BASIC PRINCIPLES OF GENETICS

In the 1860s, a monk named Gregor Mendel discovered how traits are transmitted from parents to offspring while experimenting with pea plants. This discovery led to the study of genetics, which is also known as the study of inheritance. (Common terms used in the study of genetics are listed and defined in Table 13-1.)

TABLE 13-1 Glossary of genetic terms

Protein synthesis

Protein synthesis, or the making of proteins, occurs in two steps: transcription and translation. (Transcription and translation are shown in Fig 13-1.) Transcription is the process where messenger RNA (mRNA) is synthesised from single-stranded DNA. The mRNA becomes attached to a ribosome, where translation occurs. At this point another specialised type of RNA, transfer RNA (tRNA), arranges the amino acids in the correct sequence to assemble the protein. Once the protein is made, it is released from the ribosome and is able to perform its specific function.

Figure 13-1 A, The DNA molecule contains a sequence of genes. B, During transcription, the DNA code is transcribed as mRNA. C, During translation, the mRNA code is translated at the ribosome and the proper sequence of amino acids is assembled. The amino acid strand coils or folds as it is formed. D, The coiled amino acid strand folds again to form a protein molecule with a specific complex shape.

Source: Thibodeau GA, Patton KT. The human body in health and disease. 3rd edn. St Louis: Mosby; 2009.

INHERITANCE PATTERNS

Genetic disorders can be categorised as autosomal dominant, autosomal recessive or sex-linked (X-linked) recessive disorders (see Table 13-2). If the mutant gene is located on an autosome, the genetic disorder is called autosomal. If the mutant gene is on the X chromosome, the genetic disorder is called X-linked. Family pedigrees for autosomal dominant, autosomal recessive and X-linked recessive disorders are shown in Figure 13-2.

TABLE 13-2 Comparison of genetic disorders

* Have the disease.

† Do not have the disease.

Figure 13-2 Examples of family pedigrees.

Autosomal dominant disorders are caused by a mutation of a single gene pair (heterozygous) on a chromosome. A dominant allele prevails over a normal allele. Autosomal dominant disorders show variable expression. Variable expression means that the symptoms expressed by the individuals with the mutated gene vary from person to person even though they have the same mutated gene. Although autosomal dominant disorders have a high probability of occurring in families, sometimes these disorders cause a new mutation or skip a generation. This is termed incomplete penetrance.

Autosomal recessive disorders are caused by mutations of two gene pairs (homozygous) on a chromosome. A person who inherits one copy of the recessive allele does not develop the disease because the normal allele predominates. However, such a person is a carrier.

X-linked recessive disorders are caused by a mutation on the X chromosome. Usually only men are affected by these disorders because women who carry the mutated gene on one X chromosome have another X chromosome to compensate for the mutation. However, women who carry the mutated gene can transmit the mutated gene to their offspring. It is possible for women to have X-linked recessive disorders, and this can occur when an affected male mates with an unaffected female carrier. This points to the importance of testing the carrier status of the female mate of affected males. X-linked dominant disorders do exist but they are very rare.¹

Multifactorial inherited conditions are caused by a combination of genetic and environmental factors. These disorders run in families but do not show the same inherited characteristics as the single-gene mutation conditions. Multifactorial conditions are poorly understood but include diabetes mellitus, obesity, hypertension, cancer and coronary artery disease.

HUMAN GENOME PROJECT

The Human Genome Project (HGP), which was completed in 2003, mapped the human genome (see the Resources on p 276). Analysis of the data will continue for many years. The knowledge gained through the HGP will: (1) help improve the diagnosis of diseases; (2) allow for earlier detection of genetic predisposition to diseases; and (3) play a critical role in determining risk assessment for genetic-related diseases. In addition, the results of the HGP will assist in matching organ donors with transplant recipients.

GENETIC TESTING

Genetic testing includes any procedure done to analyse chromosomes, genes or any gene product that can determine a mutation or a predisposition to a condition. Genetic tests include direct testing, linkage testing, biochemical testing and karyotyping. Direct testing examines the DNA for any mutations. Biochemical testing includes analysing gene products, such as enzymes and proteins. Karyotyping investigates the number, form, size and arrangement of the chromosomes. A blood sample or buccal smear (skin or hair can also be used) is frequently used to obtain samples for genetic testing. Tissues and cells can also be obtained prenatally.

Genetic testing has been very useful in healthcare (see Table 13-3). Some tests are used in diagnosing an illness or a risk for a disorder and provide the basis for appropriate treatments. Other tests allow families to avoid having children with devastating diseases or to identify people who are at high risk of conditions that may be prevented by monitoring or having surgery. For example, aggressive monitoring for and removal of colon growths in those inheriting a gene for familial adenomatous polyposis has saved many lives.

TABLE 13-3 Use of genetic tests

Genetic testing

CLINICAL PRACTICE

Situation

A 30-year-old woman informs you that she is 3 months pregnant. She has two children with her current husband and her youngest child has cystic fibrosis (CF). This pregnancy was unplanned. She expresses concern regarding the possibility of having another child with CF. She mentions that she would like to have genetic testing on her fetus. Her husband asks you whether they will have another child with CF.

Important points for consideration

• With complete and accurate information, the woman and her husband can make a decision on their own, without coercion from others.

• Genetic counselling is a requirement before and after obtaining genetic testing because of the complexity of the information and the emotional issues involved.

• Knowing that CF is an autosomal recessive condition, the nurse can use Punnett squares (see Fig 13-3) or a family pedigree (see Fig 13-2) to show the woman and her husband the probability of having another child with CF.

Figure 13-3 Punnett squares can be used to determine inheritance possibilities. A, If the mother and father are both carriers for cystic fibrosis, there is a 25% chance that their offspring will have cystic fibrosis. B, If the mother is a carrier for the haemophilia gene and the father has a normal genotype, there is a 50% chance that any male offspring will have haemophilia. There is a 50% chance that any female offspring will be a carrier. C, If the mother has a normal genotype and the father has Huntington’s disease, there is a 50% chance that their offspring will have the disease.

Critical thinking questions

1. What information would you give the patient regarding genetic testing in order for this couple to make a decision?

2. What options are available for this couple?

3. How would you assist this couple in making a decision about possibly terminating the pregnancy based on the results of the genetic testing?

At the same time, genetic testing of individuals opens the door for ethical and social issues. People making decisions about genetic testing should be aware that when test results are placed in their medical records, the results may not be kept private. If an individual is tested, it may uncover information about a family member who was not tested and these individuals are frequently not a part of the decision to undergo testing. Similarly, if a whole family is tested, the results may indicate that the biological relationship is not what the family believed it to be.

