IMMUNOLOGY- MCB 301

TISSUE TRANSPLANTATION/GRAFTING

Transplant, also called graft or organ transplant, in medicine, is a section of tissue or a complete organ
that is removed from its original natural site and transferred to a new position in the same person or in a
separate individual. The term, like the synonym graft, was borrowed from horticulture. Both words
imply that success will result in a healthy and flourishing graft or transplant, which will gain its
nourishment from its new environment.

Transplantation/Grafting - is a surgical procedure in which an organ/s, tissue or a group of cells are

removed from one person (the donor) and surgically transplanted into another person (the recipient), or
moved from one site to another site in the same person. Organ and tissue donation and transplantation
– can save lives. They can also restore function to improve quality of life. For example, transplanting the
clear tissue that covers the eye (cornea) can restore sight.
Types of transplantation
Transplantation is a complex area of medicine because when organs or tissues are transplanted from
one person to another, the recipient’s immune system can reject and destroy the donor organ or tissue,
and medication is needed to supress this immune response. The treatments used vary depending on the
tissue or organ being transplanted, the level of compatibility between the donor and the recipient, and
other factors.
A. Transplants of tissues in the same person
A transplant from one part of your body to another part is called an autograft and the process is called
autotransplantation.
Some examples of autografts include:
1. skin graft – uses healthy skin to help heal a wound or burn on another part of the body
2. blood vessel graft – provides an alternative route for blood flow to bypass a blocked artery, for
example, in heart bypass surgery
3. bone graft – reconstructs a damaged area of the body, for example, in spinal fusion
4. bone marrow graft – for example, in a person with cancer, bone marrow collected before
chemotherapy can replace their blood stem cells after high-dose chemotherapy.
The advantage of an autograft is that the person’s body is unlikely to reject their own cells, so long-term
medication to suppress the immune system (immunosuppressants) is not needed. However, the
retrieval (collecting) of the tissue creates a new wound in addition to the transplant site, from which the
person will need to recover.
B. Transplants from other people
A transplant between two people who are not genetically identical is called an allotransplant and the
process is called allotransplantation. Donor organs and tissues can be from people who are living, or
people who have died because of a significant brain injury or lack of circulation.

Allotransplantation can create a rejection process where the immune system of the recipient attacks the
foreign donor organ or tissue and destroys it. The recipient may need to take immunosuppressive
medication for the rest of their life to reduce the risk of rejection of the donated organ.

1
For some transplants (especially bone marrow), there is also the possibility that immune cells in the
donated bone marrow will recognise the host’s body as foreign and attack the cells of the host. This is
known as graft-versus-host disease (GvHD). Doctors can take steps to try to reduce the risk of GvHD.
A transplant between identical twins is called an isograft. The recipient will almost never reject an
isograft and so immunosuppressants are not needed.
For around 1,900 Australians currently on the organ transplant waitlist, it can be a matter of life and
death. There are an additional 13,500 people on dialysis, some of whom may benefit from a kidney
transplant. One organ donor can save up to 7 lives and help many more through eye and tissue
donation.
C. Transplants from other species
A transplant between species is called a xenotransplant and the process is called xenotransplantation.
Heart valves from cows and pigs have been used for many years to replace faulty heart valves in people.
The animal valves are treated before use to reduce the risk of the immune system rejecting the valve.
Heart valves may also be replaced with human valves (allotransplant) or mechanical heart valves.
Organs and tissues transplanted
Transplants can be for:
[Link] – heart, kidney, liver, lung, pancreas, stomach and intestine
2. tissue – cornea, bone, tendon, skin, pancreas islets, heart valves, nerves and veins
3. cells – bone marrow and stem cells
4. limbs – hands, arms and feet.
5. Multi-organ transplants, while less common than single-organ transplants, occur each year. Common
multi-organ transplants include heart and lungs, or pancreas and kidney. The approach to
transplantation varies greatly depending on the type of transplant.

