Practice nursing care to clients with Inflammation and the Immune Response

 

Most peo-lowever, are healthy more often than they are ill. Inflammation and immunity are the two major defense mechanisms protecting the immunocompetent person against diseases and other problems when the body is invaded by microorganisms. These same defenses also help the body to recover after injury or tissue damage. Therefore inflammation and immunity have critical roles in maintaining health and preventing disease. Immune function is altered to some degree by many diseases, injuries, and medical therapies. These alterations in im­mune function may be temporary or permanent, but they al­ways endanger the health of the client.

 

OVERVIEW

Immunity is composed of many cell functions that protect people against the effects of injury or microscopic invasion. People interact with many other living organisms in the environment. The size of these organisms varies from large (other humans and animals) to microscopic (bacteria, viruses, molds, spores, pollens, protozoa, and cells from other people or animals). As long as microorganisms do not enter the body's internal environment, they pose no threat to health. The body has some defenses to prevent microorganisms from gaining access to the internal environment. These defenses are not perfect, and invasion of the body's internal environment by microorganisms occurs often. Invasion occurs much more frequently than does an actual disease or illness because of proper immune functioning.

Purpose of Inflammation and Immunity

The purpose of inflammation and immunity is to neutralize, eliminate, or destroy microorganisms that invade the internal environment. To accomplish this purpose without harming the body, immune system cells use defensive actions only against non-self proteins and cells. Therefore immune system cells can distinguish between the body's own healthy self cells and other, non-self proteins and cells.

Self Versus Non-Self    

Non-self proteins and cells include infected body cells, cancer cells, and all invading cells and microorganisms. This ability to recognize self versus non-self, which is necessary to prevent healthy body cells from being destroyed along with the in­vaders, is called self-tolerance. The immune system cells are the only body cells capable of distinguishing self from non-self. The process of self-tolerance is possible because of the different kinds of proteins present on cell membranes.

All organisms are made up of cells. Each cell is surrounded by a plasma membrane (Figure 20-1).

 

Figure 20-1 Properties of human cell membranes

 

With any cell, many different proteins protrude through the plasma mem­brane. For example, in liver cells, many different proteins are present on the cell surface (protruding through the mem­brane). The amino acid sequence of each protein type differs from that of all other protein types. Some of these proteins are found on the liver cells of all animals (including humans) that have livers, because these protein types are specific to the liver and actually serve as a marker for liver tissues.

Other protein types are found only on the liver cells of humans, because these protein types are specific markers for humans. Still other protein types are found only on the liver cells of humans with a specific blood type. In addition, each person's liver cells have surface protein types that are spe­cific to that individual. These proteins are unique to the per­son and would be identical only to the proteins of an identi­cal twin. These unique proteins, found on the surface of all body cells of that individual, serve as a "universal product code" or a "cellular fingerprint" for that person (Workman, Ellerhorst-Ryan, & Koertge, 1993). The proteins that make up the universal product code for one person are recognized as "foreign," or non-self, by the immune system of another person. Because the cell-surface proteins are non-self to an­other person's immune system, they are antigens, proteins capable of stimulating an immune response.

This unique universal product code for each person is composed of the human leukocyte antigens (HLAs). "Leukocyte antigen" is actually an incorrect term, because these antigens are also present on the surfaces of nearly allbody cells, not just on leukocytes. HLAs are a normal part of the person and act as antigens only if they enter another per­son's body. These antigens specify the tissue type of a per­son. Other names for these personal cellular fingerprints are human transplantation antigens, human histocompatibility antigens, and class I antigens.

Humans have about 40 major HLAs (known as histocompatibility antigens) that are determined by a series of genes collectively called the major histocompatibility complex (MHC). However, the exact number of minor HLAs that any person has is not known. The specific antigens that any per­son has (of a large number of possible antigens) are geneti­cally determined by which MHC genes were inherited from his or her parents.

This universal product code (HLA) is a key feature for recognition and self-tolerance. The immune system cells con­stantly come into contact with other body cells and with any invader that happens to enter the body's internal environment. At each encounter, the immune system cells compare the sur­face protein universal product codes (HLAs) to determine whether or not the encountered cell belongs in the body's in­ternal environment (Figure 20-2).

 

Figure 20-2    Determination of self versus non-self cells.

 

If the encountered cell's universal product code (HLA) perfectly matches the HLA of the immune system cell, the encountered cell is considered self and is not attacked by the immune system cell. If the en­countered cell's universal product code (HLA) does not per­fectly match the HLA of the immune system cell, the en­countered cell is considered non-self, or foreign. The immune system cell takes action to neutralize, destroy, or eliminate the foreign invader.

Immune function changes during a person's life, according to nutritional status, environmental conditions, medications, the presence of disease, and age. Immune function is most ef­ficient when people are in their 20s and 30s and slowly de­clines with increasing age. The older adult has decreased im­mune function, causing greater susceptibility to a variety of pathologic conditions.

 Nursing Implications

Neutrophil counts may be normal, but activity is reduced or impaired. Clients may have an infection but not show standard changes in white blood cell counts. Not only is there potential loss of protection through inflammation, but minor infections may be overlooked until the client becomes severely infected or septic.

Older adults are less able to make new anti­bodies in response to the presence of new antigens. Thus they should receive immu­nizations, such as "flu shots" and the pneumococcal vaccination.

Older adults may not have sufficient antibodies present to provide protection when they are re-exposed to microorganisms against which they have already generated antibodies. Thus older clients need to avoid people with viral infections and to receive "booster" shots for old vaccinations and immunizations.

Skin tests for tuberculosis may be falsely negative.

Older clients are more at risk for bacterial and fungal infections, especially on the skin and mucous membranes, in the respiratory tract, and in the genitourinary tract.

 

Organization of the Immune System

 

 

 

The immune system is not confined to any one organ or area of the body. The cells of the immune system originate in the bone marrow. Some of these cells mature in the bone marrow; others leave the bone marrow and mature in different specific body sites. After maturation, most immune system cells are released into the blood, where they circulate to most areas of the body and exert specific effects.

The bone marrow is the source of all blood cells, including immune system cells. The bone marrow produces an imma­ture, undifferentiated cell called a stem cell (Guyton & Hall, 2000). This immature stem cell is also described as pluripo-tent, multipotent, and totipotent. These terms describe the po­tential future of the stem cell. When the stem cell is first cre­ated in the bone marrow, it is undifferentiated. The cell is not yet committed to maturing into a specific blood cell type. At this stage, the stem cell is flexible and has the potential to be­come any one of a variety of mature blood cells. Figure 20-3 presents a scheme showing the major possible maturational outcomes for the pluripotent stem cell. The type of mature blood cell the stem cell becomes depends on which matura­tional pathway it follows.

The maturational pathway of any stem cell depends on body needs at the time, as well as on the presence of specific hormones (cytokines, factors, or poietins) that direct commit­ment and induce maturation.

For example, erythropoietin is made in the kidney. When immature stem cells are exposed to erythropoietin, the immature stem cells commit to following the erythrocyte maturational pathway and become mature red blood cells.

White blood cells (leukocytes) are cells that protect the body from the effects of invasion by foreign microorganisms. These cells are the immune system cells. Table 20-1 summarizes the functions of different immune system cells. The leukocytes can provide protection through a variety of defensive actions (Abbas, Lichtman, & Pober, 1997). These actions include the following:

·                    Recognition of self versus non-self

·                    Phagocytic destruction of foreign invaders, cellular de­bris, and unhealthy or abnormal self cells

·                    Lytic destruction of foreign invaders and unhealthy self cells

·                    Production of antibodies directed against invaders Activation of complement

·                    • Production of hormones that stimulate increased forma­tion of leukocytes in bone marrow

·                    Production of hormones that increase specific leukocyte growth and activity

The three processes necessary for immunity and the cell types involved in these responses can be categorized as in­flammation; antibody-mediated immunity (AMI), also known as humoral immunity; and cell-mediated immunity (CMI). These three processes use different defensive actions, and each process influences or requires assistance from the other two processes. Therefore full immunity, or im-munocompetence, requires the function and interaction of all three processes.