Widespread genetic testing has limitations. It is difficult to interpret a positive result because some people who have the genetic mutation never develop the disease. For example, many people who would test positive for the apolipoprotein E gene (ApoE-4) will never develop Alzheimer’s disease (see Ch 59).

Populations of people may be tested for multiple reasons. It may be a public health matter that propels the testing, such as the practice of testing newborn children. In Australia and New Zealand, all newborns are offered testing for phenylketonuria, congenital hypothyroidism, cystic fibrosis, galactosaemia and some rare metabolic disorders. Also, population testing may be performed as a matter of practice, such as the testing offered to all prenatal women. These group testings identify a treatable disease before the onset of symptoms, which can be especially helpful in diseases where early identification improves the outcome.²

The website of the Royal Australian College of Pathologists has more information about genetic tests available in Australia,³ and the National Institute of Health in the US maintains useful information about genetic testing on the GeneTests website (see the Resources on p 276).⁴

GENE THERAPY

Gene therapy is an experimental technique that is used to replace or repair defective or missing genes with normal genes. A normal gene can be inserted into a human chromosome to counteract the effects of a missing or abnormal gene. A carrier molecule called a vector must be used to deliver the therapeutic gene to the patient’s target cells. Currently, the most common vector is a virus that has been genetically altered to carry normal human DNA. The vector unloads its genetic material containing the therapeutic human gene into the target cell. The functional protein product from the therapeutic gene restores the target cell to a normal state. Although gene therapy is a promising treatment option for a number of diseases (including inherited disorders, some types of cancer and certain viral infections), the technique remains risky and is still under study to make sure that it is safe and effective. Gene therapy is currently being tested only for the treatment of diseases that have no other cure.⁵

NURSING MANAGEMENT: GENETICS

It is imperative that nurses are knowledgeable about the fundamentals of genetics. By understanding the profound influence that genetics has on health and disease, the nurse can assist the patient and family in making critical decisions related to genetic issues, such as genetic testing. In addition, the nurse needs to collaborate with the healthcare team or doctor to involve a genetic counsellor. The nurse should be able to give patients and families accurate information pertaining to genetics, genetic diseases and probabilities of genetic disorders.^6,7

Nurses can assess inheritance patterns and explain them to the patient and family through the use of family pedigrees (see Fig 13-2) and Punnett squares (see Fig 13-3). It is important to maintain the patient’s confidentiality and respect the patient’s values and beliefs because genetic information may have major health and social implications.

Genetic testing may raise many psychological issues. Knowing that they are the carrier of a genetic disorder may influence people’s career plans and decisions for marriage and childbearing. It may also affect significant others in grappling with serious life and healthcare issues. For example, how should a husband deal with his wife who has tested positive for Huntington’s disease and shows early signs of cognitive impairment but does not yet show any other neurological manifestations of the disease?

Furthermore, there are ethical concerns. Who should know the results of a genetic test? Who should protect individuals’ privacy of test results and protect individuals from discrimination? Genetic information should not be misused to stigmatise individuals or particular groups. Attention must be paid to understanding the psychosocial needs of individuals and societal responses and healthcare policy related to genetic testing. People may be reluctant to share or disclose information about family history or genetic test results. They may fear that they are potentially vulnerable to discrimination based on their DNA. Nurses can provide information to patients about where to turn for help to discuss concerns about discrimination. Resources on genetics for nurses and nurse educators are available on p 276.

TYPES OF IMMUNITY

Immunity is classified as innate (natural) or acquired. Innate immunity exists in a person without prior contact with an antigen. It is present at birth and its primary role is first-line defence against pathogens. This type of immunity involves a non-specific response, and neutrophils and monocytes are the primary white blood cells (WBCs) involved. Innate immunity is not antigen-specific so it can respond within minutes to an invading microorganism without prior exposure to that organism. Acquired immunity is the development of immunity, either actively or passively (see Box 13-1).

ANTIGENS

An antigen is a substance that elicits an immune response. Most antigens are composed of protein. However, other substances, such as large polysaccharides, lipoproteins and nucleic acids, can act as antigens. All of the body’s cells have antigens on their surface that are unique to that person and enable the body to recognise self. The immune system becomes ‘tolerant’ to the body’s own molecules and therefore is normally non-responsive to self-antigens.

LYMPHOID ORGANS

The lymphoid system is composed of central (or primary) and peripheral lymphoid organs. The central lymphoid organs are the thymus gland and bone marrow. The peripheral lymphoid organs are the tonsils; gut-, genital-, bronchial- and skin-associated lymphoid tissues; lymph nodes; and spleen (see Fig 13-4).

Figure 13-4 Organs of the immune system.

Lymphocytes are produced in the bone marrow and eventually migrate to the peripheral organs. The thymus is important in the differentiation and maturation of T lymphocytes and is therefore essential for a cell-mediated immune response. During childhood the gland is large, but it shrinks with age and is a collection of reticular fibres, lymphocytes and connective tissue in older people.

Lymphoid tissue is found in the submucosa of the respiratory (bronchial-associated), genitourinary (genital-associated) and gastrointestinal (gut-associated) tracts. This tissue protects the body from external microorganisms. The tonsils are a typical example of lymphoid tissue.

The skin-associated lymphoid tissue primarily consists of lymphocytes and Langerhans’ cells (a type of resident macrophage) found in the epidermis of skin. When Langerhans’ cells are depleted, the skin can neither initiate an immune response nor support a skin-localised delayed hypersensitivity response.

When antigens are introduced into the body, they may be carried by the bloodstream or lymph channels to regional lymph nodes. The antigens interact with B and T lymphocytes and macrophages in the lymph nodes. The two important functions of lymph nodes are: (1) filtration of foreign material brought to the site; and (2) circulation of lymphocytes.

The spleen is important as the primary site for filtering foreign substances from the blood. It consists of two kinds of tissue: white pulp containing B and T lymphocytes, and red pulp containing erythrocytes. Macrophages line the pulp and sinuses of the spleen.

CELLS INVOLVED IN THE IMMUNE RESPONSE

Mononuclear phagocytes

The mononuclear phagocyte system includes monocytes in the blood and macrophages found throughout the body. Mononuclear phagocytes have a critical role in the immune system. They are responsible for capturing, processing and presenting the antigen to the lymphocytes. This stimulates a humoral or cell-mediated immune response. Capturing is accomplished through phagocytosis. The macrophage-bound antigen, which is highly immunogenic, is presented to circulating T or B lymphocytes and thus triggers an immune response (see Fig 13-5).