Rejection mehanisms
Humans possess complex defense mechanisms against bacteria, viruses, and other foreign materials
that enter the body. These mechanisms, which collectively make up the immune system, cannot,
unfortunately, differentiate between disease-causing microorganisms and the cells of a lifesaving
transplant. Both are perceived as foreign, and both are subject to attack by the immune system. This
immune reaction leads to rejection, the greatest problem in successful tissue and organ grafting.
Immune responses
human T cell
In order to understand why rejection occurs and how it may be prevented, it is necessary to know
something of the operations of the immune system. The key cells of the immune system are the white
blood cells known as lymphocytes. These are of two basic types: T lymphocytes (T cells) and B
lymphocytes (B cells). These cells have the capacity to distinguish “self” substances from such “nonself”
substances as microorganisms and foreign tissue cells. Substances that provoke an immune reaction are
recognized by the presence of certain molecules, called antigens, on their surface.
T lymphocytes are responsible for cell-mediated immunity, so named because the T cells themselves
attach onto the antigens of the invader and then initiate reactions that lead to the destruction of the
nonself matter. B lymphocytes, on the other hand, do not directly attack invaders. Rather, they produce

2
antibodies, proteins that are capable of initiating reactions that weaken or destroy the foreign
substance. The overall immune reaction is exceedingly complex, with T lymphocytes, B lymphocytes,
macrophages (scavenger cells), and various circulating chemicals waging a coordinated assault on the
invader.

Transplant rejection is generally caused by cell-mediated responses. The process usually occurs over
days or months, as the T lymphocytes stimulate the infiltration and destruction of the graft. The
transplant may be saved if the cell-mediated reactions can be suppressed. Antibody attack of
transplanted tissues is most apparent when the recipient has preexisting antibodies against the antigens
of the donor. This situation can arise if the recipient has been previously exposed to foreign antigens as
the result of pregnancy (during which the mother is exposed to fetal antigens contributed by the father),
blood transfusions, or prior transplants. Unlike a cell-mediated reaction, antibody-mediated rejection is
rapid, occurring within minutes or hours, and cannot be reversed.
Selection of donor and tissue matching
The factors that provoke graft rejection are called transplantation, or histocompatibility, antigens. If
donor and recipient have the same antigens, as do identical twins, there can be no rejection. All cells in
the body have transplantation antigens except the red blood cells, which carry their own system of
blood-group (ABO) antigens. The main human transplantation antigens—called the major
histocompatibility complex, or the HLA (human leukocyte antigens) system—are governed by genes on
the sixth chromosome. HLA antigens are divided into two groups: class I antigens, which are the target
of an effector rejection response; and class II antigens, which are the initiators of the rejection reaction.
Class II antigens are not found in all tissues, although class I antigens are. Certain macrophagelike tissue
cells—called dendritic cells because of their finger-like processes—have a high expression of class II
antigens. There has been much interest in trying to remove such cells from an organ graft, so that the
rejection reaction will not be initiated.

Tissue typing involves the identification of an individual’s HLA antigens. Lymphocytes are used for
typing. It is important also that the red blood cells be grouped, since red-cell-group antigens are present
in other tissues and can cause graft rejection. Although transplantation antigens are numerous and
complicated, the principles of tissue typing are the same as for red-cell grouping. The lymphocytes being
typed are mixed with a typing reagent, a serum that contains antibodies to certain HLA antigens. If the
lymphocytes carry HLA antigens for which the reagent has antibodies, the lymphocytes agglutinate
(clump together) or die. Typing serums are obtained from the blood of persons who have rejected grafts
or have had multiple blood transfusions or multiple pregnancies; as previously stated, such persons may
develop antibodies to transplantation antigens.
If the lymphocytes of both the recipient and the potential donor are killed by a given serum, then, as far
as that typing serum is concerned, the individuals have antigens in common. If neither donor nor
recipient lymphocytes are affected, then donor and recipient lack antigens in common. If the donor
lymphocytes are killed but not those of the recipient, then an antigen is present in the donor and is
missing from the recipient. Thus, by testing their lymphocytes against a spectrum of typing sera, it is
possible to determine how closely the recipient and donor match in HLA antigens. As a final precaution
before grafting, a direct crossmatch is performed between the recipient’s serum and donor