INFLAMMATION

Inflammation provides immediate protection against the ef­fects of tissue injury and invading foreign proteins. The abil­ity to produce an inflammatory response is critical to health and well-being. Inflammation differs from AMI and CMI in two important ways:

1. Inflammatory responses provide immediate but short-term protection against the effects of injury or foreign invaders rather than sustained, long-term immunity on repeated exposure to the same foreign invaders. 2. Inflammation is a nonspecific body defense to invasion or injury and can be started quickly by almost any event.

2. Inflammation is nonspecific; the same tissue responses oc­cur with any type of injury or invasion, regardless of the lo­cation on the body or the specific initiating agent.

Therefore the inflammatory processes stimulated by a scald burn to the hand are the same as the inflammatory processes stimulated by excessive acid in the stomach or the presence of bacteria in the middle ear. How widespread the symptoms of inflamma­tion are in the body depends on the intensity, severity, duration, and extent of exposure to the initiating injury or inva­sion.

For example, a splinter in the finger triggers an inflam­matory response only at the splinter site, whereas a burn in­juring 60% of the skin surface results in an inflammatory response involving the entire body.

 

Purpose

Inflammatory responses start tissue actions that cause visible and uncomfortable symptoms. Despite the discomfort, these inflammatory actions are important in ridding the body of harmful microorganisms. However, if the inflammatory response is excessive, tissue damage may result.

 

 

Infection

A confusing issue regarding inflammation is that this process occurs in response to tissue injury, as well as to invasion by microorganisms or other foreign proteins. Infection is usually accompanied by inflammation; however, inflammation can occur without invasion by microorganisms.

For example, inflammatory responses not associated with infection occur with sprain injuries to joints, myocardial infarction, sterile surgical incisions, thrombophlebitis, and blister formation. Examples of inflammatory responses caused by noninfectious invasion by foreign proteins include allergic rhinitis, contact dermatitis, and other allergic reactions. Inflammatory responses caused by infection with microorganisms include oti-tis media, appendicitis, bacterial peritonitis, viral hepatitis, and bacterial myocarditis, among others. Thus inflammation does not always mean that an infection is present.

 

Cell Types Involved in Inflammation

The leukocytes associated with inflammatory responses are neutrophils, macrophages, eosinophils, and basophils. Neu-trophils and macrophages participate in phagocytosis, destroying and eliminating foreign invaders. Basophils and eosinophils act on blood vessels to cause tissue-level responses.

 NEUTROPHILS

 

 

Natural anti-microbial expression in the human neutrophil. Neutrophils contain two types of granules that contain natural anti-microbials. The azurophil granules contain α-defensins while specific granules contain lactoferrin and the cathelicidin, hCAP-18. Lysozyme is present in both granule types.

 

 Description and Origin

Mature neutrophils normally make up between 55% and 70% of the total white blood cell count. Neutrophils arise from the stem cells and complete the maturation process in the bone

 

Figure 20-4 • The three divisions of immunity. Each division (inflammation, antibody-mediated immunity, and cell-mediated immunity) has an important independent function. In addition, the function of each division of immunity is profoundly influenced by the other two divisions. Most important, optimal function of all three divisions is necessary for complete immunity.

 

marrow (Figure 20-5). They belong to the class of leukocytes known as granulocytes because of the large number of gran­ules present inside each cell. Other names for neutrophils are based on their physical appearance and degree of maturation. Mature neutrophils are also called segmented neutrophils ("segs") or polymorphonuclear cells ("polys," PNMs,) be­cause of their segmented nucleus. Less mature neutrophils are called band neutrophils ("bands" or "stabs") because of their nuclear appearance.

 

Figure 20-5  Neutrophil maturation.

 

 

 

 

 

 

Differential

%

/mm3

 

 

 

 

 

 

Total WBC

100

10,000

segs

62

6200

bands

5

500

monos

3

300

lymphs

28

2800

eosin

1.5

150                 t

baso

0.5

50

 

 

 

 

Figure 20-6   Example of a laboratory slip showing the differential of a normal white blood cell count.

 

Usually, maturation from the stem cell to the functional segmented neutrophil requires 12 to 14 days. This time can be shortened by certain conditions that stimulate the body to pro­duce specific cytokines, such as granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor.

In the immunocompetent, healthy person, more than 100 billion fresh, mature neutrophils are released from the bone marrow into the systemic circulation daily (Abbas, Lichtman, & Pober, 1997). This massive production of neutrophils is necessary because the life span of a circulating neutrophil is extremely short, averaging only about 12 to 18 hours.

 Function

Although the neutrophils are the largest group of circulating leukocytes, each individual cell is small. This army of power­ful small cells provides the first internal line of defense, via phagocytosis, against foreign invaders (especially bacteria) in blood and extracellular fluid. It is the granules inside the neu­trophils that cause the phagocytic destruction of foreign in­vaders. The mature neutrophil has many granules containing different enzymes that can degrade invaders.

Neutrophils have a small energy supply and no way of replenishing either that energy supply or the enzymes used in degradation. Thus each neutrophil can take part in only one episode of phagocytic destruction before supplies are exhausted.

The mature, segmented neutrophil is the only neutrophil stage capable of effective phagocytosis. Because this cell type is responsible for continuous, instant, nonspecific pro­tection against microorganisms, the percentage and actual number of circulating white blood cells that are mature neu­trophils reliably measure a client's susceptibility to infec­tion: the higher the numbers, the greater the resistance to in­fection. This measurement is the absolute neutrophil count (sometimes called the absolute granulocyte count or total granulocyte count).

The differential of a normal white blood cell count shows the number and percent of all the different types of circulating leukocytes (see Figure 20-6). This test indicates that most of the neutrophils released into the blood from the bone marrow are segmented neutrophils; only a small percentage are band neutrophils. The less mature neutrophil forms should not be present in the blood. Some conditions cause the population of neutrophils in the blood to change from mostly segmented neutrophils to less mature forms. This situation is termed a left shift because the segmented neutrophil, which is seen at the far right of the neutrophil maturational pathway (see Figure 20-5), no longer represents the greatest number of circulating neutrophils. Instead, the population is made up primarily of one of the cell types found farther left on the neutrophil maturational pathway.

A left shift is a clinical sign indicating that the client's bone marrow cannot produce enough mature neutrophils to keep pace with the continuing presence of microorganisms and is releasing immature neutrophils into the blood. Unfor­tunately, most of these immature neutrophils are of no benefit, because they are not capable of phagocytosis.

 

 

Fig.  Schematic process of neutrophil adhesion and transendothelial migration. In response to inflammatory stimuli, adhesion molecules such as selectins are upregulated on endothelial cells and neutrophils, and neutrophils roll along the vascular endothelial wall through selectin-mediated weak interactions (I). This is followed by firm adhesion of neutrophils to endothelium through binding of integrins on the neutrophil surface to ICAM-1 or VCAM-1 on the endothelial cell surface (II). Subsequently, neutrophils transmigrate through the microvascular endothelium via a process involving complex interactions with endothelial cell-cell junction molecules, including VE-cadherin, JAMs, and PECAM-1 (III).

 

 

MACROPHAGES

 

 

Description and Origin

Macrophages arise from the committed myeloid stem cells in the bone marrow and form the mononuclear-phagocyte system. The stem cells first form monocytes and are released into the blood at this stage. Until they mature, monocytes have only limited activity. Most monocytes move from the blood into various tissues, where they complete the maturation process into macrophages. Some macrophages become "fixed" in position within the tissues, whereas others remain mobile in the tissue's interstitial fluid. Macrophages in various tissues have slightly different appearances and different names.