Figure 13-5 The immune response to a virus. A, A virus invades the body through a break in the skin or another portal of entry. The virus must make its way inside a cell in order to replicate itself. B, A macrophage recognises the antigens on the surface of the virus. The macrophage digests the virus and displays pieces of the virus (antigens) on its surface. C, A T helper cell recognises the antigen displayed and binds to the macrophage. This binding stimulates the production of cytokines (interleukin-1 [IL-1] and tumour necrosis factor [TNF]) by the macrophage and interleukin-2 (IL-2) and gamma-interferon (γIFN) by the T cell. These cytokines are intracellular messengers that provide communication between the cells. D, IL-2 instructs other T helper cells and T cytotoxic cells to proliferate (multiply). T helper cells release cytokines, causing B cells to multiply and produce antibodies. E, T cytotoxic cells and natural killer cells destroy infected body cells. F, The antibodies bind to the virus and mark it for macrophage destruction. G, Memory B and T cells remain behind to respond quickly if the same virus attacks again.

Lymphocytes

Lymphocytes are produced in the bone marrow and lymph nodes (see Fig 13-6). They then differentiate into B lymphocytes and T lymphocytes.

Figure 13-6 Relationships and functions of macrophages, B lymphocytes and T lymphocytes in an immune response.

B lymphocytes

In the early research on B lymphocytes (bursa-equivalent lymphocytes) in birds, it was discovered that they mature under the influence of the bursa of Fabricius; hence the name of B cells. However, this lymphoid organ does not exist in humans. The bursa-equivalent tissue in humans is the bone marrow. B cells differentiate into plasma cells when activated. Plasma cells produce antibodies (immunoglobulins) (see Table 13-4).

TABLE 13-4 Characteristics of immunoglobulins

T lymphocytes

Cells that migrate from the bone marrow to the thymus differentiate into T lymphocytes (thymus-dependent cells). The thymus secretes hormones, including thymosin, which stimulate the maturation and differentiation of T lymphocytes. T cells comprise 70–80% of the circulating lymphocytes and are primarily responsible for immunity to intracellular viruses, tumour cells and fungi. T cells live from a few months to the life span of an individual and account for long-term immunity.

T lymphocytes can be categorised into T cytotoxic cells and T helper cells. Antigenic characteristics of WBCs have now been classified using monoclonal antibodies. These antigens are classified as clusters of differentiation, or CD antigens. Many types of WBCs, especially lymphocytes, are referred to by their CD designations. All mature T cells have the CD3 antigen.

T cytotoxic cells

T cytotoxic (or cytolytic) (CD8) cells are involved in attacking antigens on the cell membrane of a foreign pathogen and releasing cytolytic substances that destroy the pathogen. These cells have antigen specificity and are sensitised by exposure to the antigen. Similar to B lymphocytes, some sensitised T cells do not attack the antigen but remain as memory T cells. As in the humoral immune response, a second exposure to the antigen will result in a more intense and rapid cell-mediated immune response.

T helper cells

T helper (CD4) cells are involved in the regulation of cell-mediated immunity and the humoral antibody response. T helper cells differentiate into subsets of cells that produce distinct types of cytokines (discussed in the next section). These subsets are called T_H1 cells and T_H2 cells. T_H1 cells stimulate phagocyte-mediated ingestion and killing of microbes, the key component of cell-mediated immunity. T_H2 cells stimulate phagocyte-independent, eosinophil-mediated immunity, which is effective against parasites, and are involved in allergic responses.

Natural killer cells

Natural killer (NK) cells are also involved in cell-mediated immunity. These cells are not T or B cells but are large lymphocytes with numerous granules in the cytoplasm. NK cells do not require prior sensitisation for their generation. These cells are involved in recognition and killing of virus-infected cells, tumour cells and transplanted grafts. The mechanism of recognition is not fully understood. NK cells have a significant role in immune surveillance for malignant cell changes.

CYTOKINES

The immune response involves complex interactions of T cells, B cells, monocytes and neutrophils. These interactions depend on cytokines (soluble factors secreted by WBCs and a variety of other cells in the body), which act as messengers between the cell types. Cytokines instruct cells to alter their proliferation, differentiation, secretion or activity. There are currently more than 100 different known cytokines, and they can be classified into distinct categories. Some of these cytokines are listed in Table 13-5. In general, the interleukins act as immunomodulatory factors, colony-stimulating factors act as growth-regulating factors for haematopoietic cells, and interferons are antiviral and immunomodulatory.

TABLE 13-5 Types and functions of cytokines^*

NK, natural killer; PMN, polymorphonuclear neutrophil.

* A more comprehensive presentation of cytokines is available at www.rndsystems.com/molecule_group.aspx?g=704&r=4.

The net effect of an inflammatory response is determined by a balance between pro-inflammatory and anti-inflammatory mediators. Sometimes cytokines are classified as pro-inflammatory or anti-inflammatory (see Table 13-5). However, it is not that clear-cut, as many other factors (e.g. target cells, environment) influence the inflammatory response to a given injury or insult.

Cytokines have a beneficial role in haematopoiesis and immune function. They can also have detrimental effects, such as those seen in chronic inflammation, autoimmune diseases and sepsis. Cytokines such as erythropoietin (see Ch 46), colony-stimulating factors (see Table 15-15), interferons (see Table 15-14) and interleukin-2 (see Table 15-14) are used clinically to: (1) stimulate haematopoiesis; (2) stimulate the bone marrow to make WBCs; and (3) treat various malignancies. In addition, inhibitors of cytokines, such as soluble tumour necrosis factor receptor antagonist and interleukin-1, are being used in clinical trials as anti-inflammatory agents. Clinical uses of cytokines are listed in Table 13-6.

TABLE 13-6 Clinical uses of cytokines

IL, interleukin; TNF, tumour necrosis factor.

* Not available in Australia.

Interferon helps the body’s natural defences attack tumours and viruses. Three types of interferon have now been identified (see Table 13-5). In addition to their direct antiviral properties, interferons have immunoregulatory functions. These include enhancement of NK cell production and activation and inhibition of tumour cell growth. Interferon is not directly antiviral but produces an antiviral effect in cells by reacting with them and inducing the formation of a second protein termed antiviral protein (see Fig 13-7). This protein mediates the antiviral action of interferon by altering the cell’s protein synthesis and preventing new viruses from becoming assembled.

Figure 13-7 Mechanism of action of interferon. Virus attacks a cell. The cell begins to synthesise viral DNA and interferon. Interferon serves as an intercellular messenger. Interferon induces the production of antiviral proteins. Virus is not able to replicate in the cell.

COMPARISON OF HUMORAL AND CELL-MEDIATED IMMUNITY

Humans need both humoral and cell-mediated immunity to remain healthy. Each type of immunity has unique properties and different methods of action, and reacts against particular antigens. Table 13-7 compares humoral and cell-mediated immunity.