3
lymphocytes. A positive crossmatch usually contraindicates the donor–recipient transplant under
consideration.
There is now considerable knowledge concerning the inheritance of transplantation antigens, but, even
so, tissue typing is not sufficiently advanced to give an accurate prediction of the outcome of a graft in
an individual case, particularly when the donor and recipient are not related to one another. In
accordance with Mendelian laws of inheritance, a person obtains one of a pair of chromosomes from
each parent. Therefore, a parent-to-child transplant will always be half-matched for transplantation
antigens. Siblings have a one-in-four chance of a complete match of the HLA antigens, a one-in-four
chance of no match, and a one-in-two chance of a half-match.
The blood transfusion effect
Following a blood transfusion, some patients become sensitized to the transplantation antigens of the
donor, so it was expected that prior blood transfusion could only harm the recipient’s prospects for a
successful organ graft. Careful analysis of results, however, showed the contrary. Specifically, the results
of kidney grafting in patients who had received previous blood transfusions without regard to HLA
matching were much better than in patients who had never received a blood transfusion. Although a
great deal of effort has been expended to determine the mechanisms involved, researchers still do not
know how the immune system is modified by prior blood transfusions. Most centres now give blood
transfusions before transplantation, though some patients do develop HLA antibodies against a wide
spectrum of the population and therefore become very difficult to transplant. This pool of highly
sensitized patients is getting larger throughout the world, not only from blood transfusions but also from
patients who have rejected kidney grafts and are back on dialysis and from women who have had
multiple pregnancies.
A special application of the blood transfusion effect involves repeated small blood transfusions from a
potential donor who is a close relative of the patient. If sensitization does not occur, subsequent kidney
graft results are excellent. Some patients, however, develop a positive crossmatch to donor lymphocytes
and cannot receive a graft from that donor. This, combined with the increasing number of patients who
readily develop HLA antibodies, has resulted in a decline in the use of donor-specific blood transfusion.
Immunosuppression
The aim of transplantation research is to allow the recipient to accept the graft permanently with no
unpleasant side effects. With current drugs that are used for this purpose, after some months the
dosage can often be reduced and sometimes even stopped without the graft’s being rejected. In such a
case, the patient is no longer as susceptible to infections. There would appear to be adaptation of the
recipient toward the graft and the graft toward the recipient. The adaptation is probably akin to
desensitization, a process used sometimes to cure patients suffering from certain types of allergies by
giving them repeated exposure to small doses of the allergen to which they are sensitive.

Immunosuppression is usually done by giving medications such as corticosteroids, cyclophosphamide,

azathioprine, or cyclosporin A, which inactivate or kill all classes of lymphocytes. In many patients these
medications are effective in the short term only; their administration does not usually alter the natural
history of the disease, and the toxicity of these drugs is considerable. This toxicity is related to
nonselective immunosuppression, which results in susceptibility of the patient to infections and
malignancies.

4
It is clear that none of the agents so far used to prevent rejection is ideal. No one would use such
dangerous agents except as a last resort in a desperate situation. This, unfortunately, is the exact plight
of a person in need of a vital organ transplant. Immunosuppression is, however, much more effective
and less dangerous than it used to be, and advances with chemical derivatives, in particular monoclonal
antibodies and nontoxic analogues of cyclosporine, have brought significant improvements in
immunosuppressive therapy.

AUTOIMMUNITY AND AUTOIMMUNE DISEASES

AUTOIMMUNITY- is a condition in which the body’s immune system mistakes its own healthy tissues as
foreign and attacks them causing autoimmune diseases. Most autoimmune diseases cause
inflammation that can affect many parts of the body. The parts of the body affected depend on which
autoimmune disease a person has. Common signs and symptoms include fatigue, fever, muscle aches,
joint pain and swelling, skin problems, abdominal pain, digestion problems, and swollen glands. The
symptoms often come and go and can be mild or severe. There are many different types of autoimmune
diseases. They are more common in women and can run in families. Also called autoimmune condition.

Autoimmune diseases vary greatly, but each causes the immune system to attack healthy tissue.
Autoimmune diseases can affect almost every body part or system. There are more than 80 of these
conditions, and some are more common than others.

Common examples of autoimmune diseases include: psoriasis, psoriatic arthritis, rheumatoid arthritis,
lupus, Hashimoto’s thyroiditis, Grave’s disease, inflammatory bowel disease (IBD), celiac disease, and
type 1 diabetes.

The immune system is a network of tissues, organs, and cells. Its role is to defend the body against
harmful organisms, such as bacteria and viruses, warding off infection and disease. In a person with an
autoimmune disease, the immune system mistakenly attacks healthy body cells and tissues.
Researchers do not know the causes of many autoimmune conditions, but genetic factors, past
infections, and environmental factors can affect their development. Long-term treatments aim to
reduce the strength of immune responses. Antibiotics have no involvement because these diseases are
not bacterial infections.