The liver and spleen contain the greatest concentration of these cells.

Tissue macrophages have relatively long life spans, lasting from months to years. Macrophages are the largest of all the leukocytes and contain many lytic enzymes.

 

Reticuloendothelial system.

 

 

TABLE 20-2   •  TISSUE

MACROPHAGES

Tissue

Macrophage

Lung

Alveolar macrophage

Connective tissue

Histiocyte

Brain

Microglial cell

Liver

Kupffer cell

Peritoneum

Peritoneal macrophage

Bone

Osteoclast

Joints

Synovial type A cell

Kidney

Mesangial cell

 

 

 

 

 Function

Macrophages play more than one role in protecting against invasion and tissue injury. These cells are important in immediate inflammatory responses and can also stimulate the longerlasting immune responses associated with antibody-mediated immunity (AMI) and cell-mediated immunity (CMI). Specific macrophage functions include phagocytosis, repair of injured tissues, antigen presenting/processing, and secretion of cytokines that help control the immune system.

The inflammation-associated macrophage function is phagocytosis. Macrophages are efficient at distinguishing between self and non-self and are especially effective at trapping invading cells. Unlike neutrophils, macrophages are able to regenerate the energy supplies and enzymes needed to degrade foreign protein. Therefore each macrophage can take part in many phagocytic events during its life span.

 

 

 

 

 

 

 

 

 BASOPHILS

 

Figure. A 3d render of a basophils

 

 

 Description and Origin

The rarest leukocytes, basophils, arise from myeloid stem cells and are released from the bone marrow after a short maturation period. Basophils cause the obvious signs and symptoms accompanying inflammation, as described in the following section.

 

Function

Basophils have granules containing many chemicals (vasoactive amines) that act on blood vessels, including heparin, histamine, serotonin, kinins, and leukotrienes. When released into the blood, most of these chemicals act on smooth muscle and blood vessel walls.

Heparin inhibits coagulation of blood macrophages.

Areas of highest concentration of tissue and other protein-containing fluids. Histamine constricts the smooth muscles of the respiratory system and small veins.

Constriction of respiratory smooth muscle narrows the lumen of airways and restricts breathing. Constriction of veins inhibits blood flow through small veins and decreases venous return. This effect causes blood to collect in capillaries and small arterioles.

Kinins cause vasodilation of arterioles and, together with serotonin, increased capillary permeability.

These actions permit the plasma portion of the blood to leak into the interstitial space. This chemical-induced process is called vascular leak syndrome.

 

EOSINOPHILS

 

 

 Description and Origin

Eosinophils arise from the myeloid line and contain more vasoactive chemicals. Usually, only 1% to 2% of the total white blood cell count is composed of eosinophils.

 

 Function

Eosinophils are not efficient phagocytes, although they can act against infestations of parasitic larvae. Eosinophil granules contain many substances with vastly different actions.

Some substances are chemicals that produce inflammatory re actions when released. In addition, certain enzymes from eosinophils degrade the vasoactive chemicals released by other leukocytes and in this way control or modulate the extent of inflammatory reactions. This is why the number of circulating eosinophils increases during an allergic response.

 

 

 

 

Phagocytosis

The key mechanism for the successful outcome of inflammationis phagocytosis.

Phagocytosis is the process by which leukocytes engulf invaders and destroy them by enzymatic degradation. Phagocytosis rids the body of debris after tissue injury and destroys foreign invaders. Of all the leukocytes, neutrophils and macrophages perform phagocytosis most efficiently.

 

 

 

 

 EXPOSURE AND INVASION

Leukocytes that engage in phagocytosis and stimulate inflammation are present in the blood and most other extracellular fluids. For phagocytosis to be initiated, leukocytes must first be exposed to debris from damaged tissues or foreign proteins (antigens). Therefore the initiating event for phagocytosis is injury or invasion.

 ATTRACTION

Phagocytosis is effective only when the phagocytic cell comes into direct contact with the target (antigen, invader, or foreign protein). Special chemical substances can act as chemical magnets that attract neutrophils and macrophages. These substances are called chemotaxins or leukotaxins. Damaged tissues and blood vessels secrete chemotaxins. In addition, substances that combine with the surface of invading foreign proteins serve as chemotaxins. This combining (and attracting) mechanism is described next.

 ADHERENCE

Because phagocytosis requires direct contact of the leukocyte with its intended target, the phagocytic cell must first bind to the surface of the target. A special process called opsonization helps provide direct contact of the phagocyte with its target.

• Opsonization

The word opsonin is Greek and literally means "to cover food with a sauce in preparation for eating." In inflammation, opsonins coat a target cell (antigen or foreign protein); this changes the target cell's surface charge and makes it easier for phagocytic cells to stick to it. Many substances can act as opsonins. Some of these substances are particles from dead neutrophils, antibodies, and activated (fixated) complement components.

• Complement Activation and Fixation

One mechanism of opsonization and phagocytic adherence to target cells is complement activation and fixation.

Twenty different inactive protein components of the complement system are present in the blood. These components are made by the liver. With proper stimulation, individual complement proteins become activated, join together, surround an antigen, and cause dramatic actions as a result of fixation (adherence) to the antigen. Complement fixation must occur quickly, but consequences can be devastating if its effects are exerted at the wrong time or in the wrong place. Therefore the complement system works as a cascade reaction (chain reaction), with many sites of activation and control.

• RECOGNITION

When the phagocytic cell sticks to the surface of the target cell, recognition of non-self occurs. The body's phagocytic cells examine the universal product codes (human leukocyte antigens [HLAs]) of whatever they encounter. Recognition of non-self is enhanced by opsonins on the surface of the target cell. Phagocytic cells proceed with phagocytosis only if the target cell is recognized either as foreign or as debris from damaged self cells.

 CELLULAR INGESTION

Because phagocytic destruction occurs inside the cell, the target cell or foreign protein must be brought inside the phagocyticcell. The phagocytic cell changes its shape and bends its membrane around to enclose (engulf) the target cell. Once the target is enclosed in the phagocytic cells, a vacuole is formed.

 PHAGOSOME FORMATION

When the phagocyte's granules are inside the vacuole, the structure is called a phagosome (or phagolysosome).

These granules break open and release enzymes into the fluid of the phagosome and destroy the ingested target.

 

DEGRADATION

The enzymes within the phagosome exert their specific effects on different parts of the ingested target. The target is broken down into smaller pieces until only minute particles remain to be removed from the body as debris.

 

 

Sequence of Inflammatory Responses

Inflammatory responses that protect the body against the effects of tissue injury or invasion by foreign proteins occur in a predictable sequence. The sequence is the same regardless of the initiating stimulus. Responses at the tissue level cause the five cardinal manifestations of inflammation: warmth, redness, swelling, pain, and decreased function. These inflammatory responses occur in three distinct stages, although the timing of the stages may overlap .

• STAGE I (VASCULAR)

In stage I of the inflammatory response, the early effects involve changes at the blood vessel level. When inflammation results from tissue injury, this stage has two phases.

 Phase I

The first phase is an immediate, short-term constriction of arterioles and venules as a direct result of physical trauma to vascular smooth muscle. This phase lasts only seconds to minutes and may be so short that the person undergoing the response is unaware of the vasoconstriction.

 Phase II

The second phase is characterized by increased blood flow to the area (hyperemia) and swelling (edema formation) at the site of injury or invasion. Injured tissues and the leukocytes in this area secrete vasoactive chemicals (histamine, serotonin, and kinins) that cause constriction of the small veins and dilation of the arterioles in the immediate area. These changes in blood vessel dilation lead to redness and increased warmth of the tissues. This response increases the supply of nutrients at the tissue level by increasing blood flow.

