ( immune) state of the host. The comparative
account of hypersensitivity types is given in Table 2.2.
Textbook of Pharmaceutical Biotechnology
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ANTIGEN–ANTIBODY REACTIONS AND THEIR APPLICATIONS
Antigen
An antigen is a foreign particle that enters the body. This could be a disease-causing agent such as
part of a bacterium or virus or could be a particle such as pollen or dust. When an antigen enters the
body, the immune system produces antibodies against that antigen.
Antibodies
An antibody is a protein made by the body’s immune system. Antibodies react with specific antigens
to enable the antigens to be removed from the body. Antibody binds to specific antigen.
The multicellular organisms have evolved defence mechanisms against the onslaught of viruses,
bacteria and other parasites. The immune system of vertebrates combines evolutionarily innate (or
natural) immunity with newer adaptive responses against specific antigens. The two systems are
tightly integrated, and several molecules and cells, in addition to their fundamental role in one
system, act as interfaces between the two.
Antigen–Antibody Reaction
The antigen– antibody reaction is a bimolecular association similar to an enzyme–substrate
interaction. It is with the distinction that it does not lead irreversible chemical alteration. The
reaction involves various noncovalent interactions between the antigenic determinant or epitope of
the antigen and variable region of the antibody (Fig. 2.4).
Table 2.2 Comparisons of hypersensitivity types
Type Alternative names Often-mentioned disorders Mediators
1 Allergy (immediate) 1. Atopy
2. Anaphylaxis
Asthma
IgE
2 Autoimmune disease, receptor mediated 1. Grave’s disease
2. Myasthenia gravis
IgM or IgG (complement)
3 Immune complex disease 1. Serum sickness
2. Arthus reaction
3. Systemic lupus erythemato-
sus (SLE)
IgG (complement)
4 Delayed-type hypersensitivity (DTH) 1. Contact dermatitis
2. Mantoux test
3. Chronic transplant rejection
T cells
5 Autoimmune disease, receptor mediated 1. Grave’s disease
2. Myasthenia gravis
IgM or IgG (complement)
Abbreviations: IgE, immunoglobulin E; IgG , immunoglobulin G; IgM, immunoglobulin M; SLE, systemic lupus erythematosus.