Autoimmune diseases are relatively common. According to some estimates, more than 23.5 million
people in the United States have at least one autoimmune condition. They are a leading cause of death
and disability in the country.

Mechanisms of developement and pathogenesis of some autoimmune diseases

Autoimmune diseases are caused by antibodies and T cells directed against self, produced when
immune system recognition fails or malfunctions. Autoimmune diseases may be initiated by viruses,
drugs, chemicals or other factors, and affect the immune system at several levels.

5
In patients with systemic lupus erythematosus, for instance, B cells are hyperactive while suppressor
cells are underactive; it is not clear which defect comes first. Moreover, production of interleukin-2 (IL-
2) is low, while levels of interferon-gamma (IFN-γ) are high.

Patients with rheumatoid arthritis, who have defective suppressor T cells, continue to make antibodies
to common viruses, a response that would normally cease after about 14 days.

Some autoantibodies are directed against specific antigens and cause localized disease (e.g.
autoantibodies to desmoglein in epithelial intercellular cement, which cause pemphigus; autoantibodies
to red blood cells, which cause anaemia; autoantibodies to pancreatic islet cells, which contribute to
juvenile diabetes; and autoantibodies to acetylcholine receptors, which are present in myasthenia
gravis).

Polyglandular autoimmune diseases are examples of autoimmune attack on many organs. Where
autoantibodies are directed against several types of cell and cellular components, including nuclear
components such as deoxyribonucleic acid (DNA), ribonucleic acid (RNA) or proteins, then generalized
disease, such as systemic lupus erythematosus, may result.

Below are examples of autoimmune diseases that occur frequently.

1. Psoriasis

Psoriasis causes the immune system to disrupt the healthy formation of skin cells. This leads to scaly,
dry, itchy patches of skin, along with joint pain. Estimates suggest that more than 8 million people in the
U.S. have psoriasis, which affects 2–3% of the world’s population. There are many types of psoriasis,
each with different symptoms. Some types are more common than others. Common triggers for
psoriasis include stress, infections, and environmental factors.

2. Psoriatic arthritis

Psoriatic arthritis is an autoimmune joint condition that develops in about 3 in 10 people who have
psoriasis. It tends to show up around 10 years after psoriasis develops. However, it is also possible to
develop psoriatic arthritis without psoriasis. In psoriatic arthritis, the body’s immune system mistakenly
attacks healthy joints as well as surrounding tendons and ligaments. This leads to symptoms such as
joint pain, stiffness, swelling, and reduced range of motion. It often affects small joints in the body, such
as those in the fingers and toes.

3. Rheumatoid arthritis

Rheumatoid arthritis is one of the most common chronic autoimmune disorders. It causes the immune
system to attack healthy joints and surrounding tissue. It often affects the hands, wrists, and knees.
About 1.3 million adults in the U.S. have this condition. It is two to three times more common in females
than in males.

Symptoms of rheumatoid arthritis include:

6
pain, tenderness, and swelling around the joints, joint stiffness, symptoms that appear on both sides of
the body, such as on both hands or knees, weight loss, fatigue, weakness.

4. Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) refers to a range of conditions marked by inflammation of the skin,
joints, and — when severe — internal organs. Lupus generally affects around 1.5 million people in the
U.S. and 5 million people worldwide. Most people with lupus are female.

Symptoms of SLE, which is the most common type of lupus, include:

muscle and joint pain, a butterfly-shaped rash on the face, sun sensitivity, tiredness and a fever

5. Hashimoto’s thyroiditis

Hashimoto’s thyroiditis, also known as Hashimoto’s disease, is an autoimmune condition in which the
immune system attacks cells that create thyroid hormones. This leads to an underactive thyroid, known
as hypothyroidism. Hashimoto’s thyroiditis affects around 5 in 100 people in the U.S. It is up to 10 times
more common in females than males.

Symptoms include:

a goiter, which is swelling at the front of the neck, weight gain, tiredness and depression, joint and
muscle pain, increased sensitivity to cold, a slowed heart rate and heavy or irregular menstruation

6. Graves’ disease

Graves’ disease is an autoimmune condition that causes the thyroid gland to produce too much thyroid
hormone. This leads to hyperthyroidism. It affects about 1 in 200 people. It is more common in females
than males.