Some of these chemicals increase capillary permeability, allowing blood plasma to leak into the interstitial space. This response causes swelling and pain. Pain, although uncomfortable, increases the person's awareness that a problem exists and encourages action to avoid further injury or inflammation.

Edema formation at the site of injury or invasion is also a helpful event. This swelling protects the area from further injury by creating a cushion of fluid. The extra fluid can dilute the concentration of any toxins or microorganisms that have entered the area. The duration of these responses depends on the severity of the initiating event.

The major leukocyte involved in stage I of the inflammatory response is the tissue macrophage. The response of tissue macrophages is immediate, because they are already in place at the site of injury or invasion. This response, however, is limited, because the number of macrophages is so small. In addition to functioning in phagocytosis, the tissue macrophages secrete several cytokines to enhance the inflammatory response. One cytokine is colony-stimulating factor, which stimulates the bone marrow to reduce the time of leukocyte production from 14 days to a matter of hours.

Tissue macrophages also secrete substances that increase the release of neutrophils from the bone marrow and attract them to the site of injury or invasion, which leads to the next stage of inflammation.

 STAGE II (CELLULAR EXUDATE)

Stage II of inflammation is characterized by neutrophilia (increased number of circulating neutrophils), secretion of many factors into the interstitial fluid, and the formation of exudate, commonly called pus.

The most active leukocyte in this stage is the neutrophil.

Under the influence of chemotactic agents and cytokines, the neutrophil count can increase up to five times within 12 hours after the onset of inflammation. At the site of inflammation, neutrophils attack and destroy foreign materials and remove dead tissue through phagocytosis.

During acute inflammatory responses, the healthy person can produce enough mature neutrophils to keep pace with the effects of injury or invasion and to prevent the invaders from multiplying. At the same time, the leukocytes secrete cytokines, which increase reproduction of tissue macrophages and bone marrow production of monocytes.

Although this reaction begins slowly, its effects are long lasting.

When infectious processes stimulating inflammation are longer or chronic, the bone marrow cannot produce and release enough mature neutrophils into the blood to keep pace with the ability of microorganisms to multiply. In this situation, the bone marrow begins to release only immature neutrophils.

Such a reduction in the number of functional phagocytic neutrophils limits the effectiveness of the inflammatory response and increases the susceptibility to microbial infections.

• STAGE III (TISSUE REPAIR AND REPLACEMENT)

Although stage III is completed last, it begins at the time of injury and is critical to the ultimate function of the inflamed area.

Some of the leukocytes involved in inflammation start the replacement of lost tissues or repair of damaged tissues by inducing the remaining healthy tissue to divide. In tissues that are unable to divide, leukocytes stimulate new blood vessel growth and scar tissue formation. Because scar tissue does not behave like normal tissue, loss of function occurs where damaged tissues are replaced with scar tissue. The extent of the functional loss is determined by the percentage of tissue replaced by scar tissue.

Inflammation alone cannot confer immunity; however, the interaction of inflammatory cells with lymphocytes helps provide long-lasting immunity against re-exposure to the same microorganisms. Long-lasting immune actions are generated by antibody-mediated immunity (AMI) and cell-mediated immunity (CMI).

ANTIBODY-MEDIATED IMMUNITY

Antibody-mediated immunity (AMI), also known as humoral immunity, involves antigen-antibody interactions to neutralize, eliminate, or destroy foreign proteins. Antibodies for these actions are produced by populations of Â-lymphocytes.

Purpose

The primary functions of B-lymphocytes are to become sensitized to a specific foreign protein (antigen) and to produce antibodies directed specifically against that protein. The antibody (rather than the actual B-lymphocyte) then takes part in one of several actions to neutralize, eliminate, or destroy that antigen.

Cell Types Involved in Antibody-Mediated Immunity

The leukocytes with the most direct role in AMI are the Blymphocytes. Macrophages and T-lymphocytes (discussed later under Cell-Mediated Immunity, p. 321) cooperate with B-lymphocytes to start and complete antigen-antibody interactions.

Therefore for optimal AMI, the entire immune system must function adequately.

B-lymphocytes start life as pluripotent stem cells in the bone marrow, the primary lymphoid tissue. The pluripotent stem cells destined to become B-lymphocytes commit early to following the lymphocyte maturational pathway (see Figure 20-3). At the point of commitment these stem cells are no longer pluripotent but are limited to differentiation into lymphocytes. The committed lymphocyte stem cells are released from the bone marrow into the blood. They then migrate into various secondary lymphoid tissues, where maturation is completed.

In humans the secondary lymphoid tissues for B-lymphocyte maturation are the spleen, germinal centers of lymph nodes, tonsils, and Peyer's patches of the intestinal tract.

Antigen-Antibody Interactions

The body learns to make enough of any specific antibody to provide long-lasting immunity against specific microorganisms or toxins. Seven steps in a series of special interactions are required for the production of a unique and specific antibody directed against a unique and specific antigen whenever the person is exposed to that antigen. These steps are exposure and invasion, antigen recognition, lymphocyte sensitization, antibody production and release, antigen-antibody binding, antibody-binding reactions, and sustained immunity memory (Figure 20-9).

 

 

• EXPOSURE AND INVASION

Antigen-antibody interactions occur in the body's internal environment. For the body to make an antibody that can exert its effects on a specific antigen, the antigen must first enter the body.

Not all exposures result in antibody production, even when exposure includes penetration. Invasion by the antigen must occur in such large numbers that some of the antigen evades detection by the normal nonspecific defenses or overwhelms the ability of the inflammatory response to get rid of the invader. Take, for example, a person who has never contracted or even been exposed to the childhood viral disease chickenpox.

This person baby-sits for three children who develop chickenpox lesions within the next 10 hours. These children, in the pre-emption stage, shed many millions of live chickenpox virus particles via droplets from the upper respiratory tract.

Because small children are often unconcerned about the finer points of infection control, they drink out of the baby-sitter's cup, kiss the baby-sitter directly (and wetly) on the lips, and sneeze and cough directly into the sitter's face. During the 5 hours spent with the children at close range, the baby-sitter is overwhelmingly invaded by the chickenpox virus (varicellazoster) and will become sick with this disease within 14 to 21 days. While the virus is incubating and the disease is developing, the sitter's leukocytes are taking part in the next steps in the series of antibody-antigen interactions to prevent the development of chickenpox more than once.

ANTIGEN RECOGNITION

To begin to make antibodies against an antigen, the "virgin" or previously unsensitized B-lymphocyte must first recognize the antigen as non-self. Â-lymphocytes cannot carry out this important function alone; they require the actions of macrophages and helper/inducer T-cells.

This cooperative effort is started by the macrophages. After the membrane of the antigen has been altered somewhat by opsonization , the macrophage recognizes the invading foreign protein (antigen) as non-self and physically attaches itself to the antigen.

This attachment to the antigen does not result in phagocytosis or in immediate destruction of the antigen. Instead, the macrophage presents the attached antigen to the helper/ inducer T-cell. At this time, the helper/inducer T-cell and the macrophage process the antigen in such a way as to expose the antigen's recognition sites (universal product code). After processing the antigen, the helper/inducer T-cell brings the antigen into contact with the B-lymphocyte so that the Blymphocyte can recognize the antigen as non-self

LYMPHOCYTE SENSITIZATION

Once the B-lymphocyte recognizes the antigen as non-self, the B-lymphocyte becomes sensitized to this antigen. A single virgin B-lymphocyte can undergo sensitization only once.

Therefore each B-lymphocyte can be sensitized to only one antigen.

As a result of sensitization, this B-lymphocyte can respond to any substance that carries the same antigens (codes) as the original antigen. Once it is sensitized to a specific antigen, the Blymphocyte always remains sensitized to that specific antigen.

In addition, all daughter cells of that sensitized B-lymphocyte are sensitized to that same specific antigen.

Immediately after it is sensitized, the B-lymphocyte (or Bblast) divides and forms two different types of lymphocytes, each one remaining sensitized to that specific antigen.