TABLE 13-7 Comparison of humoral immunity and cell-mediated immunity

Humoral immunity

Humoral immunity is antibody-mediated immunity. The term humoral comes from the Greek word humor, which means body fluid. Antibodies are produced by plasma cells (differentiated B cells) and found in plasma; therefore, the term humoral immunity is used. Production of antibodies is an essential component in a humoral immune response. Each of the five classes of immunoglobulins—IgG, IgA, IgM, IgD and IgE—has specific characteristics (see Table 13-4).

When a pathogen (especially bacteria) enters the body, it may encounter a B lymphocyte that is specific for antigens located on that bacterial cell wall. In addition, a monocyte or macrophage may phagocytise bacteria and present its antigens to a B lymphocyte. The B lymphocyte recognises the antigen because it has receptors on its cell surface that are specific for that antigen. When the antigen comes in contact with the cell surface receptor, the B cell becomes activated, and most B cells will differentiate into plasma cells (see Fig 13-6). The mature plasma cell secretes immunoglobulins. Some stimulated B lymphocytes remain as memory cells.

The primary immune response develops in 4–8 days after the initial exposure to the antigen (see Fig 13-8). IgM is the first type of antibody formed. Because of the large size of the IgM molecule, this immunoglobulin is confined to the intravascular space. As the immune response progresses, IgG is produced and can move from intravascular to extravascular spaces.

Figure 13-8 Primary and secondary immune responses. The introduction of antigen induces a response dominated by two classes of immunoglobulins, IgM and IgG. IgM predominates in the primary response, with some IgG appearing later. After the host’s immune system is primed, another challenge with the same antigen induces the secondary response, in which some IgM and large amounts of IgG are produced.

When an individual is exposed to an antigen a second time, a secondary antibody response occurs, which is faster (1–3 days), stronger and lasts for longer than the primary response. Memory cells account for the memory of the first exposure to the antigen and the more rapid production of antibodies. IgG is the primary antibody formed in the secondary immune response.

IgG crosses the placental membrane and provides the newborn with passive acquired immunity for at least 3 months. Infants may also have some passive immunity from IgA in breast milk and colostrum.

Gerontological considerations: effects of ageing on the immune system

With advancing age there is a decline in the immune system (see Box 13-2). The primary clinical evidence for this immunosenescence is the high incidence of tumours in older adults. In addition, a greater susceptibility occurs to infections (e.g. influenza, pneumonia) from pathogens that the older person had been relatively immunocompetent against earlier in life. Bacterial pneumonia is the leading cause of death from infections in older adults. The antibody response to immunisations (e.g. flu vaccine) in older adults is considerably lower than in younger adults.¹⁰

BOX 13-2 Effects of ageing on the immune system GERONTOLOGICAL DIFFERENCES IN ASSESSMENT

• Thymic involution

• ↓ Cell-mediated immunity

• ↓ Delayed hypersensitivity response

• ↓ Interleukin-1 and interleukin-2 synthesis

• ↓ Expression of interleukin-2 receptors

• ↓ Proliferative response of T and B cells

• ↓ Primary and secondary antibody responses

• ↑ Autoantibodies

Immunoglobulin levels decrease with age and therefore lead to a suppressed humoral immune response in older adults. Thymic involution (shrinking) occurs with ageing along with decreased numbers of T cells. These changes in the thymus are probably a primary cause of immunosenescence. Both T and B cells show deficiencies in activation, transit time through the cell cycle and subsequent differentiation. However, the most significant alterations involve T cells. As thymic output of T cells diminishes, the differentiation of T cells increases. Consequently, there is an accumulation of memory cells rather than new precursor cells responsive to previously unencountered antigens.

The delayed hypersensitivity response, as determined by skin testing with injected antigens, is frequently decreased or absent in older adults. This altered response reflects anergy (an immunodeficient condition characterised by lack of or diminished reaction to an antigen or a group of antigens). The clinical consequences of a decline in cell-mediated immunity are evident.

HYPERSENSITIVITY REACTIONS

Sometimes the immune response is overreactive against foreign antigens or fails to maintain self-tolerance and this results in tissue damage. This is termed a hypersensitivity reaction. Autoimmune diseases, a type of hypersensitivity response, occur when the body fails to recognise self-proteins and reacts against self-antigens. Classification of hypersensitivity reactions may be done according to the source of the antigen, the time sequence (immediate or delayed) or the basic immunological mechanisms causing the injury. Basically, four types of hypersensitivity reactions occur. Types I, II and III are immediate and are examples of humoral immunity. Type IV is a delayed hypersensitivity reaction and is related to cell-mediated immunity. Table 13-8 summarises the four types of hypersensitivity reactions.

TABLE 13-8 Types of hypersensitivity reactions

RBCs, red blood cells; TB, tuberculosis.

Type I: Ig-E mediated reactions

Anaphylactic reactions are type I reactions that occur only in susceptible persons who are highly sensitised to specific allergens. IgE antibodies, which are produced in response to the allergen, have a characteristic property of attaching to mast cells and basophils (see Fig 13-9). Within these cells are granules containing potent chemical mediators (histamine, serotonin, eosinophil chemotactic factor of anaphylaxis [ECF-A], kinins and bradykinin). (Chemical mediators of inflammation are discussed in Ch 12.) On the first exposure to the allergen, IgE antibodies are produced and bind to mast cells and basophils. On any subsequent exposures, the allergen links with the IgE bound to mast cells or basophils and triggers degranulation of the cells and the release of chemical mediators from the granules. In this process, the mediators that are released bind to target organs, causing clinical allergy symptoms. These effects include smooth muscle contraction, increased vascular permeability, vasodilation, hypotension, increased secretion of mucus and itching. Fortunately, the mediators are short acting and their effects are reversible. (The mediators and their effects are summarised in Table 13-9.)

Figure 13-9 Steps in a type I allergic reaction. GI, gastrointestinal.

TABLE 13-9 Mediators of allergic response

* see figure 12-2.

A genetic predisposition to the development of allergic diseases exists.¹¹ The capacity to become sensitised to an allergen appears to be the inherited trait rather than the specific allergic disorder. For example, a father with asthma may have a son who has allergic rhinitis.

The clinical manifestations of an anaphylactic reaction depend on whether the mediators remain local or become systemic or whether they affect particular organs. When the mediators remain localised, a cutaneous response termed the wheal-and-flare reaction occurs. This reaction is characterised by a pale wheal containing oedematous fluid surrounded by a red flare from the hyperaemia. The reaction occurs in minutes or hours and is usually not dangerous. A classic example of a wheal-and-flare reaction is the mosquito bite. The wheal-and-flare reaction serves a diagnostic purpose as a means of demonstrating allergic reactions to specific allergens during skin tests.

Common allergic reactions include anaphylaxis and atopic reactions.

