Immunologic Aspects of Organ Transplantation

Susan Smith MN, PhD

June 17, 2002

Introduction

Until the middle of the 20th century, attempts to transplant cadaveric organs terminated in rapid rejection of the donor organ. Although it was recognized that immune or genetic factors were responsible, only a few strategies (eg, total body and lymphoid irradiation) were available to suppress the vigorous response of the recipient immune system against the foreign graft. High rates of morbidity and mortality resulting from these myelotoxic strategies prohibited their widespread adoption and failed to advance transplantation into the clinic. During the last half of the 20th century, incredible progress was made in transplantation immunology and medicine. However, significant issues have yet to be overcome in man's quest for transplantation without immunosuppression.

The immune system is a large, complex network of mobile, interactive cells and molecules that circulate through the body's lymph and blood vessels, tissues, and organs to protect it from potentially harmful foreign molecules. This all-important property of immune responsiveness is also responsible for the major physiologic threat to organ transplantation -- rejection. Immunologic aspects of transplantation provide an important foundation for understanding how normal host defense mechanisms are triggered in response to transplanted organs. Transplantation immunology is a field that is constantly changing and evolving, and provides a basis for innovative research, education, and practice.

The objectives of this chapter are to:

  • Describe the basic anatomy and physiology of the immune system

  • Explain how the immune system responds to a foreign organ

  • Understand the rationale for immunosuppressive therapy

  • Examine the evidence that supports the current need for lifelong pharmacologic immunosuppression.

Isograft, Allograft, or Xenograft?

Organ transplantation is the surgical replacement of diseased organs with healthy organs (grafts) from live or cadaver donors. The genetic relationship between the donor and the recipient is fundamental to all else in transplantation. Successful transplantation between 2 individuals who are not genetically identical requires diligent assessment of those differences before transplantation, and individualized immunosuppressive therapy after transplantation, to minimize recognition and subsequent rejection of the foreign graft by the recipient's immune system.

Except in isolated experimental cases, organs used in clinical transplantation are either isografts or allografts. An isograft is an organ transplanted from a donor who is genetically identical to the recipient (ie, identical twins). Isografts are also called isogeneic and syngeneic grafts.

An allograft is an organ transplanted from a donor to a recipient of the same species who is not genetically identical. Allografts are also called allogeneic grafts and homografts. Although isografts would be preferable to allografts, for obvious reasons the majority of organs transplanted are allografts. Allografts can be donated by a person who has died (cadaveric allograft), a living-related individual (eg, a parent or a sibling), or a living-unrelated individual. A xenograft is an organ transplanted from a donor to a recipient of a different species (eg, baboon to human). Xenografting is examined in detail in Chapter 6, Xenotransplantation.

Functions of the Mature Immune System

The word immune is derived from the Latin term immunis, which translates as "free from taxes or free from burden."[1] And indeed, the human immune system (Figure 1) functions to protect us from the burden of injury related to potentially harmful environmental substances and organisms. The mature immune system consists of millions of cells capable of performing 3 general types of functions: defense, homeostasis, and surveillance.

Figure 1.

 

The immune system.

In providing defense, resistance to infection is facilitated by both nonspecific phagocytic mechanisms and more specific immune responses that not only destroy, but also remember, foreign antigens. Maintaining immunologic homeostasis encompasses keeping a balance between immune protective and immune destructive responses and the removal of senescent or dead immune cells from the body. Although the function of the immune system is inherently protective, there are conditions in which immune responses become destructive to the host, such as autoimmune diseases and anaphylactic reactions. Surveillance involves the recognition of microorganisms bearing foreign antigens. Some of the immune cells, lymphocytes in particular, are highly mobile and travel throughout the vascular and lymphatic systems in surveillance of potentially harmful antigens. Some types of cancer cells in particular are sought out and destroyed by immune cells.

Immunocompetence, then, is the possession of a mature immune system that functions in at least 3 ways to: recognize, destroy, and remember foreign antigens. A lack of this essential property of immunocompetence is termed anergy, which is manifested by an inability to mount an effective immune response to a foreign antigen. Immune responses can be classified into 2 major types: (1) nonspecific responses, which are also called natural or innate responses, and (2) specific responses, which are the acquired responses. Both types of responses play critical roles in host defense.

The Innate Immune System

Unlike other physiologic systems, the immune system cannot be associated with a single organ or tissue. The innate immune system consists of natural or nonspecific mechanisms for the protection of an individual against foreign antigens. These natural defenses are present from birth and do not necessarily require exposure to antigens for their development. Natural defenses, the body's first line of defense, consist of both anatomic and chemical barriers to microbial invasion. Anatomic barriers include the skin, mucous membranes, and ciliated epithelia. Chemical barriers include gastric acid, lysozymes, natural immunoglobulins, and the interferons (IFNs). Soluble mediators of innate immune defenses are listed in .

Table 1.  Soluble Mediators of Innate Immunity and the Inflammatory Response

Organization of the Immune System

The effectiveness of the immune system depends upon the ability of its components to get to where antigen is. Because it cannot be reliably anticipated where antigen will enter the body (except through the digestive and respiratory systems), the cells of the immune system must be mobile. Being mobile, these cells rely on established "roadways" to transport them to antigen: the circulatory (vascular) system and the lymphatic system. The vascular system is a main thoroughfare for all blood-borne elements. The lymphatics are blind-ended vessels that invade the tissues and run parallel to the capillaries and other circulatory vessels. A clear, protein-rich fluid called lymph (similar to plasma) and leukocytes are carried in the lymphatics. The function of lymphatics is to maintain fluid balance in the tissues by preventing edema (swelling caused by leakage of fluids into the tissues).

The lymphatic system. By surveying body fluid balance in the tissues, the lymphatics (Figure 1) are uniquely qualified to take up antigen if it enters the tissues by a breach of the skin. The lymphatics then deliver antigen to lymphocytes in the lymph nodes (Figure 2). Lymph nodes are located at the junctions of lymphatic vessels and form a complete network for the draining and filtering of extravasated lymph from interstitial fluid spaces. Afferent lymphatics carry lymph to the lymph nodes; efferent lymphatics serve as exit routes for lymphocytes from lymph nodes. Lymphatics dump antigen-cleared fluid into the blood system at 2 main sites: the right lymphatic duct and the thoracic duct. The right lymphatic duct drains most of the right side of the body into the right subclavian vein and the thoracic duct drains the rest of the body into the left subclavian vein and the left internal jugular vein.

Figure 2.

 

The lymph node.

What then, is the fate of antigen that has been processed by macrophages and dendritic cells in the medulla of the lymph node? Antigen is presented to T helper (Th) cells, which respond by clonal proliferation in the lymph node paracortical areas, resulting in the production of cytokines that drive the remainder of the response (Figure 3). Cytotoxic T lymphocytes (CTLs) present in the paracortical areas of the lymph node also require antigen processing and presentation. Once antigen of the appropriate specificity has been presented to the CTL (by any nucleated cell, not just macrophages or dendritic cells), the CTL undergoes clonal proliferation. These close cousins of Th cells complete their response by differentiating into killers that make bullet-like molecules, including serine esterases, perforin (related to the complement component C9, part of the membrane attack complex [MAC]), and granzymes. These molecules directly lyse the CTL target that originally presented antigen to it.

Figure 3.

 

Fate of antigen in the lymph node.

The spleen. The physiologic function of the spleen is not completely understood, but it is known that it has reticuloendothelial, immunologic, and storage functions. The spleen produces monocytes, lymphocytes, and IgM antibody-producing plasma cells. If antigen enters the system directly through the bloodstream, it is filtered by the spleen, where it encounters circulating lymphocytes.

Anatomic and Chemical Defenses

The skin is a remarkable organ. It has the distinction of being the largest and most important organ of the human body. Cells in the skin provide a barrier against penetration of excess water, evaporation of the body fluid into the environment, and protection against the ultraviolet rays of the sun. The skin also provides the initial physical barrier to external environmental antigens. The outermost skin layer, the stratum corneum, is the main barrier to microbial invasion. Certain conditions such as pH, humidity, and temperature influence the growth of potentially pathogenic organisms on the skin. Alterations in normal conditions related to these factors favor the development of infection. The normally acid pH of the skin inhibits growth of microorganisms. When the acid-base balance of the skin is altered in favor of a higher pH, this protective mechanism is lost. When water loss from epidermal cells exceeds intake, the stratum corneum can dry and crack, predisposing the host to microbial invasion. On the other hand, excessive moisture decreases barrier efficiency.

Skin cells are constantly exfoliating, and in this process organisms are sloughed along with dead skins cells. In addition, the skin is colonized with "normal flora" that, through various mechanisms, protects the host from colonization of potentially pathogenic organisms. Resident flora maintain the skin's pH in the acidic range and compete effectively for nutrients and binding sites on epidermal cells, making it difficult for nonresident flora to survive. Normal flora consists mainly of aerobic cocci and diphtheroids. When normal flora are altered, such as occurs with long-term or broad-spectrum antibiotic therapy and with the use of disinfectants or occlusive dressings, potentially pathogenic organisms become "opportunistic." Opportunistic organisms take advantage of the lack of competition for nutrients and epidermal binding sites and multiply, leading to potentially lethal infections.

The skin is not a passive organ. Normal human epidermis contains specialized dendritic antigen-presenting cells (APCs) called Langerhans cells, and keratinocytes that secrete immunoregulatory cytokines. Langerhans cells express macrophage-type surface markers and immune-response-associated antigens. These cells perform antigen presentation functions similar to those performed by the macrophages that are necessary for Th cell activation. They trap antigen, travel to the lymph nodes, and present antigen to lymphocytes capable of mounting a stronger and more complete immune response.

Cytokines are chemical messenger molecules that give orders to target cells. The binding of a cytokine to its specific receptor on the surface of a target cell initiates a chain of chemical reactions that lead to cell maturation, growth, proliferation, molecule production, and death. Cytokines can be differentiated according to their source (eg, cytokines produced by lymphocytes are called lymphokines), target cells, and effects on target cells. Many cytokines work in concert on the same target cells.