One new cell becomes a plasma cell and immediately starts to produce antibody directed specifically against the antigen that originally sensitized the B-lymphocyte.

The other new cell becomes a memory cell. The plasma cell functions immediately and has a short life span. The memory cell remains sensitized but functionally dormant until the next exposure to the same antigen .

 

 

ANTIBODY PRODUCTION AND RELEASE

Antibodies are produced by the plasma cell. When fully stimulated, each plasma cell can produce as much as 300 molecules of antibody per second. Each plasma cell produces antibody specific only to the antigen that originally sensitized the parent B-lymphocyte. For example, in the case of the baby-sitter who was exposed to and invaded by the chickenpox virus, the plasma cells that are derived from the Blymphocytes sensitized to the chickenpox virus can produce only antichickenpox antibodies. The exact antibody type (e.g., immunoglobulin G [IgG] or immunoglobulin M [IgM]) that the plasma cell can produce may vary, but the specificity of that antibody remains forever directed against the chickenpox virus.

Antibody molecules produced by the plasma cells are secreted into the blood and other extracellular fluids as free antibody.

Individual molecules of free antibody remain in the blood for 3 to 30 days. Because the antibody circulates in body fluids (or body "humors") and is separate from the Blymphocytes, the immunity provided is sometimes called humoral immunity. Circulating antibodies can be transferred from one person to another to provide the receiving person with immediate immunity of short duration.

ANTIGEN-ANTIBODY BINDING

An antibody is a Y-shaped molecule. The tips of the short arms of the Y are the areas that recognize the spe­cific antigen and bind to it. Because each antibody molecule has two tips (Fab fragments, or arms), antibody molecules can bind either to two separate antigen molecules or to two areas of the same antigen molecule.

The stem of the Y forms what is called the Fc fragment. This area of the antibody molecule can bind to Fc receptor sites on leukocytes. The leukocyte then has not only its own mechanisms of attacking antigens but also the added power of having antibodies on its surface that stick to antigens more than one antigen molecule to each antibody does not directly destroy the antigen. Agglutination starts defensive effects in at least two ways. First, it slows the movement of the antigen through the extracellular fluids. Second, the irregular shape of the antigen-antibody complex increases the chances of the complex being attacked by other leukocytes (e.g., macrophages, neutrophils, and cytotoxic/cytolytic T-cells.

 

Figure 20-11 • Basic antibody structure.

 

 ANTIBODY-BINDING REACTIONS

The action of binding antibody to antigen allows or triggers specific reactions to cause the neutralization, elimination, or destruction of the antigen. These reactions include agglutina­tion, lysis, complement fixation, precipitation, and inactiva-tion or neutralization.

 

Agglutination

Agglutination is a clumping-like antibody action that results from an antibody molecule's having at least two antigen-bind­ing sites. This clumping links antigens together, forming large and small immune complexes (Figure 20-13). The binding of more than one antigen molecule to each antibody does not directly destroy the antigen. Agglutination starts defensive effects in at least two ways. First, it slows the movement of the antigen through the extracellular fluids. Second, the irregular shape of the antigen-antibody complex increases the chances of the complex being attacked by other leukocytes (e.g., macrophages, neutrophils, and cytotoxic/cytolytic T-cells

 

 Lysis

Lysis, cell membrane destruction, occurs because of antibody binding to membrane-bound antigens of some invaders. The actual binding creates holes in the invader's membrane, changing the intracellular environment. This response usually requires that complement be involved in the antigen-antibody interaction. Bacteria and viruses are the non-self cells most susceptible to damage through lysis caused by the binding of antibody to membrane-surface antigens.

 

 Complement Fixation

Specific classes of antibodies can remove or destroy the non-self antigen through activation of the complement cascade and complement fixation. (The mechanism by which comple­ment assists in immunity is discussed earlier under Adher­ence, p. 314.) The two classes of antibody capable of stimu­lating the complement system are IgG and IgM. Binding of antibody from either of these classes to an appropriate antigen provides a binding site for the first component of complement (Clq). Once Clq is activated, other components of the com­plement system are activated in a cascade.

 

 Precipitation

Precipitation is similar to agglutination. However, in precip­itation, antibody molecules bind so much antigen that large, insoluble antigen-antibody complexes are formed. These complexes cannot stay in suspension in the blood. Instead, they form a large precipitate, which can be acted on and re­moved by neutrophils and macrophages.

The actual binding of antibody to antigen is usually not lethal to the antigen. Instead, the physical binding of the anti­body to the antigen starts other actions that neutralize, elimi­nate, or destroy the antigen.

 

Inactivation-Neutralization

Inactivation-neutralization does not result in the immediate destruction of the antigen. Usually, only a small area of the antigen, the active site, is actually responsible for causing harmful effects. The rest of the antigen is not harmful to the host. Inactivation-neutralization, through binding of antibody to an antigen, covers up the active site or changes its shape. Either mechanism inhibits the activity of the antigen and makes it harmless without destroying or eliminating it.

 

 SUSTAINED IMMUNITY: MEMORY

The sustained immunity, or memory, function of antibody-mediated immunity (AMI) provides humans with long-lasting immunity to a specific antigen. Sustained immunity occurs through the action of the B-lymphocyte memory cells made during the lymphocyte sensitization stage. These memory cells remain sensitized to the specific antigen to which they were originally exposed. On re-exposure to the same antigen, the memory cells rapidly respond. First, the cells divide and form new sensitized blast cells and new sensitized plasma cells. The blast cells continue to divide to produce even more sensitized plasma cells. The sensitized plasma cells rapidly begin to make and secrete large amounts of the antibody spe­cific for the sensitizing antigen.

This ability of the sensitized memory cells to initiate events on re-exposure to the same antigen that originally sensitized the B-lymphocyte allows a rapid and widespread immune (anamnestic) response to the antigen. This response usually removes the invading antigen completely, so that the person does not become ill. Because of this process, most people do not become ill with chickenpox or other viral dis­eases more than once, even though they are exposed many times to the causative organism. Without the process or action of memory, people would remain susceptible to specific dis­eases on subsequent exposure to the antigen, and no sustained immunity would be generated.

General Antibody Classification

All antibodies are immunoglobulins, also called gamma globulins. These names are based on the structure and function of antibodies. A globulin is a type of protein structure that is globular rather than straight. Because antibodies are composed of this type of protein, they are globulins. The term im-munoglobulin is appropriate for antibodies because they are globular proteins that provide immunity. Antibodies are called gamma globulins because all free antibodies in the plasma separate out in the gamma fraction of plasma proteins during electrophoresis (based on size and electrical charge). The five antibody types are classified by differences in antibody structure, molecular weight, and association.

 

CLASSIFICATION AND CHARACTERIZATION OF ANTIBODIES

 

Antibody-mediated immunity

IgG—defense against invading foreign microorganisms

IgA—secretory protein on mucous membranes and outer body skin surfaces (first line of defense against invasion by microorganisms)

IgM—blood group marker (probably stimulates autoimmune diseases and responses)

IgE—mediates allergic and hypersensitivity reactions, protects against parasitic infections

IgD—regulates lymphocyte activation and suppression

 

 

 

Basic structure of the Ig monomer (Figure ) consists of two identical halves connected by two disulfide bonds. Each half is made up of a heavy chain of approximately 50 kDa and a light chain of approximately 25 kDa, joined together by a disulfide bond near the carboxyl terminus of the light chain. The heavy chain is divided into an Fc portion, which is at the carboxyl terminal (the base of the Y), and a Fab portion, which is at the amino terminal (the arm of the Y). Carbohydrate chains are attached to the Fc portion of the molecule. The Fc portion of the Ig molecule is composed only of heavy chains. Fc regions of IgG and IgM can bind to receptors on the surface of immunomodulatory cells such as macrophages and stimulate the release of cytokines that regulate the immune response. The Fc region contains protein sequences common to all Igs as well as determinants unique to the individual classes. These regions are referred to as the constant regions because they do not vary significantly among different Ig molecules within the same class. The Fab portion of the Ig molecule contains both heavy and light chains joined together by a single disulfide bond. One heavy and one light chain pair combine to form the antigen binding site of the antibody. Each Ig monomer is capable of binding two antigen molecules.