Anaphylaxis

Anaphylaxis can occur when mediators are released systemically (e.g. after injection of a drug, after an insect sting). The reaction occurs within minutes and can be life-threatening because of bronchial constriction and subsequent airway obstruction and vascular collapse.^12,13 The target organs affected are shown in Figure 13-10. Initial symptoms include oedema and itching at the site of the exposure to the allergen. Shock can occur rapidly and is manifested by rapid weak pulse, hypotension, dilated pupils, dyspnoea and possibly cyanosis. This is compounded by bronchial oedema and angio-oedema. Death will occur if emergency treatment is not initiated. Some of the important allergens leading to anaphylactic shock in hypersensitive persons are listed in Box 13-3.

Figure 13-10 Clinical manifestations of a systemic anaphylactic reaction.

BOX 13-3 Allergens causing anaphylactic shock

Drugs

Penicillins

Insulins

Tetracycline

Chemotherapeutic agents

Non-steroidal anti-inflammatory drugs

Sulfonamides

Aspirin

Local anaesthetics

Cephalosporins

Wasps, hornets, bees, ants

 

Foods

Eggs

Nuts

Shellfish

Chocolate

Milk

Peanuts

Fish

Strawberries

Animal serums

Tetanus antitoxin

Diphtheria antitoxin

Rabies antitoxin

Snake venom antitoxin

Treatment measures

Blood products (whole blood and components)

Allergenic extracts in hyposensitisation therapy

Iodine-contrast media for intravenous pyelogram or angiogram test

Atopic reactions

An estimated 20% of the population is atopic, having an inherited tendency to become sensitive to environmental allergens. The atopic diseases that can result are allergic rhinitis, asthma, atopic dermatitis, urticaria and angio-oedema.

Allergic rhinitis, or hay fever, is the most common type I hypersensitivity reaction. It may occur year-round (perennial allergic rhinitis) or it may be seasonal (seasonal allergic rhinitis). Airborne substances such as pollens, dust or moulds are the primary cause of allergic rhinitis. Perennial allergic rhinitis may be caused by dust, moulds and animal dander. Seasonal allergic rhinitis is commonly caused by pollens from trees, weeds or grasses. The target areas affected are the conjunctiva of the eyes and the mucosa of the upper respiratory tract. Symptoms include nasal discharge, sneezing, lacrimation, mucosal swelling with airway obstruction, and pruritus around the eyes, nose, throat and mouth. (Treatment of allergic rhinitis is discussed in Ch 26.)

Many patients with asthma have an allergic component to their disease. These patients frequently have a history of atopic disorders (e.g. infantile eczema, allergic rhinitis, food intolerances). Inflammatory mediators produce bronchial smooth muscle constriction, excessive secretion of viscoid mucus, oedema of the mucous membranes of the bronchi and decreased lung compliance. Because of these physiological alterations, patients manifest dyspnoea, wheezing, coughing, tightness in the chest and thick sputum. (Pathophysiology and management of asthma are discussed in Ch 28.)

Atopic dermatitis is a chronic, inherited skin disorder characterised by exacerbations and remissions.¹⁴ It is caused by several environmental allergens that are difficult to identify. Although patients with atopic dermatitis have elevated IgE levels and positive skin tests, the histopathological features do not represent the typical, localised wheal-and-flare type I reactions. The skin lesions are more generalised and involve vasodilation of blood vessels, resulting in interstitial oedema with vesicle formation (see Fig 13-11). (Dermatitis is discussed in Ch 23.)

Figure 13-11 Atopic dermatitis of the lower leg.

Urticaria (hives) is a cutaneous reaction against systemic allergens occurring in atopic persons. It is characterised by transient wheals (pink, raised, oedematous, pruritic areas) that vary in size and shape and may occur throughout the body. Urticaria develops rapidly after exposure to an allergen and may last minutes or hours. Histamine causes localised vasodilation (erythema), transudation of fluid (wheal) and flaring. Flaring is due to blood vessels on the edge of the wheal dilating in response to a reaction augmented by the sympathetic nervous system. Histamine is responsible for the pruritus associated with the lesions. (Urticaria is discussed in Ch 23.)

Angio-oedema is a localised cutaneous lesion similar to urticaria but involving deeper layers of the skin and the submucosa. The principal areas of involvement include the eyelids, lips, tongue, larynx, hands, feet, GI tract and genitalia. Swelling usually begins in the face and then progresses to the airways and other parts of the body. Dilation and engorgement of the capillaries secondary to release of histamine cause the diffuse swelling. Welts are not apparent as in urticaria; the outer skin appears normal or has a reddish hue. The lesions may burn, sting or itch and can cause acute abdominal pain if in the GI tract. The swelling may occur suddenly or over several hours and usually lasts for 24 hours.

Type IV: delayed hypersensitivity reactions

A delayed hypersensitivity reaction—a type IV reaction—is a type of cell-mediated immune response. Although cell-mediated responses are usually protective mechanisms, tissue damage occurs in delayed hypersensitivity reactions. The tissue damage does not occur in the presence of antibodies or complement. Rather, sensitised T lymphocytes attack antigens or release cytokines. Some of these cytokines attract macrophages into the area. The macrophages and enzymes released by them are responsible for most of the tissue destruction. The delayed hypersensitivity response takes 24–48 hours for a reaction to occur.

Clinical examples of a delayed hypersensitivity reaction include contact dermatitis (see Fig 13-12); hypersensitivity reactions to bacterial, fungal and viral infections; and transplant rejections. Some drug sensitivity reactions also fit this category.

Figure 13-12 Contact dermatitis to rubber.

Contact dermatitis

Allergic contact dermatitis is an example of a delayed hypersensitivity reaction involving the skin. The reaction occurs when the skin is exposed to substances that easily penetrate the skin to combine with epidermal proteins. The substance is then recognised as antigenic. Over a period of 7–14 days, memory cells form to the antigen. On subsequent exposure to the substance, a sensitised person develops eczematous skin lesions within 48 hours. The most common potentially antigenic substances encountered are metal compounds (e.g. nickel, mercury), rubber compounds, cosmetics and some dyes.

In acute contact dermatitis the skin lesions appear erythematous and oedematous and are covered with papules, vesicles and bullae. The involved area is very pruritic but may also burn or sting. When contact dermatitis becomes chronic, the lesions resemble atopic dermatitis because they are thickened, scaly and lichenified. The main difference between contact dermatitis and atopic dermatitis is that contact dermatitis is localised and restricted to the area exposed to the allergens, whereas atopic dermatitis is usually widespread.

Microbial hypersensitivity reactions

The classic example of a microbial cell-mediated immune reaction is the body’s defence against the tubercle bacillus. Tuberculosis results from invasion of lung tissue by the highly resistant tubercle bacillus. The organism itself does not directly damage the lung tissue. However, antigenic material released from the tubercle bacilli reacts with T lymphocytes, initiating a cell-mediated immune response. The resulting response causes extensive caseous necrosis of the lung. After the initial cell-mediated reaction, memory cells persist, so subsequent contact with the tubercle bacillus or an extract of purified protein from the organism causes a delayed hypersensitivity reaction. This is the basis for the purified protein derivative (PPD) tuberculosis skin test read 48–72 hours after the injection. (Tuberculosis is discussed in Ch 27.)