The sebaceous glands, mammary glands, respiratory epithelium, gastrointestinal (GI) mucosa, genitourinary mucosa, and conjunctivae all secrete a protective immunoglobulin (Ig) called secretory IgA. Ciliated respiratory epithelial cells (cilia or small hairs that beat in concert to sweep antigen back out of the body cavities) facilitate the removal of bacteria and other foreign antigens from the respiratory tract, and the low pH of the gastric mucosa prevents bacterial growth in the stomach. Mucus acts as biological quicksand, trapping antigen before it can enter the organs.

Hemopoiesis

All of the cells of the immune system begin to develop in fetal life. After birth, the marrow of the long bones assumes the function of hemopoiesis (or hematopoiesis), the production of blood cells (Figure 4). There is evidence that all blood cells are derived from a single progenitor cell, a pluripotent stem cell, distinguished by 2 characteristics. The first is the ability to generate more of its own kind. Thus, the pluripotent stem cell is self-renewing. Second, some of the pluripotent stem cells that are the progeny of the initial cell become committed to different hemopoietic lineages that eventually give rise to all the formed elements of the blood: red blood cells (RBCs) or erythrocytes, white blood cells (WBCs) or leukocytes, and platelets. If you were to take a small drop of your blood, place it on the end of a glass slide, smear it up the length of the slide, and fix and stain it, the formed elements of the blood would be visible under a microscope (Figure 5). The vast majority of what you would see would be erythrocytes, with a fair number of platelets in each microscopic field. The focus of this discussion will be leukocytes.

Figure 4.

 

Hemopoeisis in the bone marrow.

Figure 5.

 

Normal blood smear.

Leukocytes

Two concepts are important to understanding how leukocytes become immunocompetent cells: proliferation and differentiation (Figure 6). Proliferation is the production of many cells from a single cell through repeated mitosis of daughter cells. Differentiation is the process of cell maturation. Through differentiation, cells acquire their ultimate functions and the protein characteristics required to perform those functions. In general, the more immature a cell is, the bigger it is and the greater its ability to proliferate. As a cell differentiates, it becomes smaller, loses its ability to proliferate, and focuses its energy instead on performing its function.

Figure 6.

 

Cell proliferation and differentiation.

Leukocytes begin as pluripotent hematopoietic stem cells in the bone marrow and develop along 1 of 2 major lineages: the myeloid lineage or the lymphoid lineage megakaryocytes, eosinophils, neutrophils, basophils/mast cells, and monocytes/macrophages. Auxiliary myeloid cells include megakaryocytes (precursors to platelets) and mast cells. Platelets are not true progeny of megakaryocytes. Instead, they are fragments of megakaryocytes.

The WBC Count

Normally, there are approximately 4000 to 11,000 leukocytes/mm3 of human blood, which equals 4 x 106 to 11 x 106 WBCs/L of blood. By contrast, there are normally about 5 x 109 RBCs/L of blood, fully 3 orders of magnitude greater than the number of leukocytes. However, in spite of their relatively small numbers, WBCs are crucial to immune defense.

The WBC Differential Count

The WBC differential count provides a snapshot of granulocytes, lymphocytes, and monocytes in the peripheral blood. The WBC total and differential counts are important diagnostic tools that aid in monitoring clinical status and the effectiveness of therapeutic interventions. Currently, routine blood cell counts are rarely performed under the microscope. Instead, automated electronic counters are used; these are designed to detect the differences in cell nuclear and cytoplasmic morphology that distinguish 1 type of leukocyte from another.

depicts a typical WBC differential count for a healthy adult. About 60% to 80% of WBCs are neutrophils, 20% to 40% are lymphocytes, and 2% to 10% are monocytes. About 80% of the lymphocytes are T cells; the remaining 20% are B cells, but up to 5% may be NK cells.

Table 2.  Normal Blood Differential Count

In general, very few basophils or eosinophils circulate in the blood. WBCs of every kind marginate on the walls of the blood vessels, ready to enter the tissues in case of bleeding, usually accompanied by the entry of foreign antigen under the skin. These marginated leukocytes are not evident in blood sampled for WBC total or differential counts.

The Myeloid Lineage

Myeloid cells make up the backbone of the natural or innate defense system. Myeloid leukocytes can be classified into 2 major groups: granulocytes and monocytes. The major function of both is phagocytosis. Phagocytosis, which means "cell eating," is the first event of host defense when a foreign material enters the body. This process is carried out by a network of highly mobile phagocytes in the blood and other tissues that is collectively referred to as the reticuloendothelial system (RES). Phagocytes have surface receptors that allow them to seek out nonspecific foreign organisms, engulf them, and ultimately destroy them. Phagocytosis is the process by which excess antigen and dead cells are removed from the body (Figure 7). Phagocytosis is also essential in the initiation of cellular and humoral immune responses by B cells and T cells. There are large numbers of macrophages strategically located ( ) in the liver, spleen, lungs, kidney, and lymph nodes, where they act as filters to remove and destroy infectious organisms and bodily debris (eg, senescent RBCs).

Table 4.  Location of Phagocytes of the Reticuloendothelial System

Figure 7.

 

Bacterial degradation by neutrophils.

Granulocytes. Granulocytes, commonly referred to as polymorphonuclear granulocytes (PMNs), "polymorphs," or "polys," are produced in the bone marrow at the rate of approximately 80 million per day, and their average life span is about 2 to 3 days. Sixty percent to 70% of all leukocytes are PMNs. These cells are called "polymorphs" because their nuclei are multilobed; they are called granulocytes because they contain intracellular granules. Their intracellular granules contain packets of hydrolytic enzymes (lysozymes), making the cells cytotoxic to foreign organisms, particularly bacteria (Figure 7). Lysozomes are encased in portions of membrane within the neutrophil until the cell encounters a bacterium. The lysozome fuses with the portion of neutrophil cell membrane that has trapped the bacterium and releases its contents, resulting in digestion and destruction of the bacterium. Granulocytes are classified into 3 more distinct types: neutrophils, eosinophils, and basophils, according to the histologic staining reactions of the intracellular granules.

Neutrophils are the most abundant cells in the bone marrow and blood, comprising about 90% of all PMNs or granulocytes. Three forms of neutrophils can be identified in the peripheral blood: segmented neutrophils or "segs," "bands," and metamyelocytes. Segmented neutrophils are fully mature, bands are slightly immature, and metamyelocytes are completely immature neutrophils. Neutrophils circulate in the blood for only about 12 hours. Then they move into the tissues, where they live for only a few days.

Neutrophils are strongly phagocytic; that is, they ingest microorganisms or other cells and foreign particles and digest the ingested material within their phagocytic vacuoles. There is an increased demand for neutrophils with infection. The bone marrow responds by releasing more neutrophils into the circulation. Immature forms of neutrophils are released along with the mature cells when the demand exceeds the supply. As a result, the percentage of bands in the peripheral blood is increased. This condition, referred to as a "shift to the left," indicates acute inflammation. In more serious conditions, metamyelocytes will also appear in increased numbers in the peripheral blood. The normal neutrophil count in the adult is 1000/mm3 to 6000/mm3 blood, or approximately 65% of circulating WBCs or the differential WBC count. Bands normally number about 600/mm3 of blood, or approximately 0% to 5% of the differential WBC count.

Eosinophils are weakly phagocytic (much less so than neutrophils) granulocytes with a bi-lobed nucleus that appear in increased numbers in the circulation, specifically during parasitic infections (ie, worm infestation) and allergic hypersensitivity reactions. Eosinophils degranulate on antigenic stimulation and kill organisms extracellularly. The normal eosinophil count is about 200/mm3 of blood, or 2% to 5% of the differential WBC count.

Basophils are granulocytes with a multilobed nucleus that are responsible for anaphylactoid reactions to allergens. Like eosinophils, basophils are capable of releasing their cytotoxic granules when stimulated by certain antigens to effect extracellular killing. Basophils are morphologically identical to mast cells, but can be differentiated from mast cells in that basophils are blood borne and mast cells reside in tissues outside the circulation. In other words, when a basophil migrates out of the circulation to reside in tissue, it becomes a mast cell. The normal basophil count is about 100/mm3 of blood, or about 0.2% of the differential WBC count. Polymorphonuclear granulocytes can be differentiated from monocytes by their multilobed nuclei and many intracellular granules.

Monocytes. Monocytes are mononuclear cells that do not contain cytotoxic granules. They do, however, release the prostaglandin PGE2, which is a mediator of the inflammatory response. Monocytes circulate in the blood for approximately 24 hours and then move into the tissues, where they develop into macrophages. Macrophages can live in the tissues for many months as phagocytes. Macrophages are nonspecific accessory cells that play a role in primary host defense, control neoplasia, scavenge damaged or dying cells, and interact with lymphocytes to facilitate cellular and humoral immunity. The normal monocyte count is about 200/mm3 to 1000/mm3 of blood, or about 5% of the differential WBC count.

The Lymphoid Lineage

Common lymphoid progenitor cells have the capacity to differentiate into either B lymphocytes (B cells) or T lymphocytes (T cells), depending on the microenvironment in which they live and develop. By virtue of antigen-specific receptors located on their membranes, these cells have the ability to distinguish 1 antigen from another. Lymphocytes are discussed in more detail in the "Acquired Immune Responses" section.

APCs

The exact origin of the APC is unknown. APCs are formed in the epidermis, where they are called Langerhans cells. APCs play an important role in linking the innate immune system with the acquired immune system. APCs carry foreign antigens that enter the host via the respiratory tract, GI tract, or skin through the lymphatic system and present them to lymphocytes in the lymph nodes and spleen, thereby triggering cellular and humoral immune responses.

Other Mediators of Innate Immunity

Other mediators of innate immunity include null cells, natural killer (NK) cells, the IFNs, and acute phase proteins.[4,5] Null cells are also referred to as third population cells because, although they are thought to be lymphoid cells, their exact lineage is unknown. They are neither T cells, B cells, nor macrophages. Null cells kill antibody-coated target cells. NK cells are large (usually granular) non-B, non-T lymphocytes that do not have T-cell receptors (TcRs) or antibodies on their surfaces. NK cells account for about 3% of the differential WBC count. NK cells are activated by IFN to spontaneously kill tumor-or virus-infected cells. Prior sensitization is not necessary for activation of NK cells.[5] IFNs are a group of proteins produced by virally infected cells and lymphocytes. IFNs are produced very early in infection and induce a state of immunity in surrounding noninfected cells by interfering with viral replication. Acute phase proteins are a group of proteins that proliferate in the serum during acute infection. Acute phase proteins promote complement binding and opsonization.