 

Class identity is determined by class-specific sequences in the Fc region of the heavy chain which are designated by Greek letters corresponding to the Ig letter designation: alpha-IgA, delta-IgD, epsilon-IgE, gamma-IgG, mu-IgM. Light chains are universal among immunoglobulins and occur as two types — kappa or lambda. These are usually designated by the Greek letters kappa and lambda.

 

Acquiring Antibody-Mediated Immunity

Two broad categories of immunity are innate-native immunity and acquired immunity.

 INNATE-NATIVE IMMUNITY

Innate-native immunity (sometimes called "natural immunity") is a genetically determined characteristic of an individ­ual, group, or species. A person either has or does not have innate immunity.

For example, humans have many innate immunities to viruses and other microorganisms that cause specific diseases in animals. As a result, humans are not sus­ceptible to such diseases as mange, distemper, hog cholera, or any of a variety of animal afflictions. This type of immunity cannot be developed or transferred from one person to another and is not an adaptive response to exposure or invasion by foreign proteins.

Innate-native immunity is nonspecific and encompasses the inflammatory responses. Other components of innate-native immunity include skin, mucosa, antimicrobial chemicals, complement, and natural killer cells (Abbas, Lichtman, & Pober, 1997).

 ACQUIRED IMMUNITY

Acquired immunity is the immunity that every person's body makes (or can receive) as an adaptive response to invasion by foreign proteins. AMI is an acquired immunity. Acquired immunity occurs either naturally or artificially and can be either active or passive.

 Active Immunity

Active immunity occurs when antigens enter the body and the body responds by making specific antibodies against the antigen. This type of immunity is active because the body takes an active part in making the antibodies. Active immunity can occur under natural or artificial conditions.

 

  NATURAL ACTIVE IMMUNITY

Natural active immunity occurs when an antigen enters the body without human assistance and the body responds by ac­tively making antibodies against that antigen (e.g., chicken-pox virus). Most of the time, the first invasion of the body by  the antigen results in development of disease. However, processes occurring in the body at the same time confer im­munity to that antigen. Thus the person will not become ill af­ter a second exposure to the same antigen. This type of immu­nity is the most effective and the longest lasting.

 

 ARTIFICIAL ACTIVE IMMUNITY

 

Artificial active immunity is a type of protection devel­oped against serious illnesses for which total avoidance is most desirable. Examples of diseases for which artificially acquired active immunity can be obtained include tetanus, diphtheria, measles, smallpox, mumps, and rubella. Small amounts of specific antigens are deliberately placed (as a vaccination) in the body, so that the body responds by ac­tively making antibodies against the antigen. Because anti­gens used for this procedure have been specially processed (attenuated) to make them less likely to proliferate within the body, this exposure does not cause the disease. Artificial active immunity lasts many years, although repeated but smaller doses of the original antigen are required as a "booster" for maintaining complete protection against the antigen.

 

 Passive Immunity

Passive immunity occurs when antibodies against a specific antigen are in a person's body but were not created there. Rather, these antibodies are transferred to the person's body after being made in the body of another person or animal. Be­cause these antibodies are foreign to the individual, the body recognizes the antibodies as non-self and takes steps to elim­inate them relatively quickly. For this reason, passive immu­nity can provide only immediate, short-term protection against a specific antigen.

 

Natural passive immunity occurs when antibodies are passed from the mother to the fetus via the placenta or to the infant through colostrum and breast milk.

 

Artificial passive immunity involves deliberately injecting a person with antibodies that were produced in another person or animal. This type of immunity is used when a person is exposed to a serious disease or illness for which he or she has little or no known actively acquired immunity. Instead, the injected antibodies are expected to inactivate the antigen. This type of immunity provides only temporary protection lasting for days to a few weeks. Some of the conditions or diseases for which artificial passive immunity may be used include exposure to rabies, tetanus, and poisonous snake bites.

AMI works with the inflammatory responses to provide protection against infection. However, AMI can provide the most effective, long-lasting immunity only when its actions are combined with those of cell-mediated immunity (CMI).

 

CELL-MEDIATED IMMUNITY

Cell-mediated immunity (CMI), or cellular immunity, involves many leukocyte actions, reactions, and interactions ranging from simple to complex. This type of immunity is provided by committed lymphocyte stem cells that mature in the secondary lymphoid tissues of the thymus and pericortical areas of lymph nodes. Certain CMI responses influence and regulate the activities of antibody-mediated immunity (AMI) and inflammation by producing and releasing cytokines. Therefore for total immunocompetence, CMI must function optimally.

 

Cell Types Involved in Cell-Mediated Immunity

The leukocytes playing the most important roles in CMI in­clude several specific T-lymphocyte subsets along with a spe­cial population of cells known as natural killer (NK) cells. T-lymphocytes further differentiate into a variety of subsets, each of which has a specific function.

One way of identifying different T-lymphocyte subsets is to determine the presence or absence of certain "marker proteins" (antigens) on the cell membrane's surface. More than 50 different T-lymphocyte proteins have been identi­fied on the cell membrane, and 11 of these (named Tl through Tl 1) are commonly used clinically to identify spe­cific cells. Antibodies have been made against each of these 11 proteins. Thus each T-lymphocyte subset can be identi­fied by how the T-lymphocyte reacts to the commercial an­tibodies. Most T-lymphocytes have more than one antigen on their cell membrane. For example, all mature T-lymphocytes contain Tl, ÒÇ, Ò10, and Tl 1 proteins. Certain subsets of T-lymphocytes also contain other specific T-lymphocyte membrane antigens.

The names used to identify specific T-lymphocyte subsets include the specific membrane antigen and the overall func­tional activities of the cells in a subset. The three T-lympho­cyte subsets that are critically important for the development and continuation of CMI are helper/inducer T-cells, suppres­sor T-cells, and cytotoxic/cytolytic T-cells.

 HELPER/ lNDUCER T-CELLS

 Description

The cell membranes of helper/inducer T-cells contain the T4 protein. These cells are usually called T4+-cells or TH-cells. A newer name for helper/inducer T-cells is CD4+ (cluster of differentiation 4). Several antibodies to the T4-cell membrane protein have been made commercially. These antibodies in­clude OKT4 and Leu-3; thus the helper/inducer T-cells may also be referred to as cells that are OKT4 positive or Leu-3 positive.

 Function

Helper/inducer T-cells are efficient in recognizing self ver­sus non-self. These cells participate in CMI by stimulating the activity of many other leukocytes. In response to the recognition of non-self (antigen), helper/inducer T-cells se­crete lymphokines that can regulate the activity of other leukocytes.

Most lymphokines secreted by the helper/inducer T-cells have overall stimulating effects on immune function. These lymphokines increase bone marrow production of stem cells and speed up the maturation of cells of myeloid and lymphoid origin. Thus helper/inducer T-cells act as organizers in "calling to arms" various squads of leukocytes involved in inflammatory, antibody, and cellular defensive actions to destroy, eliminate, or neutralize antigens.

 

         SUPPRESSOR T-CELLS

 Description

The cell membranes of suppressor T-cells contain the T8-lymphocyte antigen, and these cells are commonly called T8-cells or Ts-cells. Suppressor T-cells help regulate CMI.

 Function

Suppressor T-cells prevent continuous overreactions (hyper-sensitivity reactions) to exposure to non-self cells or pro­teins. This function is important in preventing the formation of autoantibodies directed against normal, healthy self cells, which is the basis for many autoimmune diseases.