ASSESSMENT

For a thorough assessment of a patient with allergies, a complete database must be obtained. This consists of a comprehensive patient history, physical examination, diagnostic examination and skin testing for allergens.

A comprehensive history that covers family allergies, past and present allergies, and social and environmental factors is essential. The information can be obtained from the patient or the patient’s carer. Family history, including information about atopic reactions in relatives, is especially important in identifying at-risk patients. The nurse should assess the specific disorder, clinical manifestations and treatments prescribed. Past and present allergies should be noted. Identifying the allergens that may have triggered a reaction is essential to control allergic reactions. Determination of the time of year that an allergic reaction occurs can be a clue to a seasonal allergen. It is also important to obtain information about any over-the-counter or prescription medications used to treat the allergies.

In addition to identifying the allergen, the nurse should obtain information about the clinical manifestations and course of the allergic reaction. If the patient is female, assessment of symptoms during pregnancy, menstruation or menopause may be important. Social and environmental factors, especially the physical environment, are important. Questions about pets, trees and plants on property; pollutants in the air; and floor coverings, house plants, and cooling and heating systems in the home and workplace can provide valuable information about allergens. In addition, a daily or weekly food diary with a description of any untoward reactions is important. Of particular interest is a screening for any reaction to medication. Finally, questions about the patient’s lifestyle and stress level should be reviewed in connection with the appearance of allergic symptoms.

A comprehensive head-to-toe physical examination should be given to a patient with allergies, with particular attention focused on the site of the allergic manifestations. The nurse should obtain a comprehensive assessment that includes subjective and objective data (see Table 13-10).

TABLE 13-10 Allergies

NURSING ASSESSMENT

DIAGNOSTIC STUDIES

Many specialised immunological techniques can be performed to detect abnormalities of lymphocytes, eosinophils and immunoglobulins. A full blood count (FBC) and serology tests are commonly done.

An FBC with a WBC differential is required, with an absolute lymphocyte count and eosinophil count. Cellular immunodeficiency is diagnosed if the lymphocyte count is below 1.2 × 10⁹/L. T cell and B cell quantification is used to diagnose specific immunodeficiency syndromes. The eosinophil count is elevated with type I hypersensitivity reactions involving IgE immunoglobulins. Serum IgE level is also generally elevated in type I hypersensitivity reactions and serves as a diagnostic indicator of atopic diseases.

The radioallergosorbent test (RAST) is an in-vitro diagnostic test for IgE antibodies to specific allergens. It is safe but less sensitive and takes longer than skin tests for detecting allergens. RAST is helpful in confirming reactivity to various foods or drugs in individuals with a history of severe anaphylactic reactions.

Sputum, nasal and bronchial secretions may also be tested for the presence of eosinophils. If asthma is suspected, pulmonary function tests for vital capacity, forced expiratory volume and maximum mid-expiratory flow rates are helpful.

MULTIDISCIPLINARY CARE

After an allergic disorder is diagnosed, the therapeutic treatment is aimed at reducing exposure to the offending allergen, treating the symptoms and, if necessary, desensitising the person through immunotherapy. All healthcare workers must be prepared for the rare but life-threatening anaphylactic reaction, which requires immediate medical and nursing interventions. It is extremely important that all of a patient’s allergies be listed on the chart, the nursing care plan and the medication record.

Anaphylaxis

Anaphylactic reactions occur suddenly in hypersensitive patients after exposure to the offending allergen. They may occur following parenteral injection of drugs (especially antibiotics) or blood products and following insect stings. The cardinal principle in therapeutic management is speed in: (1) recognising the signs and symptoms of an anaphylactic reaction; (2) maintaining a patent airway; (3) preventing spread of the allergen by using a tourniquet; (4) administering drugs; and (5) treating for shock. Table 13-11 summarises the emergency treatment of anaphylactic shock.

TABLE 13-11 Anaphylactic shock

EMERGENCY MANAGEMENT

IM, intramuscular; IV, intravenous; SC, subcutaneous.

In severe cases of anaphylaxis, hypovolaemic shock may occur because of the loss of intravascular fluid into interstitial spaces that occurs secondary to increased capillary permeability. Peripheral vasoconstriction and stimulation of the sympathetic nervous system occur to compensate for the fluid shift. However, unless shock is treated early, the body will no longer be able to compensate, and irreversible tissue damage will occur, leading to death. (Hypovolaemic shock is discussed in Ch 66.)

NURSING MANAGEMENT: IMMUNOTHERAPY

The nurse is often the person responsible for administering immunotherapy and should always anticipate adverse reactions, especially when using a new-strength dose, after a previous reaction or after a missed dose. Early signs and symptoms indicative of a systemic reaction include pruritus, urticaria, sneezing, laryngeal oedema and hypotension. Emergency measures for anaphylactic shock should be initiated immediately. A local reaction should be described according to the degree of redness and swelling at the injection site. If the area is greater than 1 cm in an adult, the reaction should be reported to the healthcare provider so that the allergen dosage may be decreased.

Immunotherapy always carries the risk of a severe anaphylactic reaction. Therefore, a healthcare provider, emergency equipment and essential drugs should be available whenever injections are given. Record-keeping must be accurate and can be invaluable in preventing an adverse reaction to the allergen extract. Before giving an injection, the nurse should check the patient’s name with the name on the vial and determine the vial strength, the amount of the last dose, the date of the last dose and any reaction information.

The nurse should always administer the allergen extract in an extremity away from a joint so that a tourniquet can be applied for a severe reaction. The site should be rotated for each injection. The nurse must aspirate for blood before giving an injection to ensure that the allergen extract is not injected into a blood vessel. An injection directly into the bloodstream can potentiate an anaphylactic reaction. After the injection is given, the patient should be carefully observed for 20 minutes because systemic reactions are most likely to occur immediately. However, the nurse should warn the patient that a delayed reaction can occur as much as 24 hours later.

LATEX ALLERGIES

Allergies to latex products have become a problem of increasing proportion, affecting both patients and healthcare professionals. The increase in allergic reactions has coincided with the sharp increase in glove use. It is estimated that 5–18% of healthcare workers who are regularly exposed to latex are sensitised. The more frequent and prolonged the exposure to latex, the greater the likelihood of developing a latex allergy.¹⁶ In addition to gloves, many latex-containing products are used in healthcare, such as blood pressure cuffs, stethoscopes, tourniquets, IV tubing, syringes, electrode pads, oxygen masks, tracheal tubes, colostomy and ileostomy pouches, urinary catheters, anaesthetic masks and adhesive tape. Latex proteins can become aerosolised through powder on gloves and can result in serious reactions when inhaled by sensitised individuals. It is recommended that all healthcare facilities use powder-free gloves to avoid respiratory exposure to latex proteins.