Inflammation

Inflammation is the body's attempt to restore homeostasis; it is the initial reaction to injury and the first step in the healing process. Wound healing cannot occur if the inflammatory response is fully inhibited. A series of cellular and systemic reactions are triggered during the inflammatory response that localize and destroy the offending antigen, maintain vascular integrity, and limit tissue damage. The inflammatory response can be altered or suppressed in many situations: the administration of corticosteroids and other immunosuppressive agents, malnutrition, advanced age, chronic illness, and prolonged stress. Conversely, the inflammatory response can become exaggerated in conditions such as anaphylaxis and septic shock.

Tissue injury provides the initial stimulus for activation of inflammatory mechanisms and results in the cellular release of vasoactive substances such as histamine, bradykinin, and serotonin. The circulatory effects are vasodilation and increased blood flow to the affected site; increased vascular permeability, which facilitates diapedesis of immune cells from the circulation to the tissues; and tenderness or pain. The clotting system is activated in an attempt to "plug up" the injury. Increased blood flow and capillary permeability lead to local interstitial edema and swelling. Leukocyte migration occurs as phagocytes are attracted (by a process called chemotaxis) to the affected site, and dying leukocytes release pyrogens that stimulate the hypothalamus to induce a state of fever. Pyrogens also stimulate the bone marrow to release more leukocytes, thus perpetuating the process. Consider the following example:

It is early evening, and you are walking on the beach, looking out to sea, oblivious to any obstacles in your path. Ouch, stepped on the head of a rusty nail sticking out of a piece of driftwood. Several processes occur simultaneously at the site of the wound: inflammation, the entry of leukocytes into the tissue space, and complement activation (Figure 8). Capillaries, lymphatics, and cells comprising the tissue in your foot have been injured by the nail. Immediately, blood containing immune cells, plasma, and lymph enter the tissue space. The clean-up has begun.

Figure 8.

 

Innate immunity and inflammation.

Neutrophils in the blood begin crawling through the spaces between endothelial cells to enter the tissue, where they encounter bits of antigen, including bacteria, introduced by the nail. Close contact between the neutrophil membrane and the bacterial membrane activates phagocytosis. The membrane of the neutrophil engulfs the bacterium and eventually pinches off into the cell cytoplasm to form an intracellular vacuole called a phagosome. Preformed enzymes contained within neutrophil lysozomes fuse membranes with the phagosome, forming a phagolysosome, in which the bacterium is digested.

Endothelial cells lining the capillaries are activated. Together with neutrophils, skin fibroblasts, and Langerhans cells, the endothelial cells begin to produce cytokines that are chemotactic for other leukocytes (chemokines). Chemokines such as IL-8 and RANTES (regulated upon activation, normal T-cells expressed and secreted) ( ) act as homing signals for WBCs being dumped into the tissue space by damaged capillaries and lymphatics. Diapedesis by chemotaxis is the process of cells crawling out of the vessels between endothelial cells into the tissue space, in response to chemokines. Monocytes are very sensitive to chemotactic stimuli. They begin crawling into the tissue space, where they become macrophages and begin cleaning up debris and bacteria, becoming activated in the process. Activation results in further production of cytokines, which exacerbates inflammation, and attracts more WBCs into the tissue space.

Table 1.  Soluble Mediators of Innate Immunity and the Inflammatory Response

As tissue fluid and blood continue to seep into the tissue space, the clotting cascade is activated to restrain the flow of blood. A series of plasma proteins, collectively referred to as complement, leak out of the plasma into the tissue space (Figure 9). Other proteins released from damaged cells cause the redness and pain associated with inflammation (Figure 8).

Figure 9.

 

The complement cascade.

Complement Activation

The complement system consists of a complex set of approximately 20 interacting proteolytic enzymes and regulatory proteins found in the plasma and body fluids.[6] Complement proteins are effector molecules that modulate inflammatory responses. Inflammatory cells, APCs, and lymphocytes have receptors for complement stimulation and activation. Conceptually, the complement system is similar to the coagulation system in that complement proteins react sequentially in a series of enzymatic reactions in a cascading manner. Several factors are responsible for activation of the complement system: the formation of insoluble antigen-antibody complexes, aggregated immunoglobulin, platelet aggregation, release of endotoxins by gram-negative bacteria, the presence of viruses or bacteria in the circulation, and the release of plasmin and proteases from injured tissues. Complement proteins can mediate the lytic destruction of cells, including RBCs, WBCs, platelets, bacteria, and viruses.

Complement is activated via 1 of 2 pathways: the lectin/alternative or classical pathway. The lectin alternative pathway is triggered in response to antigen, usually bacteria, alone to ensure that antigen cleanup begins immediately. The classical pathway is triggered when antibody in the plasma leaks into the tissue space and finds the bacterium for which it bears specificity, forming an antigen-antibody complex.

Regardless of which activation pathway activates the complement system, different complement components bind to either the surface of the bacterium or the stem of the antibody molecule that is bound to the bacterium (Figure 9). This binding triggers the cleavage and fixation of additional complement proteins, eventually leading to the activation of complement component C3. Activation of C3 is the critical event in complement activation, which triggers subsequent events that lead to bacterial elimination. Certain fragments of complement are chemotactic for phagocytes: C5a, C4a, and C3a. In this way, complement attracts more phagocytes to the site of antigen entry. Other complement fragments stimulate phagocytosis by coating the surface of bacteria with opsonins, making them "tastier" for phagocytes, to enhance the rate of bacterial clearance. The importance of C3 to immunity is underscored by the fact that while several other complement protein deficiencies have been identified clinically, C3 deficiency does not exist. That is, the absence of C3 is incompatible with life.

A third mechanism of bacteria clearance by complement is the generation of MAC. The MAC is an assembly of complement fragments on the surface of a bacterium that effectively forms a hole in the bacterial membrane, leading to osmotic lysis and death of the bacterium. MAC is triggered when antibody binds to a bacterium for which it bears specificity. Complement components become fixed to the stem of the antibody molecule, triggering the attachment of additional components in the cascade. Eventually, fragments C5b through C9 arrange themselves in a doughnut shape in the membrane of the bacterium, causing lysis and death. In this way, complement is also responsible for the death of cells contained in an organ allograft.

Complement activation leads to the massive production of complement molecules that act as enzymes for subsequent chemical reactions, resulting in cell lysis, phagocyte chemotaxis, and opsonization. Complement inactivators present in the liver and spleen "turn off" the complement cascade to prevent damage to normal tissue.

The body calls on the innate immune mechanisms as the first line of defense against threatening foreign antigens. However, if these mechanisms are not entirely successful, a second set of defenses, collectively referred to as the acquired immune system, is activated to work in concert with the innate immune system. The acquired immune system is composed of lymphocytes and other lymphoid structures necessary for specific immune responses.

The Acquired Immune System

Maturation of the lymphoid system occurs during the fetal and neonatal periods when lymphoid stem cells differentiate into B cells or T cells. At this time, the mechanisms for conferring genetic specificity to lymphocytes develop. This property of specificity is what differentiates the lymphoid cell from the myeloid cell, which can react with any antigen. The process of lymphopoiesis (lymphocyte origination and differentiation into functional effector cells) begins in the yolk sac and continues later in life in the thymus gland, liver, spleen, and finally the bone marrow, which is the primary site of lymphopoiesis in the full-term neonate.

Primary lymphoid tissue consists of "central" organs that serve as major sites of lymphopoiesis (Figure 10). Lymphoid stem cells, which originate in the bone marrow, give rise to the various components of the acquired immune system. Secondary lymphoid tissue is "peripheral" tissue that provides an environment for lymphocytes to encounter antigens and proliferate if necessary. Secondary lymphoid tissue consists of the spleen, lymph nodes, bone marrow, liver, and mucosa-associated lymphoid tissue (MALT) in the tonsils, respiratory tract, gut, and urogenital tract. Location of secondary lymphoid tissue is not coincidental; all of these structures provide major portals for the entry of foreign microorganisms into the body. Once in secondary lymphoid tissues, lymphocytes may migrate from one lymphoid structure to another by vascular and lymphatic channel systems.

Figure 10.

 

Primary and secondary lymphoid tissue.

Lymphocytes

Lymphocytes, the primary defenders of the acquired immune system, play a central role in regulating immune responses to all antigens; they are the only cells that have the intrinsic ability to recognize specific antigens. Lymphocytes are the major components of lymph nodes. Only about 5% of lymphocytes are blood borne; the other 95% reside in the lymph nodes and spleen. There are 2 major populations of lymphocytes: B cells and T cells. Lymphocytes have surface receptors that are specific for surface molecules, sometimes called epitopes, located on the surfaces of foreign proteins. T cells have receptors for class I and class II antigens, and B cells have receptors for immunoglobulins. B cells produce antibodies and mediate what is called the "humoral" immune response. T cells are involved in immunologic regulation and mediate what is called the "cellular" immune response. For the sake of discussion, the 2 types of lymphocytes will be described separately, but in reality there is much interaction between them, and effective host defense is dependent on this interaction.

B Cells

B cells mature in secondary lymphoid tissue and account for approximately 1% to 3% of the differential WBC count. The antigen-specific receptor on the B cell is an immunoglobulin. Once activated by the binding of antigen specific for only that receptor, the B cell produces a large quantity of antibody of the exact specificity as the original immunoglobulin receptor.

B cells are effector cells that mediate the humoral immune response (humoral immunity) through the production of antibodies, which is their major function. B cells are important in defense against pyrogenic bacterial infections, and can destroy transplanted organs by mediating hyperacute graft rejection. When a B cell is stimulated by a particular antigen, it differentiates into a lymphoblast. The lymphoblast differentiates into a plasmablast, which further differentiates into a plasma cell. Plasma cells release antibody until the antigen is destroyed (Figure 11). Following exposure of a B cell to a specific antigen, the antibody it produces may combine with a toxic site on the antigen molecule or cause its removal by phagocytes. In addition, memory of the offending antigen is retained for at least several months.