Symptoms include:

nervousness or anxiety, fatigue, a rapid, irregular heartbeat, shaky hands, high blood pressure, sweating
and difficulty tolerating hot conditions, weight loss, light, irregular menstruation, a goiter

7. Inflammatory bowel disease (IBD)

IBD is a long-term digestive condition. In a person with IBD, an immune system response to
environmental triggers leads to inflammation in the stomach and gut. The condition may affect around
1.3% of adults in the U.S., or around 3 million people.

There are two main types of IBD: Crohn’s disease and ulcerative colitis. Crohn’s disease involves chronic
inflammation occurring anywhere from the mouth to the end of the large intestine. Ulcerative colitis
involves long-term inflammation of the large intestine.

7
Symptoms of IBD include: stomach pain, bloating, persistent diarrhea, blood in stool, weight loss and
fatigue.

8. Celiac disease

Celiac disease is an immune disorder that causes the lining of the small intestine to become inflamed
after the person eats foods that contain gluten. It can lead to abdominal pain, an inability to absorb key
nutrients, and some other symptoms, such as joint pain and characteristic rashes. The immune response
is genetically determined and targets gliadin, a component of gluten. Gluten is a protein in wheat, rye,
and barley. Eliminating it from the diet helps control the signs and symptoms of celiac disease.

About 2 million people in the U.S. may have celiac disease, although many of them may be unaware.
When a person with the condition eats gluten, their immune system attacks healthy tissue in the small
intestine. Over time this damages the organ, preventing it from absorbing nutrients properly.

Symptoms of celiac disease include: inflammation and pain in the abdomen, a burning sensation in the
chest, tiredness, weight loss, a rash, joint pain, vomiting or diarrhea.

Celiac disease is different from gluten intolerance or sensitivity. Either of these issues can cause
symptoms similar to those of celiac disease, but there is no damage to the digestive system.

9. Type 1 diabetes

Type 1 diabetes causes the immune system to destroy cells in the pancreas that create insulin, known as
beta cells. As a result, the pancreas is less able to make insulin, leading to insulin deficiency. Not having
enough insulin means that sugars cannot transport around the body properly, leading to high blood
sugar levels. About 1 in 300 people in the U.S. have type 1 diabetes by age 18. Symptoms include:
frequent urination, increased thirst, a loss of energy, blurred vision, hunger and nausea.

Risk factors of autoimmune disease

Autoimmune diseases can develop in anyone, but certain factors increase the risk. The risk factors of
autoimmune disease includes:

i. Genetics: Some autoimmune conditions run in families. A person may inherit genes that predispose
them to a condition but only develop it after exposure to a combination of triggers.

Environmental factors: Sunlight, certain chemicals, and viral or bacterial infections can all affect the
development of autoimmune conditions.

ii. Sex: More females have autoimmune disorders than males. Doctors believe that hormonal factors
play a role. The disorders often develop during a female’s childbearing years.

8
iii. Race: This appears to play a role in the diagnosis and severity of certain autoimmune diseases. For
example, more white people receive a diagnosis of type 1 diabetes, while lupus is more severe in African
American and Hispanic people.

Other autoimmune conditions: A person with one autoimmune disorder has an increased risk of
developing another.

Diagnosis of autuimmune diseases

Diagnosing autoimmune diseases can be a challenging, lengthy process. For some, it may take years to
receive the right diagnosis. This can be due to a variety of reasons:

i. Not all symptoms always appear at the same time.

ii. Symptoms can be intermittent or gradually develop over time.

iii. Certain symptoms can overlap with the symptoms of other issues, particularly other autoimmune
disorders.

For example, lupus can affect the joints similarly to rheumatoid arthritis, but the symptoms tend to be
less severe. IBD causes similar symptoms to celiac disease, but IBD is not typically a result of consuming
gluten.

The diagnostic process also differs depending on the specific disease. However, it usually involves blood
tests.

In some cases, blood tests can indicate various conditions. For instance, diagnosing Hashimoto’s
thyroiditis and Graves’ disease requires a simple test to measure levels of thyroid hormone.

A test known as a complete blood count allows a doctor to check the levels of white and red blood cells
in the body. When the immune system is fighting off something, the levels are different from the usual
baseline.

A doctor may be able to diagnose an autoimmune disease by analyzing antibodies that the immune
system produces. However, sometimes autoantibody blood tests are positive for many years before
symptoms develop.