NURSING AND COLLABORATIVE MANAGEMENT: LATEX ALLERGIES

The identification of patients and healthcare workers sensitive to latex is crucial in the prevention of adverse reactions. A thorough health history and history of any allergies should be collected, especially on patients with any complaints of latex contact symptoms. Not all latex-sensitive individuals can be identified, even with a careful and thorough history. The greatest risk factor is long-term multiple exposures to latex products (e.g. healthcare personnel, individuals who have had multiple surgeries, rubber industry workers). Additional risk factors include a patient history of hay fever, asthma and allergies to certain foods (see above).

Latex precaution protocols should be used for those patients who are identified as having a positive latex allergy test or a history of signs and symptoms related to latex exposure. Many healthcare facilities have created latex-free product carts that can be used for patients with latex allergies. Occupational health and safety guidelines have been published by the various states and territories in Australia (see Box 13-4).

Because of the potential for severe symptoms of food allergy, patients should be taught to avoid those foods. Other recommendations for people with latex and food allergies include wearing a medical alert bracelet or necklace and carrying an injectable adrenaline pen.

MULTIPLE CHEMICAL SENSITIVITIES

Multiple chemical sensitivities (MCS) is an acquired disorder in which certain people exposed to various chemicals and foods in the environment have many symptoms related to multiple body systems.¹⁷ These symptoms are usually subjective and are not found during physical examination. The patient experiences wide-ranging symptoms, but evidence of pathology or physiological dysfunction is lacking.

Primarily, MCS is found in women. Symptoms include fatigue, headache, nausea, pain, irritable bowel symptoms, dizziness, mouth irritation, disorientation and cough. Almost any chemical can initiate the symptoms of MCS. Odour seems to be the principal trigger. Gas exhaust, perfumes, cigarette smoke, plastics, pesticides and industrial solvents are some of the most common odours associated with MCS. Also, food additives, drugs and naturally occurring foods, including drinking water, often cause sensitivity. The uniqueness of MCS is that symptoms occur at levels below the established guidelines of toxic levels and concentrations.

The causes of MCS are thought to be from immunological, psychological, toxicological and sociological factors. Diagnosis is usually made on the basis of the patient’s health history. There is no established test used to diagnose MCS. Diagnostic tests that are used include provocation–neutralisation and immunological testing (e.g. FBC, lymphocyte subsets, antibody titres), but immunological testing has not been widely accepted as a diagnostic test. The provocation–neutralisation test is done by exposing the patient to certain environmental substances to produce symptoms and then at higher and lower doses to initiate the disappearance of symptoms.

The most effective treatment for MCS is to avoid the chemicals that may trigger the symptoms and create a chemical-free home/workplace. However, this can be difficult in a chemical-dependent society. Other commonly recommended treatments include regular exercise, physiotherapy, massage, prayer and meditation.

AUTOIMMUNE DISEASES

Generally, autoimmune diseases are grouped according to organ-specific and systemic diseases. (Box 13-5 presents examples of autoimmune diseases.) Systemic lupus erythematosus is a classic example of a systemic autoimmune disease characterised by damage to multiple organs. It occurs most frequently in women aged 20–40 years. The aetiology is unknown, but there appears to be a loss of self-tolerance for the body’s own DNA antigens. In SLE, tissue injury appears to be the result of the formation of antinuclear antibodies. For some reason (possibly a viral infection), the cell membrane is damaged and DNA is released into the systemic circulation, where it is viewed as non-self. This DNA is normally sequestered inside the nucleus of cells. On release into the circulation, the DNA antigen reacts with an antibody. Some antibodies are involved in immune complex formation and others may cause damage directly. Once the complexes are deposited, complement is activated and further damages the tissue, especially the renal glomerulus. (SLE is discussed in Ch 64.)

APHERESIS

Apheresis has been used effectively to treat autoimmune diseases and other diseases and disorders.¹⁸ Apheresis is the use of a procedure to separate components of the blood, followed by the removal of one or more of these components. Compound words are often used to describe any particular apheresis procedure, depending on the blood components being collected.¹⁹ Plateletapheresis is the removal of platelets, usually for collection from normal individuals to infuse into patients with low platelet counts (e.g. patients taking chemotherapy who develop thrombocytopenia). Leucocytapheresis is a general term indicating the removal of WBCs and is used in chronic myelogenous leukaemia to remove high numbers of leukaemic cells. Lymphocytapheresis is used to decrease high lymphocyte counts, such as in individuals with chronic lymphocytic leukaemia. Another type of apheresis is peripheral stem cell collection (also called haematopoietic progenitor cell collection), which is used to collect stem cells from peripheral blood. These stem cells can then be used to repopulate a person’s bone marrow after high-dose chemotherapy (see section on haematopoietic stem cell transplants in Ch 15).

PRIMARY IMMUNODEFICIENCY DISORDERS

The basic categories of primary immunodeficiency disorders are: (1) phagocytic defects; (2) B cell deficiency; (3) T cell deficiency; and (4) a combined B cell and T cell deficiency (see Table 13-12).

TABLE 13-12 Primary immunodeficiency disorders

PMNs, polymorphonuclear neutrophils

SECONDARY IMMUNODEFICIENCY DISORDERS

Some of the important factors that may cause secondary immunodeficiency disorders are listed in Box 13-6. Drug-induced immunosuppression is the most common. Immunosuppressive therapy is prescribed for patients to treat autoimmune disorders and to prevent transplant rejection. In addition, immunosuppression is a serious side effect of drugs used in cancer chemotherapy. Generalised leucopenia often results, leading to a decreased humoral and cell-mediated response. Therefore, secondary infections are common in immunosuppressed patients.

Malnutrition alters cell-mediated immune responses. When protein is deficient over a prolonged period, atrophy of the thymus gland occurs and lymphoid tissue decreases. In addition, an increased susceptibility to infections always exists.

Hodgkin’s lymphoma greatly impairs the cell-mediated immune response, and patients may die from severe viral or fungal infections. (Hodgkin’s lymphoma is discussed in Ch 30.) Viruses, especially rubella, may cause immunodeficiency by direct cytotoxic damage to lymphoid cells. Systemic infections can place such a demand on the immune system that resistance to a secondary or subsequent infection is impaired.

Radiation can destroy lymphocytes either directly or through depletion of stem cells. As the radiation dose is increased, more bone marrow atrophies, leading to severe pancytopenia and suppression of immune function. Splenectomy in children is especially dangerous and may lead to septicaemia simply from respiratory infections.