Figure 11.

 

Antigenic stimulation and subsequent antibody production.

Antibodies

Antibodies are also referred to as immunoglobulins. Immunoglobulins are specifically modified proteins present in serum and tissue fluids that are capable of selectively reacting with inciting antigens. All antibodies have the same basic structure, but each antibody varies from all others in 1 region so that each antibody is unique. Therefore, each antibody is specific and can recognize only 1 antigen. The body produces several million antibodies that are capable of reacting with just as many antigens. Antibodies are involved in a wide range of immune responses that lead to destruction and elimination of potentially harmful antigens. When viruses or bacteria, for instance, enter the body, their structural surface features are recognized by the body as not belonging to it. Antibodies are then formed and attracted to these foreign structures for which they have identical matching receptors. In this way, antibodies bind with antigens, which is called antigen-antibody complex formation.

Antibodies can be divided into 5 major classifications: IgM, IgG, IgA, IgD, and IgE. IgM is the principle mediator of the primary immune response. IgM is a "natural" antibody; there is no known contact with the antigen that stimulated its production. About 10% of all antibodies are of the IgM type. IgG is the principal mediator of the secondary immune response, which requires repeated exposure to the same antigen. IgG is the major antibody against bacteria and viruses. About 75% of all antibodies are of the IgG type. IgA is the secretory immunoglobulin present in body secretions and offers natural protection against nonspecific foreign antigens. About 15% of all antibodies are of the IgA type. The function of IgD is not known, but about 1% of antibodies are of this type. Although only about 0.002% of antibodies are of the IgE type, IgE antibodies present on basophils and mast cells play a significant role in inflammatory and immune reactions.

Structurally, antibodies consist of 4 polypeptide chains, 2 heavy and 2 light chains (Figure 12). The light chains have an adaptor component (Fab) that binds to antigen, and the heavy chains have an adaptor component (Fc) that activates complement. Using these adaptor components, the antibody forms a bridge between the antigen and a phagocyte, which facilitates destruction of the antigen. Mechanisms of antigen inactivation by antibody include neutralization, opsonization, and complement fixation (Figure 13).

Figure 12.

 

B cell antigen receptor.

Figure 13.

 

Elimination of antigen by antibody.

Neutralization. Imagine that a bacterial neurotoxin has entered the lymph node. If not cleared, the toxin will seek and destroy neural cells. However, because the acquired immune response is in a ready state, the toxin binds to the surface of the B cell with the correct specificity, which responds by making the appropriate antitoxin antibody. By binding to the remaining toxin, the antibodies form a basket around the antigen, sequestering it from neurons within the host. This antigen-antibody complex is now a target for phagocytosis and elimination via the kidneys.

Opsonization. Certain complement protein fragments behave as opsonins. Antibodies are also efficient opsonins. By coating the surface of the antigen for which they bear specificity, antibodies attract phagocytes that bear receptors for the stems of the antibody molecules. The phagocytes then chew up antigen-antibody complexes, effectively removing antigen from the host.

Complement fixation. As noted previously, the classical pathway of complement activation is triggered by antigen-antibody complex formation, a signal for the initial proteins in the complement cascade to attach to the stem of the antibody molecule. The cascade ultimately generates the MAC, which punches holes in the offending cellular antigen.

T Cells

Immature T cells develop in the thymus. During this immature phase of T-cell development, reactivity of these cells to self-antigens is eliminated and tolerance to self-antigens occurs. Under continued thymic hormonal influence, functionally active T cells develop. T cells account for approximately 15% of the differential WBC count.

T cells have molecules on their surfaces called TcRs, which recognize peptide fragments presented with human leukocyte antigen (HLA) class I and HLA class II molecules found on the surface of APCs. The structure of the TcR is similar to the structure of an antibody and also varies in one region so that each TcR is unique (Figure 14).

Figure 14.

 

T cell receptor (TcR)

T cells are divided into 4 functionally distinct, but interactive, cell populations or subsets: cytotoxic (CTL), memory (Tm), Th, and suppressor (Ts). Tc and Tm cells are referred to as effector cells because they are cytotoxic to antigen-bearing cells. Th and Ts cells are referred to as regulatory cells.

Effector cells. CTLs respond to processed peptide presented by nucleated cells of the body that have been infected (ie, virus). Like Th cells, CTLs clonally proliferate, but finish their response under the influence of Th cell-derived cytokines. CTLs bind to target cells and facilitate their destruction via substances known as lymphokines that stimulate inflammatory cells and via the production of cytolytic proteins. Tm cells are T cells that have been sensitized to a specific antigen and then cloned to remember the antigen. Memory cells remain present in the body for many years and are therefore available for defense on repeated exposure to an antigen. Repeated exposure to an antigen that the host has been previously sensitized to will result in a more rapid and accelerated immune response than on the first exposure.

Regulatory cells: Th cells and Ts cells . Th cells produce multiple lymphokines that promote the proliferation and activation of other lymphocytes and macrophages. There are 2 types of Th cells: Th1 cells and Th2 cells. Th1 cells produce cytokines (IL-2 and IFN-gamma) that activate macrophages to kill antigen-containing cells. Th2 cells produce enzymes that activate B cells to produce antibody. The cytokines produced by Th2 cells give chemical instructions to immune cells to: enter a site of antigen concentration, proliferate in response to antigen (IL-4 and IL-5 induce proliferation of B cells), and directly kill or phagocytose antigen (cytotoxic cytokines affecting T cells include lymphotoxin and TNF-beta, IFN-gamma activates macrophages). Thus, cytokine-producing Th cells effect antigen clearance by producing the molecules that activate immunocompetent cells in the presence of antigen (Figure 15). Cytotoxic T cells effect antigen clearance by directly killing cells whose surface tissue antigens become altered by exposure to infectious organisms or damaging toxins. Like phagocytes, CTLs depend on Th cell-produced cytokines to do their job.

Figure 15.

 

Elimination of antigen by T cells.

Ts cells produce a soluble factor that suppresses the cytotoxic response by effector cells and inhibits antibody production.[7] Helper and suppressor T cell activity is normally balanced to maintain immunologic homeostasis. Too much suppressor T-cell function, for instance, will inhibit Th cell function.

In addition to being functionally distinct, T cell subset populations have different surface antigens or "markers" called clusters of differentiation (CD) that can be detected by mAbs. CD4 and CD8 molecules are found on the surfaces of Th and Tc cells, respectively. CD4+ T cells recognize antigen combined with HLA class II molecules; CD8+ T cells recognize antigen combined with HLA class I molecules.

As mediators of the cellular immune response (cell-mediated immunity), T cells defend the body against viruses, fungi, and some neoplastic conditions, and destroy transplanted organs by mediating accelerated and acute rejection responses. T cell function is inhibited by viral and parasitic infections, malnutrition, prolonged general anesthesia, radiation therapy, uremia, Hodgkin's disease, and advanced age.

Lymphokines

Lymphokines are 1 of the 2 soluble products of lymphocytes, the other being antibodies. Lymphokines and monokines (released from monocytes) are inflammatory and regulatory hormones of the immune system that serve a variety of functions, such as the recruitment of macrophages to antigen sites (chemotaxis), augmentation of T cell function in general, and inhibition of viral replication. Lymphokines carry molecular signals between immunocompetent cells for amplification of the immune response. Their role in amplification of the T-cell response is crucial to cellular immunity. There are many lymphokines, including families of related cytokines, which are listed in .

Table 5.  Lymphokines: Immune Mediators Released From Antigen Activated B and T Cells

The lymphokines most relevant to transplantation are IL-2 and IFN-gamma. IL-2 is produced and released by activated CD4 T cells. IL-2 activates B cells, NK cells, and monocytes, and promotes B- and T-cell division (and T-cell proliferation and maturation into CTLs) and the release of other cytokines such as IFN-gamma from T cells. IFN-gamma is produced by activated T cells and NK cells. IFN-gamma induces the expression of HLA molecules on cells, increases activity of APCs, activates T cells and macrophages, and promotes differentiation of B cells into plasma cells.

Antigen Recognition by Receptors

All cells express foreign antigens. Foreign cells, of course, express antigens that are genetically different from those of the host. It is through specific "receptors" on the surfaces of lymphocytes that B cells and T cells can be differentiated, and it is also through these receptors that B cells and T cells are able to recognize foreign antigens. During lymphocyte maturation, each B cell and T cell acquires specific cell membrane surface receptors that allow them to "match up" with certain foreign antigens. On B-cell surfaces, immunoglobulins function as receptors; the nature of T-cell surface antigens is not entirely clear. This matching between host lymphocytes and foreign antigens is the recognition phase of the acquired immune response. When this occurs, lymphocytes are activated to differentiate, proliferate, and clone to mount an effective immune response against the offending antigen.

Specific genes are responsible for the receptors on lymphocytes and distinguish those that respond to particular antigens from those that do not. These genes are responsible for the property of uniqueness that allows each individual to recognize antigens that are genetically different from their own. No 2 persons are identical with respect to which antigens will incite an immune response; instead, the human population is extremely heterogenous in this respect.

Chromosomes and Genes

All somatic cells in the human body contain within their nuclei the genetic material (chromosomes) that provides the instructions for our life processes (Figure 16). The 23 chromosomes within each cell contain a large number of genes that encode proteins with specific functions. Each gene contains deoxyribonucleic acid that provides blueprints for proteins. Proteins can be expressed on the surface of the cells that make them (eg, receptors for growth factors), or they can be secreted by the cells that make them (eg, insulin and cytokines).

Figure 16.

 

Genes and proteins.

Each gene is located in a particular location (locus) on a particular chromosome, waiting to be activated by biochemical signals. While every cell in the body contains the exact same genetic material, cells receive signals to turn on only those genes that are appropriate to their function. For example, all cells in the body possess the gene that encodes insulin. However, only the beta cells of the pancreas receive the biochemical signals that turn on the insulin gene, resulting in the production of insulin.