The suppressor T-cells secrete lymphokines that have an overall inhibitory action on most cells of the immune system. These lymphokines inhibit both the growth and activation of immune system cells.

Suppressor T-cells have the opposite action of helper/ inducer T-cells. Therefore for optimal function of CMI, a bal­ance between helper/inducer T-cell activity and suppressor T-cell activity must be maintained. This balance occurs when the helper/inducer T-cells outnumber the suppressor T-cells by a ratio of 2:1. When this ratio increases, overreactions can occur, some of which are tissue damaging, as well as un­pleasant. When the helper-suppressor ratio decreases, im­mune function is suppressed, and the body is more vulnerable to invasion by non-self cells and to infections of all types.

 

 CYTOTOXIC/CYTOLYTIC T-CELLS

 Description

Cytotoxic/cytolytic T-cells are also called Tc-cells. Because they have the T8 protein present on their surfaces, they are a subset of suppressor cells. Cytotoxic/cytolytic T-cells func­tion in CMI by destroying cells that contain a processed anti­gen major histocompatibility complex (MHC). This activity is most effective against self cells infected by parasitic organ­isms, such as viruses or protozoa.

 Function

Parasite-infected self cells have both self MHC proteins (uni­versal product code) and the parasite's antigens on the cell sur­face. This allows the person's immune system cells to recog­nize the infected self cell as abnormal, and the cytotoxic/ cytolytic T-cell can bind to it.

The binding of the cytotoxic/cytolytic T-cell to the infected cell's antigen MHC complex stimulates activities that result in the death of the infected cell. The cytotoxic/cytolytic T-cell makes holes in the membrane of the infected cell and delivers a "lethal hit" of enzymes to the infected cell, causing it to lyse and die. Once the lethal hit has been administered to the in­fected cell, the cytotoxic/cytolytic T-cell releases the dying in­fected cell and can attack and destroy other infected cells that carry the same antigen MHC complex.

 

 NATURAL KILLER CELLS

■       Description

Natural killer (NK) cells are extremely important in providing CMI. The actual site of differentiation and maturation of NK cells is unknown. Although this cell population has some T-cell characteristics, it is not considered a true T-cell subset (Abbas, Lichtman, & Pober, 1997).

 

 Function

NK cells direct cytotoxic effects on target non-self cells. Un­like cytotoxic/cytolytic T-cells, NK cells can exert these cyto­toxic effects without first undergoing a period of sensitization to non-self cell membrane antigens. Moreover, NK cells do not need to share any of the MHC proteins in common with the non-self cell to initiate defensive actions against the non-self cell. The defensive actions of NK cells appear to be to­tally unrelated to either antigen sensitivity or the interactions of other leukocytes. NK cells conduct "seek and destroy" mis­sions in the body to eliminate invaders and unhealthy self cells.

NK cells are most effective in destroying unhealthy or ab­normal self cells. The non-self cells most susceptible to de­fensive actions of NK cells are those body cells that are vi-rally infected and cancer cells.

 

Cytokines

The inducing and regulatory aspects of CMI are controlled through the selected production and activity of cytokines. Cytokines are small protein hormones produced by the various leukocytes. Cytokines made by the mononuclear phagocytes (macrophages, neutrophils, eosinophils, and monocytes) are termed monokines; cytokines produced by T-lymphocytes are termed lymphokines.

Cytokine activity is similar to the action of any other kind of hormone: one cell produces and secretes a cytokine, which in turn exerts its effects on other cells of the immune system. The cells responding to the cytokine may be located close to or remote from the cytokine-secreting cell. The cells that change their activity in response to the cytokine are known as "responder" cells. For a responder cell to respond to the presence of a cytokine, the membrane of the respon­der cell must have a specific receptor for the cytokine to bind to and initiate changes in the responder cell's activity.

Cytokines regulate a variety of inflammatory and immune responses. Most cytokines are produced as needed, rather than stored. The actions of some cytokines are pleiotropic in that the effects are widespread within the immune system, set­ting into motion various immunomodulating actions. Other cytokines have specific actions limited to only one type of cell.

 

Table 20-5 summarizes the activities of the currently known cytokines.

 

Protection Provided by Cell-Mediated Immunity

Cell-mediated immunity (CMI) helps provide protection to the body through its highly developed ability to differentiate self from non-self. The non-self cells most easily recognized by CMI are those self cells infected by organisms that live within host cells and cancer cells. CMI provides a surveil­lance system for ridding the body of self cells that might po­tentially harm the body. CMI is important in preventing the development of cancer and metastasis after exposure to carcinogens.

 

Transplant Rejection

Natural killer (NK) cells and cytotoxic/cytolytic T-cells also destroy cells from other people or animals. Although this ac­tion is generally helpful, it is also responsible for rejection of grafts and transplanted organs. Because the solid organ trans­planted into the host is seldom a perfectly identical match of universal product codes (human leukocyte antigens [HLAs]) between the donated organ and the recipient host, the client's immune system cells recognize a newly transplanted organ as non-self. Without intervention, the host's immune system ini­tiates standard inflammatory and immunologic actions to de­stroy or eliminate these non-self cells. This activity causes re­jection of the transplanted organ. Graft rejection is a result of a complex series of responses that change over time and in­volve different components of the immune system. Graft re­jection can be hyperacute, acute, or chronic.

 

 

 

 

T-helper cell making and releasing a cytokine (MAF—macrophage activating factor)

 

Leukocyte with one type of surface receptor

 

 

 

Leukocyte with a surface receptor specific for the cytokine released by the T-helper cell

 

 

Cytokine binding to a cytokine-specific receptor on the leukocyte (macrophage)

Figure 20-14    •   Cytokine receptors on leukocytes.

 

■ HYPERACUTE REJECTION

Hyperacute graft rejection begins immediately on trans­plantation and is an antibody-mediated response. Antigen-an­tibody complexes form in the blood vessels of the trans­planted organ (Cotran, Kumar, & Collins, 1999). The host's blood has pre-existing antibodies to one or more of the antigens (including blood group antigens) present in the donated organ. The antigen-antibody complexes adhere to the lining of blood vessels and activate complement. The activated-fixated complement in the blood vessel linings initiates the blood clotting cascade; microcoagulation occurs throughout the or­gan vasculature. Widespread coagulation and occlusion lead to ischemic necrosis, inflammation with phagocytosis of the necrotic blood vessels, and release of lytic enzymes into the transplanted organ. These enzymes cause massive cellular destruction and graft loss.

Hyperacute rejection occurs primarily in transplanted kid­neys. The following persons are at greatest risk for hyperacute rejection:

1.   Those who have received donated organs of an ABO blood type different from their own

2. Those who have received multiple blood transfusions at any time in life before transplantation

3.   Those who have a history of multiple pregnancies

4. Those who have received a previous transplant

The manifestations of hyperacute rejection become appar­ent within minutes of attachment of the donated organ to the host's blood supply. The process cannot be stopped once it has started, and the rejected organ must be removed as soon as hyperacute rejection is diagnosed.

ACUTE REJECTION

Acute graft rejection occurs within 1 week to 3 months af­ter transplantation. Two mechanisms are responsible. The first mechanism is antibody mediated and results in vas-culitis within the transplanted organ. This reaction differs from that of hyperacute rejection in that blood vessel necro­sis (rather than thrombotic occlusion) leads to the organ's destruction.

The second mechanism is cellular. Host cytotoxic/cytolytic T-cells and NK cells enter the transplanted organ through the blood, infiltrate the organ cells (rather than the blood vessel cells), and cause lysis of the organ cells (Bush, 1999).

Diagnosis of acute rejection is made by laboratory tests in­dicating impaired function of the specific organ, along with biopsy of the grafted organ. Symptoms of acute rejection vary with the individual and with the specific organ transplanted. For example, when acute rejection occurs in a transplanted kidney, the client usually experiences some tenderness in the kidney area and may experience other general symptoms of inflammation.