Stress may alter the immune response. This response involves interrelationships among the nervous, endocrine and immune systems.

HUMAN LEUCOCYTE ANTIGEN AND DISEASE ASSOCIATIONS

The early interest in HLA was stimulated by its potential role in matching donors and recipients of organ transplants. During the last few years, interest in the association between HLA and disease has grown. Strong associations between HLA type and susceptibility to certain diseases have been demonstrated.²⁰ HLA disease associations mean that the frequency of a defined HLA allele is significantly increased in patients with a certain disease when compared with ethnically matched controls. Most of the HLA-associated diseases are classified as autoimmune disorders. Examples of HLA types and disease associations include: (1) HLA-B27 and ankylosing spondylitis; (2) HLA-DR2 and HLA-DR3 and SLE; and (3) HLA-DR3 and HLA-DR4 and diabetes mellitus.

The discovery of HLA associations with certain diseases is a major breakthrough in understanding the genetic bases of these diseases. It is now known that at least part of the genetic basis of HLA-associated diseases lies in the HLA region, but the actual mechanisms involved in these associations are still unknown. However, most individuals who inherit an HLA type associated with a disease will never develop the disease.

The association between HLA and certain diseases is presently of little practical clinical importance. Nevertheless, there is promise for the development of clinical applications in the future. For example, with certain autoimmune diseases it may be possible to identify members of a family at greatest risk of developing the same or a related autoimmune disease. These persons would need close medical supervision, preventative measures implemented (if possible), and early diagnosis and treatment instituted to prevent chronic complications.

TISSUE TYPING

The recipient must receive a transplant from an ABO blood group–compatible donor (see Table 29-10). The donor and recipient do not need to share the same Rh factor.

TRANSPLANT REJECTION

Rejection is one of the major problems following organ transplantation. Rejection of organs will occur as a normal immune response to foreign tissue. The rejection can be controlled by immunosuppression therapy, ABO and HLA matching, and ensuring that the cross-match is negative. Unfortunately, many different HLAs exist and a perfect match is nearly impossible unless the tissue is from oneself or an identical twin. Rejection can be hyperacute, acute or chronic. Prevention, early diagnosis and treatment of rejection are essential for long-term graft function.

Acute rejection

Acute rejection most commonly manifests in the first 6 months after transplantation. This type of rejection is usually mediated by the recipient’s lymphocytes, which have been activated against the donated (foreign) tissue or organ (see Fig 13-15). Another type of acute rejection occurs when anti-donor antibodies develop after transplantation.

Figure 13-15 Mechanism of action of T cytotoxic lymphocyte activation and attack on transplanted tissue. The transplanted organ (e.g. kidney) is recognised as foreign and activates the immune system. T helper cells are activated to produce interleukin-2 (IL-2), and T cytotoxic lymphocytes are sensitised. After the T cytotoxic cells proliferate, they attack the transplanted organ.

It is not uncommon to have at least one rejection episode, especially with organs from deceased donors. These episodes are usually reversible with additional immunosuppressive therapy that may include increased corticosteroid doses or polyclonal or monoclonal antibodies. Unfortunately, immunosuppressants increase the risk for infection. To combat acute rejection, all patients with transplants require long-term use of immunosuppressants, putting them at a high risk for infection, especially in the first few months after transplant when the immunosuppression doses are highest.

IMMUNOSUPPRESSIVE THERAPY

Immunosuppressive therapy requires a balance. On the one hand, the immune response needs to be suppressed to prevent rejection of the transplanted organ. On the other hand, an adequate immune response needs to be maintained to prevent overwhelming infection and the development of malignancies. Many of the medications used to achieve immunosuppression have significant side effects. Two are of particular concern: (1) increased risk of infection; and (2) increased risk of malignancies. Furthermore, because transplant recipients must take immunosuppressants for life, the risk of toxicity continues for the rest of their lives.

Immunosuppressant drugs are listed in Table 13-13. By using a combination of agents that work in different phases of the immune response (see Fig 13-16), lower doses of each drug produce effective immunosuppression while minimising side effects. The major immunosuppressive agents are: (1) calcineurin inhibitors, including cyclosporin and tacrolimus; (2) corticosteroids (prednisone, methylprednisolone); (3) mycophenolate mofetil; and (4) sirolimus. Azathioprine and cyclophosphamide have been used in the past, but are not commonly used now because they have been replaced with safer, more effective drugs. Antilymphocyte globulin (ALG) and muromonab-CD3 are IV medications used for short periods to prevent early rejection or reverse acute rejection.

TABLE 13-13 Immunosuppressive therapy

DRUG THERAPY

GI, gastrointestinal; IL, interleukin; IV, intravenous; PO, by mouth.

Figure 13-16 Sites of action for immunosuppressive agents.

Immunosuppressive protocols are highly variable among transplant centres, with different combinations of medications being used. Most patients are initially on triple therapy. The standard triple therapy usually includes a calcineurin inhibitor, a corticosteroid and mycophenolate mofetil. The doses of immunosupressant drugs will be reduced over time. Patients taking corticosteroids may be weaned off after a few years. There is a trend in many transplant centres to use immunosuppression protocols that do not contain corticosteroids because of their many side effects.

Monoclonal antibodies

Monoclonal antibodies are used for preventing and treating acute rejection episodes. (Fig 13-17 shows how monoclonal antibodies are made.) Muromonab-CD3 was the first of these monoclonal antibodies to be used in clinical transplantation. It is a mouse monoclonal antibody that binds with the CD3 antigen found on the surface of human thymocytes and mature T cells. It is an anti–antigen receptor antibody that interferes with the function of the T lymphocyte, the pivotal cell in the response to graft rejection. It is administered via IV push daily for 7–14 days. All T cells are affected rather than just the subset active in graft rejection. Within minutes after the initial infusion of muromonab-CD3, the number of circulating T cells decreases significantly.

Figure 13-17 Monoclonal antibodies are identical antibodies made by clones of a single antibody-producing cell. The target antigen is injected into a mouse. Plasma cells are harvested from the spleen of the mouse and fused with myeloma cells. The fused cells, or hybridomas, are then cloned. A clone can secrete monoclonal antibodies over a long period of time.

A flu-like syndrome occurs during the first few days of treatment due to cytokine release. Side effects include fever, rigors, headache, myalgias and various GI disturbances. To reduce the expected side effects of muromonab-CD3, patients should receive acetaminophen, diphenhydramine and IV corticosteroids before administering the dose.

Newer generation monoclonal antibodies include daclizumab and basiliximab. These monoclonal antibodies are a hybrid of mouse and human antibodies and have fewer side effects than muromonab-CD3 because they have been humanised.