Genes come in different "flavors" called alleles. Alleles are alternative forms of a gene that provide a variety of phenotypes or appearances. That is, different alleles of a gene recognize variants of the gene product.

The Major Histocompatibility Complex (MHC)

Each species expresses a set of proteins on their cell surfaces that identify their tissues as belonging to that species, and that species only. These proteins are encoded by a set of genes we call the MHC (Figure 17). In humans, the MHC is also known as the HLA complex. The HLA complex is a cluster of genes located on the short arm of chromosome 6 (Figure 18).

Figure 17.

 

The major histocompatibility complex.

Figure 18.

 

Association between HLA protein and self - non-self peptides.

HLA-encoded proteins are the most polymorphic proteins known. However, the diversity afforded by polymorphism of HLA alleles gives populations survival advantages. The consequences of inadequate diversity were illustrated by the smallpox epidemic among North American indigenous populations in the 17th-19th centuries. Seeking trade and the opportunity to convert indigenous peoples to Christianity, Europeans inadvertently carried smallpox to Indian villages. Relative homogeneity in the HLA allele pool among Indians and lack of previous exposure to smallpox resulted in decimation of the population. As much as 80% of village populations were lost to smallpox by the turn of the 20th century. These populations have yet to recover. The lesson here is that as much as we are drawn to the things we share, the differences among us may indeed be healthy!

In humans, the genetic factor that determines specific antigen recognition is called the MHC.[8] The MHC is the HLA genetic complex located on the short arm of the 6th chromosome. (Figure 17) The major function of the MHC is regulation of immune responsiveness. The HLA gene complex encodes cell surface molecules (antigens) that are highly immunogenic or antigenic against cells lacking the same genetic makeup. HLA molecules facilitate the distinction by the lymphoid system of self from nonself. HLA antigens are present on most cells in the body, including leukocytes and platelets, and are widely distributed in tissues and organs. They are not present on mature erythrocytes. These antigens are responsible for leukocyte reactions during blood transfusions and are important determinants of allograft rejection, hence the name "histocompatibility antigens." (Figure 19)

Figure 19.

 

Histocompatibility and transplantation immunology.

The gene products of the MHC (HLA molecules or antigens) are divided into 2 classes on the basis of structure, tissue distribution, function, and the specific types of antigen expressed on their surfaces. The 2 classes of HLA molecules are known as class I and class II antigens (Figure 20) that function as "billboards" to display what is going on inside the cell (class I) or outside the cell (class II).[9]

Figure 20.

 

Importance of the HLA complex and HLA-encoded proteins.

Class I antigens. Class I antigens (HLA A, B, and C antigens) are expressed on the plasma membranes of all nucleated cells.[10] They function as surface recognition molecules for CTLs. CTLs have receptors that recognize class I antigens and are activated against an antigen only if they share at least 1 class I HLA determinant with the antigen. Antiviral and antitumor activity and acute graft rejection are facilitated by the recognition of "nonself" class I antigens on foreign cell surfaces by host T cells. HLA types A, B, and C express class I antigens. Class I HLA molecules represent a problem for some patients awaiting transplantation because they greatly decrease the number of potentially compatible donors. Many individuals are exposed to class I HLA molecules through pregnancy, blood transfusions, or prior transplants. Those previously exposed develop antibodies to HLA class I molecules.

When considering class I HLA proteins and their relationship to foreign antigen, it is useful to think of the example of viral infection. In reading the viral genome, the host cell produces viral proteins that become complexed to HLA class I molecules in the course of normal turnover of the cell membrane proteins. In other words, when the nucleated cell changes its coat, this foreign viral protein appears on its insignia. This complexing of foreign peptide to the self class I protein is the first signal in the activation cascade for CD8+ CTLs (Figure 21).

Figure 21.

 

T cell-HLA protein interactions.

Class II antigens. Class II antigens (HLA-DR, HLA-DQ, and HLA-DP antigens) have limited tissue distribution. In contrast to class I antigens, class II antigens are expressed only on immune cells that have the ability to process and present antigens to T cells.[10] Regulatory T cells have receptors that recognize class II antigens. Th cells and Ts cells can recognize antigen only in the context of the class II molecules that they carry. If a macrophage or dendritic cell has internalized and processed antigen, a small peptide fragment of that antigen is complexed to the class II proteins normally expressed on the surface of the cell. This combination of self-tissue protein (MHC/HLA class II) and peptide fragment is the first signal in the activation cascade for CD4+ Th cells (Figure 21).

Any contact with foreign antigen leads to processing by host APCs, which leads to formation of a complex between a fragment of the antigen and the HLA self protein that is normally expressed on the surface of the APC (Figure 22). The T cell with specificity for that antigen fragment makes contact with this particular APC. This is the signal for the T cell to sit up and take notice that foreign peptide has complexed to self-HLA protein.

Figure 22.

 

Direct antigen presentation.

Inheritance of HLA Antigens

HLAs are inherited as a set of the 3 HLA groups: HLA-A, HLA-B, and HLA-DR. Each locus contains many individual alleles. The allelic specificities are designated by numbers following the locus symbol (eg, HLA-A1 or HLA-B5). Because human chromosomes exist in pairs, it is possible to identify a total of 6 HLA antigens in a given individual, 2 from each chromosome (HLA-A, HLA-B, and HLA -DR). The expression of HLA antigens on the individual's 6th chromosome is called a phenotype (Figure 23). One haplotype, or half of the total HLA identity, is inherited from each parent. Therefore, each individual has 2 haplotypes and there are a total of 4 different haplotype combinations from 2 parents. The 2 inherited haplotypes represent the individual's genotype. Each offspring of the same biologic parents has a 25% possibility of having the same HLA type as a sibling, a 25% possibility of having a totally dissimilar HLA type as a sibling, and a 50% possibility of sharing 1 haplotype with a sibling. If 2 children inherit the very same HLA from their parents, they are an HLA "identical match."

Figure 23.

 

Inheritance of HLA haplotypes.

The Cellular Immune Response: Th1 Cells

The cellular immune response is, again, mediated by T cells. Whereas B cells bind to soluble antigen on the surface of macrophages, T cells can recognize antigen only in association with a class I MHC antigen displayed on the surfaces of macrophages or APCs. T cells are triggered by stimulation of antigen receptors on their cell surfaces. Under the influence of alloantigen and Th1-derived IL-2, clones of alloantigen-responsive CTLs proliferate and seek direct contact with alloantigen-bearing cells (Figure 24). CTLs are programmed to produce molecules such as perforin (closely related to the C9 component of complement) and granzymes (serine esterases). These molecules pass from the T-cell cytoplasm into the donor cell, where they mediate the killing of the donor cell. The steps in the cellular immune response can be summarized in the following sequence:

  • The presence of a foreign antigen is necessary to initiate the response.

  • Initially, macrophages encounter the antigen and begin to phagocytize it. Antigenic fragments complexed with MHC antigens are released, which are carried to T cells in the lymph nodes by APCs.

  • Resting virgin or memory T cells are activated when the antigen-APC complex binds with the T-cell surface receptor.

  • APCs are stimulated to produce IL-1, which summons Th cells.

  • Th cells are then responsible for a number of actions, including the release of IL-2, which causes the differentiation and proliferation of T cells. The Th cells also stimulate antibody production by B cells.

  • Clonal expansion increases the sensitized T cell population approximately a 1000-fold.

  • Ultimately, the antigen-bearing cells are destroyed by the direct cytotoxic effect of effector T cells. Some sensitized T cells are returned to the lymphoid system with the memory of the antigen for future challenge.

Examples of cellular immune responses include tumor cell surveillance, destruction defense against viral and fungal infection, acute organ rejection (a type IV hypersensitivity reaction), graft-vs-host disease (GVHD, a type IV hypersensitivity reaction), and autoimmune diseases (type IV hypersensitivity reactions).

Figure 24.

 

The allogeneic response - Th1 cells.

The Humoral Immune Response: Th2 Cells (Figure 25)

Th2 cells drive the humoral arm of the allogeneic response by producing cytokines that stimulate B-cell proliferation and differentiation. In addition to being carried by APCs, alloantigen enters the lymph nodes directly, where it binds to specific immunoglobulin receptors on the surfaces of B cells. B-cell clonal proliferation occurs under the influence of the combination of alloantigen and Th2-derived IL-4 and IL-5. IL-2 produced by Th1 cells also stimulate the burst of proliferation experienced by B cells under the influence of alloantigen.

Figure 25.

 

The allogeneic response - Th2 cells and B cells

Following the proliferation of separate clones of B cells responding to a variety of alloantigens in this manner, there is a period of differentiation driven by the Th2-derived cytokine IL-6. At this time, the morphology of B cells changes drastically, surface immunoglobulin becomes practically undetectable, and the rough endoplasmic reticulum responsible for protein production predominates in the cytoplasm. B cells differentiate into plasma cells (the antibody factories of the immune system) under the influence of alloantigens and Th2-derived cytokines. The steps in the humoral immune response can be summarized in the following sequence:

  • As with the cellular immune response, the presence of a foreign antigen is necessary to initiate the process. Unlike T cells, B cells can recognize antigen in its native configuration.

  • Initially, macrophages encounter the antigen and begin to phagocytize it. Antigenic fragments are released that are carried to B cells in the lymph nodes and spleen by APCs. Resting virgin or memory B cells are activated when antigen binds to surface immunoglobulin.

  • IL-1 is released by APCs, and Th cells stimulate the sensitization and clonal proliferation of effector B cells. B cells are activated to differentiate and produce antibody when antigen binds to their receptors.

  • Antigen-antibody complexes form and ultimately the antigen-bearing cells are destroyed.

  • As in the cellular immune response, some of the plasma cells with specific memory of the antigen are cloned and returned to the lymphoid system.

In addition, B cells can process and present antigen to T cells. Examples of humoral immune responses include resistance to encapsulated pyrogenic bacteria such as pneumococci, streptococci, meningococci, and Haemophilus influenzae, and type II and III hypersensitivity reactions, including hyperacute rejection of a transplanted organ.