An episode of acute rejection after solid organ transplan­tation does not automatically mean that the client will lose the transplant. Pharmacologic manipulation of host immune re­sponses at this time may limit the damage to the organ and al­low the graft to be maintained (Bush, 1999).

 

CHRONIC REJECTION

The origin of chronic rejection is not clear, but it resembles the aftermath of chronic inflammation and scarring. Func­tional tissue of the transplanted organ is replaced with fi-brotic, scarlike tissue. Because this fibrotic tissue does not re­semble the organ tissue in either structure or function, the ability of the transplanted organ to perform differentiated tasks diminishes in proportion to the percentage of normal tis­sue replaced by fibrotic tissue. This type of reaction is long­standing and occurs continuously as a response to chronic is­chemia caused by blood vessel injury. In transplanted hearts this process is called accelerated graft atherosclerosis (AGA) and is the major cause of death in clients who have survived 1 or more years after heart transplantation (Augus­tine, 2000).

Although good control over host immune function can de­lay the manifestations of this type of rejection, the process probably occurs to some degree with all solid organ trans­plants. Because the fibrotic changes are permanent, there is no cure for chronic graft rejection. When the fibrosis in­creases to the extent that it significantly interferes with the functional capacity of the transplanted organ, the only re­course is retransplantation.

 

 TREATMENT OF TRANSPLANT REJECTION

Rejection of transplanted solid organs involves all three com­ponents of immunity, although cell-mediated immune re­sponses are most significant in the rejection process.

 

 Maintenance Therapy

The drugs generally used for routine immunosuppressive therapy after solid organ transplantation are combinations of very specific immunosuppressants (cyclosporine [Sandim-mune]), less specific immunosuppressants (azathioprine [Imuran] or mycophenolate mofetil [CellCept]), and one of the corticosteroids, such as prednisone (Apo-Prednisone4*, Deltasone<#>) or prednisolone (Delta-Cortef) (Table 20-6). Cyclosporine induces the most specific and the most effective suppression of rejection. This drug, however, induces signifi­cant long-term adverse actions and is very expensive (see the Cost of Care box on p. 327). The dosage of all immunosup­pressive agents is adjusted to the immune response of each client. Treatment with these agents increases the risk for bac­terial and fungal infections.

A newer approach to prevention of transplant rejection for clients undergoing kidney transplantation is the use of mono­clonal antibodies directed against the interleukin-2 receptor site on activated T-lymphocytes (especially helper/inducer T-cells). These antibodies, basiliximab (Simulect) or da-clizumab (Zenapax), are administered intravenously within 2 hours before the transplant surgery and within the first few days after the surgery. By binding the antibodies to the interleukin-2 receptor site, T-lymphocyte proliferation and activation are re­duced for several months.

 

  Rescue Therapy

Certain agents are used not to maintain the graft within the host but rather to reduce the host's immunologic responses during rejection episodes, especially acute rejection. These agents may be used in addition to or in place of any of the maintenance drugs in the host's post-transplantation treat­ment regimen.

■   ANTILYMPHOCYTE GLOBULIN

Antilymphocyte globulin (ALG) is an antibody (or group of antibodies) produced in an animal after the animal has been exposed to human lymphocytes. The globulin can be made more specific by exposing the animal to human T-cells in­stead of mixed lymphocytes. When these antihuman lym­phocyte antibodies are administered to humans, the anti­bodies selectively attack and clear lymphocytes from the blood, extracellular fluids, and tissues into which they have infiltrated (such as the transplanted organ). This agent is given only for a short time to combat the acute rejection episode.

Most clients receiving ALG have some immunologic side effects, ranging from low-grade fever and malaise to serum sickness and anaphylaxis. The response usually increases in intensity on repeated exposure to ALG.

■ MUROMONAB-CD3 (ORTHOCLONE OKT3)

Muromonab-CD3 is an antibody directed specifically against the human T-cell cell-surface antigen, CD3. This antibody is generated with a murine (mouse) model rather than an equine (horse) model. Because the agent is generated in mice, the hu­mans receiving it rapidly develop antimouse antibodies. These antimouse antibodies attack the CD3 and prevent its anti-T-cell activities. Thus this antibody is most effective against rejection during the first episode for which it is used. Its utility in combating graft rejection decreases with each subsequent use.

Tacrolimus/FK 506 (Prograf)

Tacrolimus is used in maintenance therapy and rescue therapy, primarily after liver transplantation. It is similar in chemical composition to erythromycin and specifically suppresses T-cell actions, including production of interleukin-2 (IL-2).

These effects are achieved through various mechanisms. In the presence of tacrolimus/FK 506, receptor sites for IL-2 are inhibited on helper/inducer T-cells and cytotoxic/cytolytic Tcells.

Without continuous stimulation by IL-2, these lymphocytes are slow to reproduce and do not perform their usual functions. In addition, tacrolimus/FK 506 is able to prevent activation of immature or unsensitized cytotoxic/cytolytic Tcells.

Because cytotoxic/cytolytic T-cells are responsible for immunologic destruction of transplanted cells and tissues,  and because helper/inducer T-cells boost the activity of cytotoxic/ cytolytic T-cells, selective suppression of the activity of these two cell populations allows the transplanted organ to remain free from immunologic destruction. It does this without resulting in so profound an immunosuppressive state as to put the host at great risk for infection.

 

Problems/Precautions

Is a monoclonal antibody raised in a mouse model May induce anaphylaxis or other immune side effects Has limited duration of action May be inactivated by human antimouse antibodies Induction of capillary leak syndrome is common May require premedication with corticosteroids ¯ Tacrolimus/FK 506 (Prograf)

Tacrolimus is used in maintenance therapy and rescue ther­apy, primarily after liver transplantation. It is similar in chem­ical composition to erythromycin and specifically suppresses T-cell actions, including production of interleukin-2 (IL-2). These effects are achieved through various mechanisms. In the presence of tacrolimus/FK 506, receptor sites for IL-2 are inhibited on helper/inducer T-cells and cytotoxic/cytolytic T-cells. Without continuous stimulation by IL-2, these lympho­cytes are slow to reproduce and do not perform their usual functions. In addition, tacrolimus/FK 506 is able to prevent activation of immature or unsensitized cytotoxic/cytolytic T-cells. Because cytotoxic/cytolytic T-cells are responsible for immunologic destruction of transplanted cells and tissues, and because helper/inducer T-cells boost the activity of cyto­toxic/cytolytic T-cells, selective suppression of the activity of these two cell populations allows the transplanted organ to remain free from immunologic destruction. It does this without resulting in so profound an immunosuppressive state as to put the host at great risk for infection.C

OST OF C

ARETRANSPLANT REJECTION PROPHYLAXIS

Cost of Care

•  The most useful agent in preventing rejection of transplanted solid organs is cyclosporine.

•  The cost of maintaining therapeutic levels of this drug for an average-size adult ranges between $1100 and $1500 per month.

•  Clients must take this drug daily for the life of the trans planted organ.

•  The effectiveness of this drug is highly dependent on following the manufacturer's directions for mixing and administering.

•  An antifungal agent, ketoconazole, when taken orally, has been demonstrated to slow metabolism of cyclosporine andmaintain therapeutic blood levels at lower doses (approximately 40% to 50% of cyclosporine dose needed when taken without ketoconazole).

•  The cost of ketoconazole daily maintenance therapy is approximately $100 per month.

 

Implications for Nursing

Because of the high cost of medications for preventing trans­plant rejection, nurses need to incorporate proper medication administration into their client teaching plans and reinforce this information frequently. Nurses can assist in cost reductions by observing for sustained therapeutic blood levels of cyclosporine in clients and exploring what factors may be contributing to this effect.