Other tests can indicate unusual inflammation — an issue that is fairly common among all autoimmune
diseases. These tests include a C-reactive protein test and an erythrocyte sedimentation rate test.

To help the diagnostic process, experts recommend:

i. writing out a family health history

ii. recording symptoms over time

iii. seeing a specialist

9
Because autoimmune diseases can involve a single organ or be systemic in nature and involve multiple
organs, it is important for a person to meet with a specialist.

If it involves a single organ such as the thyroid or pancreas, an endocrinologist — a specialist in that
organ — is the best type of doctor for a person to see. For a systemic disease involving the connective
tissue, such as the joints and muscles, a rheumatologist may be the best doctor for a person to see.

Treatment of autoimmune diseases

While there is no cure for any autoimmune condition, treatments can reduce or eliminate symptoms,
slow the progression of the illness, and improve quality of life.

1. Relieving symptoms

This may involve taking aspirin or ibuprofen to reduce mild pain and swelling or prescribed alternatives,
depending on the severity of the [Link] medications can also help with: depression,
anxiety, fatigue, sleep problems and rashes.

In many cases, getting regular exercise and having a balanced, nutritious diet can also help.

2. Taking replacement drugs

Some autoimmune disorders affect the body’s ability to produce what it needs. For instance, type 1
diabetes keeps the body from creating enough insulin, and thyroid disease prevents it from producing
the right amount of thyroid hormone.

Various medications can replace these substances. A person may have insulin injections or take pills that
contain synthetic versions of thyroid hormone.

3. Taking immunosuppressants

For many people, medications that suppress the immune system can relieve the symptoms of an
autoimmune disorder and slow its progression. However, these drugs, known as immunosuppressants,
can cause side effects.

4. Avoiding triggers

In some cases, avoiding things that trigger the immune system reaction can help ease or eliminate
symptoms and slow down the progression of the disease. Common triggers include: diet, infection,
smoking and stress.

VACCINES

Vaccination- is the act of introducing a vaccine into the body to produce protection from a specific
disease.

10
Immunization- A process by which a person becomes protected against a disease through vaccination.
This term is often used interchangeably with vaccination or inoculation.

Who discovered the principle of vaccination and how?

Dr Edward Jenner created the world's first successful vaccine which is ''The smallpox vaccine''. He found
out that people infected with cowpox were immune to smallpox. In May 1796, English physician Edward
Jenner expands on this discovery and inoculates 8-year-old James Phipps with matter collected from a
cowpox sore on the hand of a milkmaid.

Principle of vaccination and immunisation

Immunity is the biological state of being able to resist disease or a toxin: the primary objective of
vaccination is to induce an immunological memory against specific diseases, so that if exposure to a
disease-causing pathogen occurs, the immune response will neutralise the infection or toxins it releases
before the disease can occur.

Steps involved in vaccination process are as follows:

1. Immune recognition

One of the primary ways in which the immune system achieves elimination of pathogens and other
unwanted foreign material is being able to distinguish ‘self’ from ‘non-self’. Each cell in the body is
equipped with a type of molecule that identifies the individual from any other, much like a 3D barcode.
Pathogens not only lack the individual’s ‘self’ marker, they also contain ‘virulence factors’ that alert the
immune system to danger.

Antigens (antibody generators) are the drivers of the specific immune response. Antigens are molecular
shapes, such as part of a protein or glycoprotein, that the immune system recognises as foreign and can
trigger an adaptive immune response. While some vaccines contain the entire weakened or attenuated
organism (live viral vaccines like measles, mumps and rubella vaccines), increasingly, newer vaccines
contain purified or recombinant protein antigens (as in acellular pertussis, HPV or pneumococcal
vaccines).

The first process that occurs when a foreign antigen, such as a vaccine antigen, is introduced to the body
is the recognition that the antigen is non-self by triggering an inflammatory response. The antigen is
taken up at the local site (such as the injection site) by specialist phagocytic cells called antigen-
presenting cells – macrophages and dendritic cells. Once inside the antigen-presenting cells, the foreign
protein (or microbe) is dismantled into tiny fragments that are displayed on cell surface alongside a ‘self’
molecule. These antigen-presenting cells carry the antigen to through the lymph to the local lymph node
where the adaptive immune response is initiated.

2. Induction of the adaptive immune response

11
The response that occurs the first time an antigen is ‘seen’ by the immune system is called the primary
immune response.