A first exposure of an antigen to an activated lymphocyte evokes a primary immune response. Repeated exposure of the identical antigen to activated lymphocytes evokes an accelerated secondary response. In the secondary immune response, the latent period is shorter and the amount of antigen required to initiate the response is less.

Histocompatibility

"Histo" means "tissue." Histocompatibility is defined as a measure of how well 2 tissues "get along with one another" when they find themselves in a confined space. The major physiologic barrier in transplantation is the potential for rejection of transplanted organs as a result of normal, protective host immune responses. Put another way, tissue transplanted from 1 individual to another will be rejected if the recipient's immune system recognizes the transplanted organ or tissue as foreign.

Histocompatibility testing is used to minimize graft foreignness and reduce donor-specific immune responses to the transplanted organ. The type of histocompatibility testing performed varies, depending on the organ or tissue transplanted. The reasons for this variability are that the immunogenicity of organs and tissues varies and the cold ischemic times for different organs and tissues vary considerably depending on the expression of class II MHC antigens and the relative number of APCs in the tissues. Therefore, it is desirable to perform more extensive histocompatibility testing for the most immunogenic organs, but the length of cold ischemia time an organ will tolerate limits the extent of testing that can be done. In some cases this is a severely limiting factor. For example, the maximum cold ischemia time for heart transplantation is 4 hours. In this case, there simply is not enough time to perform HLA typing between donor and recipient. Tissues and organs are listed in according to their capacity to induce allogeneic reactions. Bone marrow is most immunogenic; the liver is the least immunogenic.

Table 6.  Immunogenecity of Different Tissues

The ABO and HLA systems have been identified as the major transplantation antigens in man. ABO antigens are present in most body tissues as well as on RBCs. Two categories of histocompatibility testing are routinely performed in preparation for organ and some types of tissue transplantation -- typing and matching procedures.

Typing Procedures: Determining the Presence of Potentially Reactive Antigens

Typing procedures identify the exact antigens that would be responsible for incompatibility between the donor and recipient tissue.

ABO typing. Basic ABO compatibility depends on the presence or absence of antigens on donor RBCs and the presence or absence of specific antibodies to these antigens in the recipient's serum. Anti-ABO antibodies are of the IgM classification and cause agglutination, complement fixation, and hemolysis. If an ABO-incompatible graft is transplanted, hyperacute rejection will occur (the possible exception being a liver graft). In kidney transplantation, preformed circulating cytotoxic antibodies in the recipient react with ABO isoagglutinins produced by the graft, and the graft quickly turns dark and soft as a result of diffuse thrombosis of the microvasculature.

Rho (D) antigens. Rho antigens are not expressed on endothelial tissue and therefore play no apparent role in graft rejection or survival. In other words, an organ from a donor with ABO type B positive can be safely transplanted into a recipient with ABO type B negative.

Minor red cell antigens. At least 15 different minor red cell antigen systems have been identified in humans. The most important of these appears to be the Lewis system.[11] Transplant recipients who are highly sensitized to minor red cell antigens as a result of numerous blood transfusions, for example, may experience antibody-mediated rejection responses (hyperacute or chronic rejection). For this reason, the potential recipient's blood is screened for the presence of antibodies to the known minor red cell antigens before transplantation.

Vascular endothelial antigens. Vascular endothelial antigens are known to occur, but are not easily detected and therefore cannot necessarily be avoided. These antigens may stimulate antibody production in the recipient and trigger hyperacute rejection. Sensitization to these antigens occurs from exposure to monocytes through blood transfusions. In the early 1970s, there was some evidence that blood transfusions administered to kidney recipients before transplantation had beneficial effects related to increased graft survival. However, many centers have stopped this practice because of the relatively high incidence of patients who become sensitized to HLA antigens.

HLA typing (microlymphocytotoxicity testing). Microlymphocytotoxicity testing is used to detect class I MHC antigens in order to "match" as many class I antigens between the donor and recipient as possible. When 2 people share the same HLAs, they are said to "match." In other words, their tissues are immunologically compatible with each other.

HLA tissue typing is performed serologically by adding a standard panel of typing antisera, complement, and tryphan blue stain to purified lymphocytes and observing for lymphocytotoxicity. Cell death confirms that the test cells (recipient and donor cells) possess the antigens being tested for, namely HLA-A, HLA-B, and HLA-DR antigens. There are many different specific HLA proteins within each of these groups. For example, there are 59 different HLA-A proteins, 118 different HLA-B, and 124 different HLA-DR.

HLA matching improves kidney, heart, and lung graft survival, but an HLA-based (ABO, HLA, lymphocytotoxicity cross-match) donor organ allocation has been implemented only for kidney transplantation. Many studies have shown a stepwise decrease in graft survival of cadaver kidneys with increasing numbers of HLA mismatch.[12] The superior results with 0 HLA-A, HLA-B, and HLA-DR mismatches have led to a system of mandatory sharing of such donor kidneys. Time constraints regarding the preservation of donor hearts and lungs do not permit prospective HLA matching for these organs. However, cross-matching may be done for cardiothoracic transplantation if the patient is HLA sensitized.

Rapid graft rejection can occur even when MHC-matched tissues are transplanted due to minor histocompatibility (mH) antigens, which are peptides from allelically polymorphic host proteins other than MHC molecules, presented in the groove of MHC class I and II molecules.[13] The mH antigens explain the need (in some cases) for systemic immunosuppressive therapy to recipients of HLA-identical organ grafts and GVHD after HLA-identical stem cell transplantation.

Mixed leukocyte culture (reaction). The mixed leukocyte culture detects class II antigens and measures donor-recipient compatibility between HLA-D loci. HLA-D loci disparity can occur even when HLA-A and HLA-B loci are identical. Because this test takes several days to complete, it is used only in preparation for living-related donor kidney transplantation.

During recent years, alternative strategies for HLA matching considered in kidney transplantation include cross-reactive group (CREG) matching, "public" epitope matching (the conventional HLA antigens are called "private" epitopes), and residue matching (determined from amino acid residue sequence information of HLA antigens).[12] All 3 strategies are based on the concept that HLA molecules contain multiple antigenic determinants and that some are more important for matching than others. CREG-matching strategies are now being implemented in kidney transplantation.

Histocompatibility testing for liver transplantation remains somewhat of an enigma. HLA compatibility does not seem to benefit the overall group of liver transplant recipients.[12] In fact, several studies have shown lower survival rates for HLA-DR-matched livers. HLA matching seems to have a dualistic effect on liver transplant outcome. First, it reduces graft rejection. Second, it promotes other immune mechanisms of graft injury related to viral infection (eg, cytomegalovirus and hepatitis viruses) and recurrent disease. Moreover, a liver allograft has a distinguished feature of promoting a hematolymphoid chimeric state associated with transplant tolerance, but liver graft-derived immunocompetent cells may also induce GVHD.

Matching Procedures: Detecting Preformed Circulating Antibodies

Matching procedures provide an opportunity for donor and recipient antigens to interact and predict the degree of compatibility between donor and potential recipient. Pretransplantation cross-matching involves mixing the recipient's serum with potential donor lymphocytes to identify preformed antibodies in the recipient. Cross-matching can be done between the recipient and a specific potential donor or between the recipient and a panel of random potential donors.

White cell cross-match. The white cell cross-match is done to identify in the potential recipient the presence of preformed circulating cytotoxic antibodies to antigens on the lymphocytes of a specific donor. The recipient's serum is incubated with a specific donor's lymphocytes. A negative cross-match means that the recipient does not have cytotoxic antibodies against the donor's lymphocytes. A positive cross-match means that the recipient has cytotoxic antibodies in their serum against the donor's lymphocytes. A positive cross-match is a contraindication for organ transplantation because of the risk for hyperacute rejection and the higher incidence of vascular rejection during the early posttransplant period. This applies particularly for kidney and heart transplants, whereas the liver allograft is more resistant to antibody-mediated injury.

In kidney transplantation, several modifications of the cross-match assay have been used to increase its sensitivity, including antihuman globulin augmentation, flow cytometry, enzyme-linked immunoassays (ELISA), and B-cell cross-matches.[12] Recently, additional serologic methods have been developed that do not utilize lymphocytotoxicity as an end point.[12] One is based on flow cytometry analysis of alloantibodies binding to panel donor lymphocytes with different HLA types. Serum screening is also being done with an ELISA assay.

Mixed lymphocyte cross-match. The mixed lymphocyte cross-match is also done to identify preformed circulating cytotoxic antibodies in the recipient. Patients can have HLA antibody as a result of transfusions, prior transplants, and/or pregnancies. The potential recipient's serum is mixed with a randomly selected panel of 60 donor lymphocyte samples to measure their extent of reactivity against the panel. This procedure is also referred to as percentage panel reactive antibody (PRA). For example, if the patient's serum reacts with 30 out of 60 samples, then the patient's PRA is 50%. The PRA can vary from 0% (nonsensitized) to 80% to 100%, indicating a high degree of sensitization. A high PRA suggests a low probability of finding a cross-match-negative donor. Patients with a high PRA must wait much longer for a transplant than patients with a low PRA, and some may never receive a kidney.

In addition to determining the actual PRA, it is important to know the antibody specificity. Some patients have as few as 1 or 2 antibody specificities, while others have numerous specificities. Because the development of antibodies may change over time, the potential renal transplant candidate is usually screened on a regular basis (ie, monthly).

Donor-specific cross-matching has limited relevance to liver transplantation because the liver allograft is relatively resistant to humoral rejection. In some sensitized patients, a liver allograft may even protect a subsequent kidney transplant from hyperacute rejection.[12]

Rejection: The Allogeneic Immune Response

Transplantation of organs or tissues between genetically nonidentical individuals of the same species (and different species) is plagued by rejection and its associated problems. "Foreignness" is equated with the presence on transplanted tissue membrane of antigens that the host does not have and therefore recognizes as foreign or nonself. If all other factors are optimal (eg, donor management, the functional state of the donor organ, the surgical procedure, and intraoperative management of the recipient), the major reason for transplant failure is rejection.

The transplanted organ represents a continuous source of HLA alloantigens capable of inducing a rejection response at any time posttransplantation. Because it cannot be eliminated, the allograft continuously activates the immune system, resulting in lifelong overproduction of cytokines, constant cytotoxic activity, and sustained alteration in the graft vasculature. Therefore, lifelong immunosuppression is required to ensure allograft survival.

Transplanted organs express donor MHC molecules, resulting in 2 pathways of antigen recognition (allorecognition) by T cells: direct and indirect. Allorecognition refers to T cell recognition of genetically encoded polymorphisms between members of the same species.[13] The primary targets of the immune response to allogeneic tissues are MHC molecules on donor cells.

Direct and indirect pathways of T-cell allorecognition are mediated by different APCs, and their cellular mechanisms are different (Figure 26). The direct pathway requires that recipient T cells recognize intact donor MHC molecules complexed with peptide and expressed on donor cells. Allorecognition via the indirect pathway requires that recipient APCs process the donor-MHC antigen before presenting it to recipient T cells. Both pathways are important in mechanisms of allograft rejection. It is thought that the direct pathway is responsible for acute rejection and that the indirect pathway is responsible for chronic rejection.

Figure 26.

 

Direct and indirect antigen presentation.

Complete activation of T cells requires 2 distinct, but synergistic, signals (Figure 27).[14] The first signal is provided by a specific antigen and is delivered via the T-cell receptor. The second signal (costimulatory signal) is not antigen-specific. Instead, many T-cell molecules may serve as receptors for costimulation. The most well characterized costimulatory molecule is CD28, which has 2 ligands (B7-1 [CD80] and B7-2 [CD86]) that are expressed primarily on APCs. Another molecule, CTLA-4, is similar to CD28 and is also expressed on T cells. Although CTLA-4 binds B7-1 and B7-2, it transmits an inhibitory signal that serves to terminate the immune response.

Figure 27.

 

T cell activation.

Rejection is an immunologic response involving the recognition of HLA antigens on donor endothelial tissue cells by recipient lymphocytes or antibodies and subsequent destruction of the antigen-bearing graft. Transplantation of a vascular organ induces MHC sensitization by direct stimulation of circulating host immune cells (ie, macrophages, reticular [RE] cells) that encounter donor MHC antigens on allograft cell surfaces. The MHC epitopes are recognized, the antigen is processed by the RE cells and presented to the lymphoid system by APCs.

Both donor and host factors contribute to the immune response of rejection. The major donor factor is the expression of MHC antigens on the donor tissue and the presence of APCs within the transplanted graft. The major host factor is prior sensitization against ABO and HLA antigens expressed on the graft. In addition, microbial or other non-MHC antigens may stimulate antibodies that cross-react with MHC antigens. Rejection is generally classified as 1 of 3 types: hyperacute, acute, or chronic, according to temporal and histopathologic characteristics of the allograft.

Hyperacute Graft Rejection

Hyperacute rejection occurs immediately, within minutes to hours of vascularization of the transplanted graft, and is caused by a humoral immune response. Hyperacute rejection is an antibody-mediated cytotoxic response to the fixation of antibodies to specific class I antigens on vascular endothelium, followed by entrapment of formed blood elements and clotting factors in the microvasculature of the graft, resulting in complement activation, massive intravascular coagulation, lack of tissue perfusion, and graft necrosis. Hyperacute rejection results in immediate thrombotic occlusion and loss of the allograft.

Antibodies responsible for hyperacute rejection include antibodies to ABO blood group antigens and those produced against vascular endothelial antigens and histocompatibility antigens. For example, if an ABO blood group O recipient receives a kidney from an ABO blood group A donor, once blood circulates through the transplanted kidney, antibody to the A antigen will combine with antigens on the endothelial cells of the kidney and activate the complement system. The activated complement system causes chemotaxis for phagocytes and induces fibrin deposition. Recruited phagocytes degranulate and release hydrolytic enzymes that cause tissue destruction and rapid rejection of the kidney. Hyperacute rejection most commonly occurs while the patient is still in the operating room; the kidney frequently turns black before the surgical team's eyes.

Antibody-to-transplant antigens can develop in recipients who have received multiple blood transfusions or prior transplants or who have had multiple pregnancies. Transfusion exposes the potential transplant recipient to foreign HLA proteins, which naturally stimulate the production of anti-HLA antibodies. Ensuring ABO blood group compatibility and avoiding positive lymphocyte cross-matches are universally accepted methods for prevention of hyperacute rejection.

Initially, hyperacute rejection was thought to occur only in transplanted kidneys. However, all solid organs are susceptible. Liver grafts in particular, however, are more tolerant of ABO and HLA incompatibility than are renal and heart grafts.[15] Retrospective histocompatibility antigen typing and lymphocyte cross-matching have not shown these factors to be relevant to liver graft survival. Although the reason that hyperacute rejection does not occur in liver grafts is not fully understood, it is speculated that the enormous cell mass of the liver is capable of absorbing circulating antibody.[16] Another reason may be differences in microvascular structures (capillaries vs sinusoids).[17] The major complication associated with ABO-incompatible liver transplantation is hemolysis.[18] A form of graft-vs-host reaction is caused by B lymphocytes in lymphoid tissue transplanted with the graft. Donor B lymphocytes produce antibodies to ABO antigens on recipient RBCs, resulting in lysis or hemolysis.

Accelerated Acute Graft Rejection

A variation of hyperacute rejection, accelerated acute rejection, is a cellular immune response. Accelerated acute rejection can occur when the recipient has been exposed previously to low levels of donor tissue antigens and makes a rapid memory response when the donor organ is transplanted. Accelerated acute rejection manifests within a few days to a few weeks following transplantation, and leads to allograft loss.

Acute Graft Rejection

Acute rejection occurs within a week to approximately 4 months after transplantation; the risk is greatest during the first 6 months and few episodes occur after the first year posttransplantation. The vast majority of acute rejection episodes do not lead to graft loss because they are diagnosed and treated promptly and aggressively.

Acute rejection is a cellular immune response involving mononuclear, cytotoxic and Th cells, monokines, and lymphokines (Figure 28). Acute rejection occurs when antigen is trapped within recipient macrophages and cannot be cleared by the RE system. Quiescent, nonactivated Th cells encounter specific class II antigens displayed on the donor organ, become activated, and synthesize receptors for lymphokines that are simultaneously released from monocytes. Activated monocytes release the lymphokine IL-1, which causes clonal expansion of activated Th cells. Monocytes also release the lymphokine IL-2, which activates and causes the clonal expansion of CTLs. Clinical signs of rejection are nonspecific and vary depending on the organ transplanted. A biopsy is required to make a definitive diagnosis of acute rejection.

Figure 28.

 

Graft damage from the allogeneic response - CTLs, endothelial cells.

Acute rejection has short-term and long-term implications. The short-term implications seem obvious -- increased need for immunosuppressive therapy with consequent morbidity and increased cost of care for monitoring and treating acute rejection episodes. Only recently has acute rejection been appreciated for its adverse impact on long-term outcomes. In fact, the acute rejection history is the most significant immunologic predictor of chronic renal allograft dysfunction.[19] The frequency, histologic type, and timing of acute rejection are important with respect to the effect on long-term graft function. Multiple and late-occurring episodes are particularly predictive.

Of the 4 types of rejection, acute rejection has the greatest clinical significance for nurses, because it can be prevented and treated through pharmacologic interventions administered and monitored by nurses. A significant amount of time spent caring for an organ transplant recipient involves clinical assessment of the patient for rejection responses and administration of immunosuppressive agents to treat rejection. Diagnosis of acute rejection depends on the specific organ transplanted, but is generally based on clinical and laboratory evidence of graft injury or dysfunction and biopsy findings. Patient responses to acute rejection vary, depending on the organ being rejected.

Chronic Graft Rejection

Chronic rejection probably begins at the time of transplantation, but may take months or years to manifest clinically. While the clinical and biochemical signs are organ-specific, the result of chronic rejection is the same for all solid organ allografts. Slowly deteriorating graft function caused by fibrosis of the graft parenchyma and widespread arteriopathy are the hallmarks of chronic rejection that lead to loss of function and eventual graft loss. A comprehensive review of the pathophysiology of chronic allograft rejection has been previously published in Medscape Transplantation.[20]

The cause of chronic rejection is unclear. However, there is evidence that both immune and nonimmune events are responsible. T cells and B cells contribute to the damage characteristic of chronic rejection. Overproduction of cytokines, including TGF-beta and platelet-derived growth factor, contribute to fibrosis. Continuous production of alloantibody by B cells under the influence of T cells contributes to the arteriopathy. Formerly thought to be the product of donor factors including reduced nephron mass, prolonged cold ischemia time, advanced donor kidney age, and donor hypertension, recent evidence suggests that recipient immune reactivity against the allograft also contributes to the development of DGF.

Chronic rejection is a prolonged process of declining allograft function. Thus, it is not surprising that transplant recipients who develop chronic rejection often experience many of the same health problems associated with primary organ failure. In addition, they develop the complications and cumulative adverse effects associated with years of daily administration of immunosuppressive agents. Susceptibility to infection, development of skin cancer, cardiovascular disease, osteoporosis, and mood changes are common in patients who receive substantial doses of corticosteroids.

Treatment for Chronic Rejection

Although retransplantation is the only cure for chronic rejection, prevention is the strategy of choice. This requires understanding and controlling the risk factors for chronic rejection. For kidney, lung, and liver allografts, there is evidence that patients who experience acute rejection episodes are at higher risk for developing chronic rejection. Hypertension, high atherogenic serum lipid levels, and diabetes mellitus also increase the risk of chronic rejection among kidney and heart allograft recipients. The use of pravastatin, an HMG CoA reductase inhibitor with relatively low lipophilicity, has been associated with enhanced heart allograft survival and a reduced incidence of acute rejection among recipients of kidney allografts. Thus, the cardiovascular benefits of pravastatin are compounded by the immunologic benefits in a transplant setting.

GVHD

GVHD is the principal limitation to allogeneic and syngeneic bone marrow transplantation.[21] Although rare, GVHD can also occur after solid organ transplantation. GVHD occurs when donor immunocompetent T cells recognize immuno-incompetent recipient tissues as foreign and attempt to destroy them, and is usually associated with reduced levels of immunosuppression. The skin (dermatitis), liver (hepatitis), and GI tract (enteritis) are the main target organs of GVHD. Lung involvement can also occur. GVHD can manifest as an acute or chronic disease process ( ). Acute GVHD can occur as early as the 7th to 10th posttransplant day or as late as 80 days after transplantation. Subclinical GVHD also occurs but is difficult to diagnose.