The adaptive immune responses occur in lymphoid tissue, primarily in the spleen and in the 500–600
lymph nodes distributed throughout the body.

The adaptive immune response to most vaccines occurs at the draining lymph node proximal to the site
of injection. The spleen and lymph nodes are densely populated with important effector lymphocytes of
the immune response: T-cells and B-cells. In the lymph node, the vaccine antigen is presented to the
specific T-cells and B-cells.

Among the trillions of specific T and B lymphocytes (there are ~1016 possibilities), there usually exists a
match for the antigen. Cells that recognise the antigen are activated through communication with the
antigen presenting cell and the primary immune response can be initiated. This process and the
response matures over a period of four to six weeks.

An early outcome of the interaction between these antigen-presenting cells and T and B lymphocytes is
the production of antibody-producing B-cells. Antibody can be measured in the blood as soon as 4–7
days after this interaction, but is usually more effectively measured weeks to months later. Initially, this
is low in quantity and of low affinity for the antigen (it binds weakly to the antigen), and primarily
consists of the antibody subtype immunoglobulin M (IgM), often referred to as ‘early antibody’. It peaks
at around 10 days then declines relatively quickly.

For most vaccine-preventable diseases this process is too slow following infection, and disease occurs
before an effective immune response can be mounted. Injecting a part or a weakened version of the
pathogen in the form of a vaccine, readies the immune system so that it can mount a more rapid and
effective response when the wild disease is encountered.

3. Development of immune memory and the secondary response

The response that occurs the second time an antigen is ‘seen’ by the immune system is called the
secondary immune response.

During the primary immune response, over a period of around two months, cells that are less specific
for the specific antigen are deleted, and those that are highly specific are retained and multiply within
the lymph node. Antibody production also switches from IgM to more specific IgG or IgA subtypes.
During this time immunological memory cells also develop, but it takes around four months, after the
initial antigen is cleared, to fully form immune memory.

The next time the same antigen is introduced, either as a pathogen component or as a further dose of
vaccine, the immunological memory cells that recognise it will be activated and begin to proliferate.
Highly specific antibody (primarily of the IgG subtype, but also IgA) is rapidly produced in large amounts.

12
The lag phase is much shorter than the primary immune response (see Figure 1.1), at just 1–4 days; the
antibody level peaks very quickly and lasts much longer.

The immune system has been readied by the vaccine; if the actual disease pathogen enters the body,
then it is recognised promptly and neutralised by the immune system preventing it from causing
disease.

Classification of Vaccines

There are two basic types of vaccines. Their characteristics are different and determine how each type
is used.

1. Live, attenuated vaccines

2. Inactivated vaccines

1. Live, Attenuated Vaccines

Live vaccines are derived from “wild” viruses or bacteria. These wild viruses or bacteria are attenuated
(weakened) in a laboratory, usually by repeated culturing. For example, the measles virus used as a
vaccine today was isolated from a child with measles disease in 1954. Almost 10 years of serial passage
using tissue culture media were required to transform the wild virus into the attenuated vaccine virus.

To produce an immune response, live, attenuated vaccines must replicate in the vaccinated person. A
relatively small dose of administered virus or bacteria replicates in the body and creates enough of the
organism to stimulate an immune response. Although live, attenuated vaccines replicate, they usually do
not cause disease such as that caused by the wild form of the organism. When a live, attenuated
vaccine does cause disease, it is usually much milder than the natural disease and is considered an
adverse reaction to the vaccine. The immune response to a live, attenuated vaccine is virtually identical
to that produced by a natural infection because the immune system does not differentiate between an
infection with a weakened vaccine virus and an infection with a wild virus. Injected live, attenuated
vaccines produce immunity in most recipients with one dose. However, a small percentage of recipients
do not respond to the first dose of an injected live, attenuated vaccine (such as measles, mumps, and
rubella [MMR]) and a second dose is recommended to provide an extremely high level of immunity in
the population. Orally administered live, attenuated vaccines require more than one dose to produce
immunity.

A live, attenuated vaccine may cause severe or fatal infections as a result of uncontrolled replication of
the vaccine virus or bacteria. However, this only occurs in persons with a weakened immune system
(e.g., from leukemia, treatment with certain drugs, or human immunodeficiency virus [HIV] infection). A
live, attenuated vaccine virus could theoretically revert to its original pathogenic form. This is known to
happen only with live (oral) polio vaccine, which is no longer available in the United States. Active
immunity from a live, attenuated vaccine may not develop because of interference with the vaccine
virus by circulating antibody.