Table 7.  Clinical Allograft Rejection

Acute GVHD occurs from 1 week to 3 months after transplantation of hemopoietic cells mismatched at MHC loci into an immunocompromised recipient. Risk factors for the development of GVHD are listed in . The chronic form of GVHD is thought to be primarily related to mismatched mH antigens and usually manifests any time after the 3rd month following transplantation. There are 3 forms of chronic GVHD: (1) de novo, (2) quiescent, and (3) progressive. De novo chronic GVHD occurs after a lag period following the apparent resolution of acute GVHD. Quiescent chronic GVHD occurs after a lag period following the apparent resolution of acute GVHD. Progressive chronic GVHD, the most serious form, cannot be separated in time from acute GVHD but bears the histology and clinical complications of chronic disease.

Table 7.  Clinical Allograft Rejection

Diagnosis of GVHD is made via target tissue biopsies and demonstration of chimeric levels in peripheral blood by in situ polymerase chain reaction.[22] Acute GVHD is characterized by leukopenia, fever, and cytolytic destruction of the recipient's skin, GI tract, and liver. Chronic GVHD is characterized by scleroderma-like changes in the skin, GI tract, and liver. Clinical GVHD in solid organ transplantation usually resolves with immunotherapy and therefore does not represent a major source of mortality after liver transplantation.

Skin Involvement

The skin is the most common organ involved and often shows the first changes specific to GVHD. The skin reaction usually begins as a fine, maculopapular, erythematous rash on the palms of the hands, soles of the feet, and earlobes and may spread to the chest and back. As the reaction progresses, generalized erythroderma, wet desquamation, blistering, and loss of superficial skin layers may occur. The severity of skin involvement is staged, based on the extent of injury to the skin ( ). A skin biopsy is necessary to confirm the diagnosis of GVHD. Skin biopsy reveals epidermal basal cell degeneration and the presence of eosinophilic bodies, which represent dead epidermal basal cells. Severe involvement causes necrosis of basal cells, leading to separation of dermal epidermal junction and frank denudation resembling toxic epidermal necrolysis.

Table 8.  Acute and Chronic GVHD

Liver Involvement

The liver is not involved when GVHD occurs after liver transplantation because the liver graft is the carrier of the donor immunocompetent T cells. Liver involvement results in physical and laboratory changes. Although patients with mild liver involvement may be asymptomatic, alkaline phosphatase and serum bilirubin levels generally are elevated. In addition, symptoms of right upper quadrant pain, hepatomegaly, and jaundice may occur. The severity of liver involvement is staged, based on the serum bilirubin level ( ). A liver biopsy is required to confirm liver involvement of GVHD. Liver biopsy reveals atypical degeneration of small bile ducts in early GVHD, progressing to hepatic necrosis as the disease worsens.

Table 8.  Acute and Chronic GVHD

GI Tract Involvement

Initial signs and symptoms of GI tract involvement include green, watery, and sometimes bloody diarrhea, abdominal cramping, nausea, vomiting, and anorexia. Severe hypoalbuminemia can occur in extreme cases. As the severity of involvement increases, villi are destroyed and the intestinal mucosa sloughs. Absorption in the GI tract is diminished and transit time decreases, resulting in copious volumes of diarrhea, fluid and electrolyte imbalances, malabsorption syndrome, guaiac-positive stool, and occasionally massive GI bleeding. Examination of the stool reveals leukocytes in the absence of pathogenic organisms. The severity of GI involvement is staged, based on volume of diarrhea and/or ileus and pain level ( ). A biopsy of intestinal tissue through endoscopy or sigmoidoscopy is required to confirm GI involvement of GVHD. Small bowel biopsy reveals crypt cell necrosis. Later, crypt abscesses and cellular dropout occur. The bowel wall becomes thickened with flattening of villi and infiltration by mononuclear cells. Diffuse denudation of the mucosa can occur.

Table 8.  Acute and Chronic GVHD

Lung Involvement

The main symptom of acute GVHD with lung involvement is acute respiratory distress. Signs and symptoms of chronic lung involvement include bronchitis, obstructive airway disease, sinopulmonary infection, and chronic pulmonary aspiration.

Care of the Patient With GVHD

Prophylaxis of GVHD is preferable to treatment. Two main strategies are used for GVHD prophylaxis: (1) recipient immunosuppression, and (2) elimination of T cells responsible for GVHD prior to the transfer of donor cells. Treatment of GVHD includes supportive and immunosuppressive therapy. GVHD predisposes patients to infection at a number of sites where skin and gut protective barriers are broken. Care of the patient with GVHD requires acute observation skills, documentation of serial changes in the patient's condition, and evaluation of patient responses to the disease and treatment. Nursing care of the patient is focused on detection of early signs and symptoms, support of patient comfort, and implementation of the medical plan of care, including fluid and electrolyte replacement, antidiarrheal therapy, antibiotic (particularly antifungal) therapy, immunosuppressive therapy, and nutritional support. Topical corticosteroid creams may be applied to the skin in patients with minimal skin involvement. In addition, patients with gut involvement may require narcotic analgesia to control pain. Adjustments to increase the level of immunosuppression with standard regimens are made. In addition, methotrexate has been used effectively in GVHD after bone marrow transplantation.

Conclusion

The immune response to an allogeneic organ transplant is orders of magnitude greater than the nominal immune response because of:

  • alloantigen - individual HLA/MHC peptides that recruit recipient T cells

  • the vast number of T cell clones recruited to the response

  • antigen presentation by donor APCs (direct antigen presentation) and by recipient APCs (indirect antigen presentation).

Until tolerance can be routinely established in all types of solid organ transplant recipients, the success of transplantation will continue to depend largely on the utmost respect for the powerful and complex forces of the human immune system and chronic administration of immunosuppressive therapy. Although the repertoire of agents at our disposal is ever-increasing and ever-improving, clinicians remain faced with the challenge of attaining the often-elusive balance between preventing rejection and imposing drug-related toxicity. These issues will be considered in detail in Chapter 3, "Immunosuppressive Therapies for Organ Transplantation."

References

  1. Smith SL. Physiology of the immune system. Critical Care Quarterly. 1986;9:7-13.

  2. Boggs DR. Winkelstein A. White Cell Manual. Philadelphia, Pa: EA Davis Co; 1984.

  3. Roitt I, Brostoff J, Male D. Cells involved in the immune response. In: Roitt I, Brostoff J, Male D (eds). Immunology. St. Louis, Mo: The CV Mosby Co; 1985: 2.1-2.16.

  4. Bellanti JA, Kadlec JV. General immunology. In: Bellanti JA (ed). Immunology III. Philadelphia, Pa: WB Saunders Co; 1985: 16-53.

  5. Herscowitz MB. Immunophysiology: cell function and cellular interactions in antibody formation. In: Bellanti JA (ed). Immunology III. Philadelphia, Pa: WB Saunders Co; 1985: 117-159.

  6. Graziano FM, Bell CL. The normal immune response and what can go wrong. Med Clin North Am. 1986;69:440-451.

  7. Bellanti JA, and Rocklin RE. Cell-mediated immune function. In: Bellanti JA (ed). Immunology III. Philadelphia, Pa: WB Saunders Co; 1985: 176-188.

  8. Roitt I, Brostoff J, Male D. Major histo-compatibility complex. In: Roitt I, Brostoff J, Male D (eds). Immunology. St. Louis, Mo: The CV Mosby Co; 1985: 4.1-4.12.

  9. Sompayrac L. How the Immune System Works. Malden, Mass: Blackwell Science, Inc; 1999.

  10. McDevitt HO. The HLA system and its relation to disease. Hosp Pract. 1985;July:57-72.

  11. Braun WE. Histocompatibility and renal transplantation. In: Garovy MR, Guttman RD (eds). Renal Transplantation. New York, NY: Churchill Livingstone; 1986: 15-27.

  12. Duquesnoy RJ. Histocompatibility testing in organ transplantation. Available at:
    http://tpis.upmc.edu /tpis/immuno /wwwHL Atyping.htm. Accessed May 31, 2002.

  13. Cjte I, Rogers NJ, Lechler RI. Allorecognition. Transfus Clin Biol. 2001;8:318-323.

  14. Sayegh MH, Turka LA. The role of T-cell costimulatory activation pathways in transplant rejection. N Engl J Med. 1998;338:1813-1821.

  15. Ramsey G, Wolford J, Boczkowski DJ, Cornell FW, Laron P, Starzl TE. The Lewis blood group system in liver transplantation. Transplant Proc. 1987;19:4591-4594.

  16. Gordon RD, Iwatsuki S, Esquivel CO, Tsakis A, Todo S, Starzl TE. Liver transplantation across ABO blood groups. Surgery. 1986;100:342-348.

  17. Iwatsuki S, Iwaki Y, Kano T, et al. Successful liver transplantation from positive crossmatch donors. Transplant Proc. 1981;13:286-288.

  18. Angstadt J, Jarrell W, Maddrey S, et al. Hemolysis in ABO-incompatible liver transplantation. Transplant Proc. 1987;19:4595-4597.

  19. Paul LC. Immunologic risk factors for chronic allograft dysfunction. Transplantation. 2001;71:SS17-SS23.

  20. Demetris AJ, Duquesnor RJ, Fung JJ, et al. Pathophysiology of chronic allograft rejection. Medscape Transplantation. 2000. Available at:
    http://transplantation.medscape.com/Medscape/transplantation/ClinicalMgmt/CM.v02/public/index.CM.v02.html. Accessed May 31, 2002.

  21. Parkmann R. Cyclosporine: graft versus host disease and beyond. N Engl J Med. 1988;319:110-111.

  22. Tzakis AG. Intestinal and multiorgan transplantation. In: Mazzioti A, Cavallari A (eds). Techniques in Liver Surgery. London, UK: Greenwich Medical Media; 1997:337-348.