13
Antibody from any source (e.g., transplacental transfer to infants, transfusion of blood products) can
interfere with replication of the vaccine organism and lead to poor response or no response to the
vaccine (also known as vaccine failure). Live, attenuated vaccines are fragile and can be damaged or
destroyed by heat and light. They must be stored and handled carefully. The live, attenuated viral
vaccines currently available and routinely recommended in the United States are MMR, varicella,
rotavirus, and influenza (intranasal).

Other non-routinely recommended live vaccines include adenovirus vaccine (used by the military),
typhoid vaccine (Ty21a), and Bacille Calmette-Guerin (BCG). BCG is not used as a vaccine in the United
States, but as a treatment for bladder cancer.

2. Inactivated Vaccines

Inactivated vaccines are not live and cannot replicate. These vaccines cannot cause disease, even in an
immunodeficient person. Inactivated antigens are less affected by circulating antibody than are live
antigens, so they may be given when antibody is present in the blood (e.g., in infancy or following
receipt of antibody-containing blood products). The immunity provided by inactivated vaccines is
generally not as long-lasting as that obtained from live, attenuated vaccines. Multiple doses over time
are needed to obtain ongoing immunity. In general, the first dose does not produce protective
immunity, but “primes” the immune system. A protective immune response develops after the second
or third dose. Unlike live vaccines, which produce an immune response that closely resembles natural
infection, the immune response to an inactivated vaccine is mostly antibody production. Little or no
cellular immunity results. Antibody titers against inactivated antigens diminish with time. As a result,
some inactivated vaccines may require periodic supplemental doses to increase, or “boost,” antibody
titers. Inactivated vaccines include whole-cell inactivated vaccines (e.g., polio, hepatitis A, and rabies
vaccines), subunit vaccines (e.g., influenza and pneumococcal vaccines), toxoids (e.g., diphtheria and
tetanus toxoid), and recombinant vaccines (e.g., hepatitis B, human papillomavirus [HPV], and influenza
[Flublok brand]).

i. Whole-cell inactivated vaccines contain bacteria or viruses that have been killed through a physical
or chemical process. Whole-cell inactivated viral vaccines against polio, hepatitis A, and rabies are
available in the United States. A vaccine made from whole killed pertussis (whooping cough) bacteria is
available outside the United States. Subunit vaccines contain a portion of the bacteria or virus. The
portion of the organism selected is the part needed to produce a protective immune response. Antigens
in subunit vaccines can be protein, polysaccharide, or a combination of polysaccharide and protein
molecule (i.e., conjugate vaccine).

ii. Conjugate subunit vaccines (e.g., Haemophilus influenzae type b and pneumococcal conjugate
vaccines) are produced by chemically attaching a polysaccharide from the surface of bacteria to a
protein molecule through a process called conjugation. Conjugating a polysaccharide antigen to a
protein molecule produces long-lasting protective immunity to the polysaccharide antigen. The immune
response to a pure polysaccharide vaccine is typically T-cell-independent, which means these vaccines
can stimulate B-cells without the assistance of T-helper cells. T-cell-independent antigens, including

14
polysaccharide vaccines, are not consistently immunogenic in children younger than age 2 years,
probably because of immaturity of the immune system. Attaching the polysaccharide antigen to a
protein makes it possible to prevent bacterial infections in populations where a polysaccharide vaccine
is not effective or provides only temporary protection.

iii. Toxoid vaccines are made using inactivated toxins produced by bacteria. These protein-based toxins
are inactivated using heat, chemicals, or other methods. Some bacteria (e.g., tetanus, diphtheria) cause
disease by producing toxins. The ability of the immune system to recognize and eliminate these toxins
provides protection from the disease. Recombinant vaccines are produced by recombinant DNA
technology. Recombinant DNA technology enables the combination of DNA from two or more sources.
Hepatitis B, human papillomavirus (HPV), and influenza (Flublok brand) vaccines are produced by
insertion of a segment of the respective viral gene into the gene of a yeast cell or virus. The modified
yeast cell or virus produces pure hepatitis B surface antigen, HPV capsid protein, or influenza
hemagglutinin when it grows. Serogroup B meningococcal vaccines are proteins and outer membrane
vesicles generated by recombinant technology.

15